Synthesis and antiviral activity of novel 2′,4′-doubly branched carbocyclic nucleosides

Article abstract of DOI:10.1081/NCN-120039252

A series of 2′ and 4′-doubly branched carbocyclic nucleosides 15, 16, 17 and 18 were synthesized starting from simple acyclic ketone derivatives. The required 4′-quaternary carbon was constructed using Claisen rearrangement. In addition, the installation

Full text of DOI:10.1081/NCN-120039252

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Synthesis and Antiviral Activity of Novel 2′,4′‐Doubly
Branched Carbocyclic Nucleosides
Aihong Kim a & Joon Hee Hong Dr. a
a College of Pharmacy , Chosun University , Kwangju, 501‐759, South Korea
Published online: 17 Aug 2006.
To cite this article: Aihong Kim & Joon Hee Hong Dr. (2004) Synthesis and Antiviral Activity of Novel 2′,4′‐Doubly
Branched Carbocyclic Nucleosides, Nucleosides, Nucleotides and Nucleic Acids, 23:5, 813-822, DOI: 10.1081/
NCN-120039252
To link to this article: http://dx.doi.org/10.1081/NCN-120039252
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 23, No. 5, pp. 813–822, 2004
Synthesis and Antiviral Activity of Novel 2’ ,4’ -Doubly
Branched Carbocyclic Nucleosides
*
Aihong Kim and Joon Hee Hong
College of Pharmacy, Chosun University, Kwangju, South Korea
ABSTRACT
A series of 2’ and 4’-doubly branched carbocyclic nucleosides 15, 16, 17 and 18 were
synthesized starting from simple acyclic ketone derivatives. The required 4’-
quaternary carbon was constructed using Claisen rearrangement. In addition, the
installation of a methyl group in the 2’-position was accomplished using a Grignard
carbonyl addition of isopropenylmagnesium bromide. Bis-vinyl was successfully
cyclized using a Grubbs’ catalyst II. Natural bases (adenine, cytosine) were efficiently
coupled by using Pd(0) catalyst.
Key Words: Branched carbocyclic nucleosides; Claisen rearrangement; Grignard
addition; Antiviral agents.
INTRODUCTION
Since the discovery of 3’-azido-and 3’-deoxythymidine (AZT) as antiviral agents
for the treatment of acquired immunodeficiency syndrome (AIDS), much attention has
been focused on nucleosides as reverse transcriptase inhibitors in search for more active
and less toxic compounds. Currently, seven nucleoside reverse transcriptase inhibitors
such as AZT,[1] ddC,[2] ddI,[3] d4T,[4] 3TC,[5] viread,[6] and abacavir[7] are available for
*
Correspondence: Dr. Joon Hee Hong, College of Pharmacy, Chosun University, Kwangju 501-
759, South Korea; Fax: 82-62-222-5414; E-mail: hongjh@chosun.ac.kr.
813
DOI: 10.1081/NCN-120039252
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com
Copyright D 2004 by Marcel Dekker, Inc.

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Figure 1. Structures of biologically active carbocyclic nucleosides and target compounds.
the treatment of AIDS. However, toxicities[8,9] and side effects as well as the
emergence of the drug resistant viral strains[10,11] limit the usefulness of the currently
available nucleosides as anti-HIV agents. Furthermore, the disadvantage of normal
nucleosides and their analogs is that susceptible glycosidic bond to enzymatic
hydrolysis by phosphorylase.[12] Various strategies have been employed in attempts to
overcome the latter problem, among which are carbocyclic nucleoside analogs.[13,14]
For example, abacavir (Fig. 1) has been approved by the Food and Drug Administration
as an anti-HIV agent.[7] A carbocyclic nucleoside with an exomethylene double bond,
Scheme 1. Synthesis of 2,4-disubstituted cyclopentene systems.

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815
Scheme 2. Construction of final doubly branched nucleosides.
entecavir, is also currently undergoing phase III clinical trials for the treatment of
chronic hepatitis B virus infection.[15]
Furthermore, various carbocyclic nucleosides such as aristeromycin and neplanocin
A (Fig. 1) are considered as potent inhibitors of the cellular enzyme, S-adenosyl-L-
homocysteine (AdoHcy) hydrolase,[16,17] which catalyze the reversible hydrolysis of S-
adenosyl-L-homocysteine to adenosine and homocysteine. AdoHcy hydrolase is very
important in regulating S-adenosyl methionine (SAM) dependent methylation reactions.
Methyl transferases are necessary for the maturation of the mRNA. Inhibition of methyl
transferase via blocking the metabolism of AdoHcy can therefore, disrupt viral mRNA
maturation. AdoHcy inhibitors usually display broad-spectrum of antiviral activities.
Moreover, this mechanism might be exploited in combination therapies in association
with the nucleosides with a different mechanism of action. In view of these interesting
mechanisms and antiviral activities of carbocyclic nucleosides, we have synthesized
and assayed 2’ and 4’-doubly branched novel carbocyclic nucleosides as potential
antiviral agents.
RESULTS AND DISCUSSIONS
For the synthesis of target nucleosides, aldehyde derivatives 3 and 4 were selected
as starting materials, which were readily prepared from acetol and 2-hydroxyaceto-
phenone, respectively, following the reported procedure.[18] The carbonyl addition by
CH2 = C(CH3)MgBr yielded the bis-olefins 5 and 6 as stereoisomeric mixtures
(Scheme 1). Without purificarion, the stereomeric mixture of 5 and 6 are subjected to
the standard ring-closing metathesis (RCM) conditions using a Grubbs’ catalyst II
[(Im)Cl2PCy3RuCHPh] to provide the cyclopentenols 7b, 7a, 8b and 8a, respectively.a
The stereochemistry of compounds 7b and 7a was unambiguously determined on the
basis of NOE correlations between the proximal hydrogen and methyl group (H-1,
vs. CH3-4). The stereochemistry of 8b and 8a was also assigned by the similar
NMR studies.
aThis metathesis did not progress with the Grubbs’ catalyst I.

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Table 1. The antiviral activity of the synthesized compounds.
HIV-1
EC50(mg/mL)
HSV-1
EC50(mg/mL)
HCMV
EC50(mg/mL)
CoxB3
EC50(mg/mL)
Cytotoxicity
IC50(mg/mL)
Compounds
15
16
> 100
> 100
> 100
> 100
0.0005
ND
> 100
> 100
> 100
> 100
ND
56.6
> 100
> 100
> 100
ND
> 100
27.4
> 100
35.4
ND
> 100
> 100
> 100
> 100
0.5
17
18
AZT
Ganciclovir
Ribavirin
1.35
ND
ND
ND
ND
30.25
> 10
> 300
ND
ND: Not Determined.
In order to couple the cyclopentenols with the bases (A = adenine, C = cytosine)
using a simple and convenient nucleophilic substitution type reaction, 7a and 8a were
subjected to a mesylation reaction (MsCl, TEA, CH2Cl2). Unexpectedly, the reactions
resulted in a very low yield (10–15%) and were irreproducible. Therefore, attention
was turned to palladium(0) catalyzed reactions[19] for the purpose of base coupling.
The cyclopentenols 7b and 8b were activated to compounds 9 and 10 using ethyl
chloroformate in a high yield (88–90%), which were coupled with an adenine anion
generated by NaH/DMSO using the well-known coupling catalyst [tris(dibenzylidene-
acetone)-dipalladium(0)-chloroform] adduct to give compounds 11, 12, 13 and 14. The
required stereochemistry of the nucleosides 11, 12, 13 and 14 were successfully
controlled from the b-configuration of compounds 9 and 10 through a double inversion
mechanism via a Pd(0) catalyzed p–allyl complex. The regioisomer of N-7 adenine
nucleoside (ratio N-9/N-7 = 3/1) was readily separable by normal chromatography. The
desilylations of compounds 11, 12, 13 and 14 were performed by a treatment with
tetrabutylammonium fluoride (TBAF) to give the final nucleosides 15, 16, 17 and 18 in
a 78–88% yield (Scheme 2).
The antiviral assays against the HIV-1, HSV-1, HCMV and CoxB3 were
performed. As shown in Table 1, cytosine analogues 16 and 18 showed moderate
activity against CoxB3 without significant cytotoxicity to the host cell. In addition,
adenine analogue 15 showed weak antiviral activity against the HCMV.
In summary, a concise synthetic method for synthesizing 2’ and 4’-doubly branched
carbocyclic nucleosides from simple a-hydroxyketone derivatives were developed. This
procedure highlights the simplicity and efficiency in constructing the double alkyl
branches in the cyclopentene ring systems of nucleosides. Extensions of the current
strategy to prepare other systems, which may represent novel class of nucleosides, are
under investigation in our laboratory.
EXPERIMENTAL SECTION
All the chemicals were of reagent grade and were used as purchased. All the
moisture-sensitive reactions were performed in an inert atmosphere with either N2 or

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817
Ar using distilled dry solvents. The NMR spectra were recorded on a bruker 300
Fourier transform spectrometer. Elemental analyses were performed using an Elemental
Analyzer System (Profile HV-3).
(rel)-(3R and 3S,5S)-5-(t-Butyldimethylsilyloxymethyl)-2,6-dimethyl-hepta-1,6-
dien-3-ol (5): To a cooled (À 20 °C) solution of compound 3 (5.0 g, 20.6 mmol) in
dry THF (80 mL) isopropenylmagnesium bromide (22.7 mL, 1.0 M solution in THF)
was added slowly. After 3 h, a saturated NH4Cl solution (20 mL) was added, and the
reaction mixture was warmed slowly to room temperature. The mixture was extracted
with EtOAc (2 x 200 mL). The combined organic layer was dried over MgSO4,
filtered, and evaporated. The residue was purified by silica gel column chromatography
(EtOAc/hexane, 1:25) to give diastereomeric mixture 5 (5.2 g, 89%) as a colorless oil:
1
as diastereomeric mixture for H NMR (CDCl3, 300 MHz) d 5.89 (dd, J = 17.7, 11.4
Hz, 1H), 5.72 (dd, J = 17.4, 6.9 Hz, 1H), 5.05–4.89 (m, 2H), 4.70 (s, 1H), 4.10 (d,
J = 8.1 Hz, 1H), 4.64 (s, 1H), 3.51–3.32 (m, 2H), 1.65 (s, 3H), 1.59–1.53 (m, 2H),
1.00 (s, 3H), 0.83 (s, 9H), 0.04 (s, 6H); 13C NMR (CDCl3, 75 MHz) d 148.42, 148.23,
145.33, 143.84, 113.42, 112.31, 109.85, 109.76, 72.23, 71.87, 70.63, 70.37, 45.28,
45.06, 41.29, 41.18, 25.83, 22.85, 20.61, 18.25, 18.17, 18.01, À 5.49; Anal calc for
C16H32O2Si: C, 67.54; H, 11.34. Found: C, 67.60; H, 11.45.
(rel)-(3R and 3S,5S)-5-(t-Butyldimethylsilyloxymethyl)-2-methyl-6-phenyl-
hepta-1,6-dien-3-ol (6): Diastereomeric mixture 6 was prepared from compound 4
using the method described for compound 5: yield 85%: as diastereomeric mixture for
1H NMR (CDCl3, 300 MHz) d 7.48–7.32 (m, 5H), 6.09–6.03 (m, 1H), 5.44–4.23 (m,
4H), 4.25–3.53 (m, 3H), 2.138–2.19 (m, 2H), 1.86 (s, 3H), 0.96 (m, 9H), 0.10 (s, 3H),
0.05 (s, 3H); 13C NMR (CDCl3, 75 MHz) d 148.19, 144.65, 143.17, 142.42, 128.10,
127.59, 127.42, 126.48, 115.23, 114.07, 109.99, 72.18, 72.02, 69.03, 67.90, 49.39,
43.04, 42.25, 25.79, 18.19, 17.83, À 5.52, À 5.78; Anal calc for C21H34O2Si: C, 72.78;
H, 9.89. Found: C, 72.44; H, 10.11.
(rel)-(1R,4S)-4-(t-Butyldimethylsilyloxymethyl)-2,4-dimethyl-cyclopent-2-enol
(7b); and (rel)-(1S,4S)-4-(t-Butyldimethylsilyloxymethyl)-2,4-dimethyl-cyclopent-2-
enol (7a): To a solution of compound 5 (1.8 g, 6.32 mmol) in dry CH2Cl2 (10 mL)
Grubbs’ catalyst II (263 mg 0.31 mmol) in dry CH2Cl2 (3 mL) was added slowly over
a 10 minute period under N2 atmosphere. The reaction mixture was refluxed overnight,
and cooled to room temperature. The mixture was then concentrated under vacuum, and
the residue was purified by silica gel column chromatography (EtOAc/hexane, 1:10) to
give the cyclopentenols, 7b (713 mg, 44%) and 7a (697 mg, 43%), respectively, as
1
colorless oil. Compound 7b: H NMR (CDCl3, 300 MHz) d 4.99 (s, 1H), 4.19 (dd,
J = 11.1, 7.5 Hz, 1H), 3.28 (dd, J = 11.7, 2.1 Hz, 2H), 1.86 (dd, J = 14.1, 7.2 Hz, 1H),
1.71 (s, 3H), 1.68 (d, J = 14.1 Hz, 1H), 0.91 (s, 3H), 0.86 (s, 9H), 0.61 (s, 6H); 13C
NMR (CDCl3, 75 MHz) d 143.34, 133.75, 78.94, 69.82, 49.47, 46.07, 25.85, 23.60,
18.57, 13.85, À 5.45; Anal calc for C14H28O2Si: C, 65.57; H, 11.00. Found: C, 65.38;
1
H, 10.79: Compound 7a: H NMR (CDCl3, 300 MHz) d 5.27 (s, 1H), 4.60 (t, J = 6.6
Hz, 1H), 3.27 (t, J = 9.9 Hz, 2H), 2.34 (dd, J = 13.5, 7.5 Hz, 1H), 1.74 (s, 3H), 1.36
(dd, J = 13.5, 4.8 Hz, 1H), 1.06 (s, 3H), 0.86 (s, 9H), 0.06 (s, 6H); 13C NMR (CDCl3,

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Kim and Hong
75 MHz) d 141.58, 134.88, 79.69, 70.88, 48.99, 45.56, 25.85, 24.70, 18.24, 13.48,
À 5.50; Anal calc for C14H28O2Si: C, 65.57; H, 11.00. Found: C, 65.79; H, 10.73.
(rel)-(1R,4S)-4-(t-Butyldimethylsilyloxymethyl)-2-methyl-4-phenyl-cyclopent-2-
enol (8b); and (rel)-(1S,4S)-4-(t-Butyldimethylsilyloxymethyl)-2-methyl-4-phenyl-
cyclopent-2-enol (8a): Compound 8b and 8a were prepared from compound 6 using
the method described for compounds 7b and 7a: yield for 8b, 46%, yield for 8a, 46%;
1
Compound 8b: H NMR (CDCl3, 300 MHz) d 7.26–7.11 (m, 5H), 5.55 (s, 1H), 4.26
(dd, J = 11.4 Hz, 1H), 3.62 (d, J = 9.3 Hz, 1H), 3.44 (d, J = 9.3 Hz, 1H), 2.35 (dd,
J = 13.8, 6.9 Hz, 1H), 2.10 (d, J = 13.8 Hz, 1H), 1.81 (s, 3H), 0.81 (s, 9H), 0.05 (s,
6H); 13C NMR (CDCl3, 75 MHz) d 145.61, 144.98, 129.79, 128.38, 126.47, 78.24,
70.25, 58.05, 46.45, 25.97, 18.59, 14.07, À 5.42; Anal calc for C19H30O2Si: C, 71.64;
1
H, 9.49. Found: C, 71.48; H, 9.54: Compound 8a: H NMR (CDCl3, 300 MHz) d
7.36–7.23 (m, 5H), 5.83 (s, 1H), 4.75 (d, J = 6.6 Hz, 1H), 3.69 (d, J = 9.6 Hz, 1H),
3.62 (d, J = 9.6 Hz, 1H), 2.86 (dd, J = 13.2, 7.5 Hz, 1H), 1.95 (dd, J = 13.2, 5.7 Hz,
1H), 1.91 (s, 3H), 0.89 (s, 9H), 0.07 (s, 6H); 13C NMR (CDCl3, 75 MHz) d 146.60,
143.49, 131.13, 128.12, 126.55, 126.07, 79.38, 71.19, 56.62, 46.12, 25.79, 18.16, 13.71,
À 5.62; Anal calc for C19H30O2Si: C, 71.64; H, 9.49. Found: C, 71.89; H, 9.12.
(rel)-(1R,4S)-1-Ethoxycarbonyloxy-4-(t-butyldimethylsilyloxymethyl)-2,4-di-
methyl-cyclopent-2-ene (9): To a solution of compound 7b (3.5 g, 13.6 mmol) in
anhydrous pyridine (15 mL) ethyl chloroformate (1.95 mL, 20.5 mmol) and DMAP
(170 mg, 1.4 mmol) were added. The reaction mixture was stirred overnight at room
temperature, and the reaction mixture was quenched using a saturated NaHCO3 solution
(1.5 mL) and concentrated under vacuum. The residue was extracted with EtOAc, dried
over MgSO4, filtered, and concentrated. The residue was purified by silica gel column
chromatography (EtOAc/hexane, 1:40) to give compound 9 (3.93 g, 88%) as a colorless
1
syrup: H NMR (CDCl3, 300 MHz) d 5.45 (m, 2H), 4.18 (q, J = 7.5 Hz, 2H), 3.35 (s,
2H), 2.02 (dd, J = 15.0, 7.5 Hz, 1H), 1.77 (dd, J = 15.0, 3.9 Hz, 1H), 1.70 (s, 3H), 1.29
(t, J = 7.5 Hz, 3H), 1.02 (s, 3H), 0.86 (s, 9H), 0.04 (s, 6H); 13C NMR (CDCl3, 75
MHz) d 155.31, 138.47, 136.87, 85.32, 71.03, 63.71, 49.31, 41.56, 25.89, 23.70, 18.29,
14.30, 13.81, À 5.48; Anal calc for C17H32O4Si: C, 62.15; H, 9.82. Found: C, 61.87;
H, 9.74.
(rel)-(1R,4S)-1-Ethoxycarbonyloxy-4-(t-butyldimethylsilyloxymethyl)-2-methyl-
4-phenyl-cyclopent-2-ene (10): Compound 10 was prepared from compound 8b using
1
the method described for compound 9: Yield 90%: H NMR (CDCl3, 300 MHz) d
7.37–7.25 (m, 5H), 6.09 (s, 1H), 5.57 (t, J = 3.6 Hz, 1H), 4.32 (q, J = 6.9 Hz, 2H),
3.80 (dd, J = 12.9, 9.3 Hz, 2H), 2.69 (dd, J = 14.4, 7.8 Hz, 1H), 2.37 (dd, J = 14.4, 3.6
Hz, 1H), 1.93 (s, 3H), 1.42 (t, J = 6.9 Hz, 3H), 0.90 (s, 9H), 0.04 (s, 6H); 13C NMR
(CDCl3, 75 MHz) d 155.30, 145.79, 138.61, 135.55, 127.93, 126.94, 126.05, 84.70,
71.39, 63.80, 57.25, 41.82, 25.77, 18.19, 14.31, 13.98, À 5.60; Anal calc for
C22H34O4Si: C, 67.65; H, 8.77. Found: C, 67.38; H, 8.60.
(rel)-(1’R,4’S)-9-[4-(t-Butyldimethylsilyloxymethyl)-2,4-dimethyl-cyclopent-
2-en-1-yl] adenine (11): Adenine (201 mg, 1.47 mmol) was added to pure NaH

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819
(35.1 mg, 1.47 mmol) in anhydrous DMSO (5.3 mL). The reaction mixture was stirred
for 30 min at 50–55°C and cooled to room temperature. Simultaneously, P(O-i-Pr)3
(0.288 mL, 0.66 mmol) was added to a solution of Pd2(dba)3Á CHCl3 (21 mg, 11.25
mmol) in anhydrous THF (5.0 mL), which was stirred for 40 min. The catalyst solution
of THF and 9 (433.6 mg, 1.32 mmol) dissolved in anhydrous THF (3 mL) were added
slowly to the adenine solution in DMSO. The reaction mixture was stirred overnight at
a refluxing temperature and quenched with water (2 mL). The reaction solvent was
removed under reduced pressure. The residue was purified by silica gel column
chromatography (MeOH/CH2Cl2, 1:10) to give compound 11 (207 mg, 36%) as a white
1
solid: mp 178–181°C; UV (MeOH) lmax 261.0 nm; H NMR (CDCl3, 300 MHz) d
8.37 (s, 1H), 7.91 (s, 1H), 5.66 (t, J = 7.8 Hz, 1H), 5.56 (d, J = 7.2 Hz, 1H), 3.51 (d,
J = 9.6 Hz, 1H), 3.45 (d, J = 9.6 Hz, 1H), 2.34 (dd, J = 14.4, 9.3 Hz, 1H), 2.09 (dd,
J = 14.4, 6.0 Hz, 1H), 1.64 (s, 3H), 1.09 (s, 3H), 0.89 (s, 9H), 0.02 (s, 6H); Anal calc
for C19H31N5OSi: C, 61.09; H, 8.36; N, 18.75. Found: C, 61.30; H, 8.51; N, 18.83.
(rel)-(1’R,4’S)-1-[4-(t-Butyldimethylsilyloxymethyl)-2,4-dimethyl-cyclopent-2-
en-1-yl] cytosine (12): Compound 12 was prepared from compound 9 using the
method described for compound 11; Yield 35%; mp 160–161°C; UV (MeOH) lmax
1
271.0 nm; H NMR (CDCl3, 300 MHz) d 7.81 (d, J = 6.6 Hz, 1H), 5.82 (d, J = 6.6 Hz,
1H), 5.78 (dd, J = 7.5, 3.9 Hz, 1H), 5.49 (s, 1H), 3.40 (dd, J = 10.5, 9.0 Hz, 2H), 2.14
(dd, J = 14.4, 7.8 Hz, 1H), 1.79 (dd, J = 14.4, 4.5 Hz, 1H), 1.76 (s, 3H), 1.06 (s, 3H),
0.87 (s, 9H), 0.03 (s, 6H); Anal calc for C18H31N3O2Si: C, 61.85; H, 8.94; N, 12.02.
Found: C, 61.69; H, 8.78; N, 12.23.
(rel)-(1’R,4’S)-9-[4-(t-Butyldimethylsilyloxymethyl)-2-methyl-4-phenyl-cyclo-
pent-2-en-1-yl] adenine (13): Compound 13 was prepared from compound 10 using
the method described for compound 11: yield 35%; mp 198–200°C; UV (MeOH) lmax
1
261.5 nm; H NMR (CDCl3, 300 MHz) d 8.29 (s, 1H), 7.96 (s, 1H), 7.31–7.19 (m,
5H), 5.84 (s, 1H), 5.59 (dd, J = 8.4, 7.2 Hz, 1H), 3.75 (s, 2H), 2.85 (dd, J = 13.5, 8.7
Hz, 1H), 2.50 (dd, J = 13.5, 6.6 Hz, 1H), 1.59 (s, 3H), 0.84 (s, 9H), 0.02 (s, 6H); Anal
calc for C24H33N5OSi: C, 66.17; H, 7.64; N, 16.08. Found: C, 66.30; H, 7.50; N, 15.84.
(rel)-(1’R,4’S)-1-[4-(t-Butyldimethylsilyloxymethyl)-2-methyl-4-phenyl-cyclo-
pent-2-en-1-yl] cytosine (14): Compound 14 was prepared from compound 10 using
the method described for compound 11: yield 32%; mp 180–182°C; UV (MeOH) lmax
1
271.5 nm; H NMR (CDCl3, 300 MHz) d 7.50 (d, J = 6.9 Hz, 1H), 7.30–7.22 (m, 5H),
5.94 (m, 2H), 5.57 (m, 1H), 3.79 (s, 2H), 2.91 (dd, J = 14.0, 8.6 Hz, 1H), 2.55 (dd,
J = 14.0, 6.8 Hz, 1H), 1.62 (s, 3H), 0.86 (s, 9H), 0.05 (s, 6H); Anal calc for
C23H33N3O2Si: C, 67.11; H, 8.08; N, 10.21. Found: C, 67.41; H, 7.92; N, 10.36.
(rel)-(1’R,4’S)-9-[4-(Hydroxymethyl)-2,4-dimethyl-cyclopent-2-en-1-yl]adenine
(15): TBAF (0.48 mL, 1.0 M solution in THF) was added to a solution of compound
11 (150 mg, 0.401 mmol) in THF (3 mL) at 0°C. The mixture was stirred at room
temperature for 4 h, and concentrated. The residue was purified by silica gel column
chromatography (MeOH/CH2Cl2, 1:4) to give compound 15 (91 mg, 88%) as a white
1
solid: mp 181–183°C; UV (H2O) lmax 262.5 nm; H NMR (DMSO-d6, 300 MHz) d

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Kim and Hong
8.30 (s, 1H), 8.08 (s, 1H), 7.19 (br s, 2H), 5.50 (m, 2H), 3.33 (s, 2H), 2.07 (dd,
J = 13.5, 6.3 Hz, 1H), 1.96 (dd, J = 13.5, 6.0 Hz, 1H), 1.41 (s, 3H), 1.03 (s, 3H); Anal
calc for C13H17N5O: C, 60.21; H, 6.61; N, 27.01. Found: C, 60.57; H, 6.78; N, 26.80.
(rel)-(1’R,4’S)-1-[4-(Hydroxymethyl)-2,4-dimethyl-cyclopent-2-en-1-yl]cytosine
(16): Compound 16 was prepared from compound 12 using the method described for
compound 15; Yield: 85%; mp 166–168°C; UV (H2O) lmax 271.5 nm; 1H NMR
(DMSO-d6, 300 MHz) d 7.62 (d, J = 7.4 Hz, 1H), 5.97 (d, J = 7.4 Hz, 1H), 5.60 (s,
1H), 5.55 (br s, 1H), 3.47 (dd, J = 12.8, 4.5 Hz, 2H), 2.32 (dd, J = 13.0, 8.6 Hz, 1H),
2.03 (dd, J = 13.0, 6.0 Hz, 1H), 1.54 (s, 3H), 1.12 (s, 3H); Anal calc for C12H17N3O2:
C, 61.26; H, 7.28; N, 17.86. Found: C, 61.33; H, 7.44; N, 17.81.
(rel)-(1’R,4’S)-9-[4-(Hydroxymethyl)-2-methyl-4-phenyl-cyclopent-2-en-1-yl]ad-
enine (17): Compound 17 was prepared from compound 13 using the method
described for compound 15; Yield: 86%; mp 202–204°C; UV (H2O) lmax 261.0 nm;
1H NMR (DMSO-d6, 300 MHz) d 8.16 (s, 1H), 8.10 (s, 1H), 7.35–7.22 (m, 5H), 5.97
(s, 1H), 5.47 (br s, 1H), 3.65 (d, J = 3.9, Hz, 2H), 2.49 (dd, J = 14.0, 9.4 Hz, 1H), 2.01
(dd, J = 14.0, 6.0 Hz, 1H), 1.57 (s, 3H); Anal calc for C18H19N5O: C, 67.27; H, 5.96;
N, 21.79. Found: C, 67.38; H, 5.82; N, 21.90.
(rel)-(1’R,4’S)-1-[4-(Hydroxymethyl)-2-methyl-4-phenyl-cyclopent-2-en-1-yl]cy-
tosine (18): Compound 18 was prepared from compound 14 using the method
described for compound 15; Yield: 78%; mp 179–181°C; UV (H2O) lmax 271.0 nm;
1H NMR (DMSO-d6, 300 MHz) d 7.48 (d, J = 7.2 Hz, 1H), 7.32–7.18 (m, 5H), 5.94
(s, 1H), 5.76 (d, J = 7.2 Hz, 1H), 5.46 (t, J = 7.5 Hz, 1H), 3.54 (d, J = 9.0 Hz, 2H),
3.15 (d, J = 9.0 Hz, 1H), 2.43 (dd, J = 13.5, 9.3 Hz, 1H), 2.01 (dd, J = 13.5, 6.6 Hz,
1H), 1.55 (s, 3H); Anal calc for C17H19N3O2: C, 68.67; H, 6.44; N, 14.13. Found: C,
68.55; H, 6.62; N, 14.15.
ACKNOWLEDGMENT
The authors wish to acknowledge Dr. C.-K. Lee (Korea Research Institute of
Chemical Technology) for the antiviral assays.
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Received February 12, 2004
Accepted March 25, 2004

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