Synthesis and biological evaluation of novel 2′,3′,4′- triply branched carbocyclic nucleosides as potential antiviral agents

Article abstract of DOI:10.1002/ardp.200400918

Novel 2′,3′,4′-triply branched carbocyclic nucleosides were synthesized in this study. The introduction of two methyl groups in the 2′- and 3′-position was accomplished by a Horner-Wadsworth-Emmons reaction and isopropenyl magnesiumbromide addition, respe

Full text of DOI:10.1002/ardp.200400918

Arch. Pharm. Pharm. Med. Chem. 2004, 337, 579−586
Triply Branched Carbocyclic Nucleosides as Antiviral Agents 579
Ok Hyun Ko,
Joon Hee Hong
Synthesis and biological evaluation of novel
2Ј,3Ј,4Ј-triply branched carbocyclic
nucleosides as potential antiviral agents
College of Pharmacy,
Chosun University,
Kwangju 501-759,
Republic of Korea
Novel 2Ј,3Ј,4Ј-triply branched carbocyclic nucleosides were synthesized in this
study. The introduction of two methyl groups in the 2Ј- and 3Ј-position was
accomplished by a Horner-Wadsworth-Emmons reaction and isopropenyl
magnesiumbromide addition, respectively. The construction of the required 4Ј-
quaternary carbon was carried out using a [3,3]-sigmatropic rearrangement. Bis-
vinyls were successfully cyclized using a Grubbs’ catalyst II. The natural bases
(adenine, cytosine) were efficiently coupled using a Pd(0) catalyst. The antiviral
activities of the synthesized compounds were evaluated against HIV-1, HSV-1,
HSV-2 and HCMV. Compound 30 displayed moderate anti-HCMV activity
(EC50 = 30.1 µg/mL), without exhibiting any cytotoxicity at up to 100 µM.
Keywords: Antiviral Agents; Triply Branched Carbocyclic Nucleosides; [3,3]-
Sigmatropic Rearrangement
Received: June 30, 2004; accepted: September 10, 2004 [FP918]
DOI 10.1002/ardp.200400918
Introduction
pounds exhibit interesting biological activities, particu-
larly in the areas of antiviral and anticancer chemo-
Emerging drug-resistant virus strains and toxicity are
major problems in antiviral chemotherapy, and a num-
ber of structurally modified nucleosides have been
synthesized to overcome these drawbacks. Recently,
several branched nucleosides were synthesized and
evaluated as potent antitumor or antiviral agents.
Among them, 4Ј-C-hydroxymethyl-thymidine 1 [1], 4Ј-
C-ethenyl-2Ј-deoxycytidine 2 [2], 3Ј-C-methyladeno-
sine 3 [3] and 2Ј-C-methyl-2Ј-deoxycytidine 4 [4],
which have additional branches at the 2Ј-, 3Ј- or 4Ј-
position, were reported to exhibit potent antiviral and
antitumor activities (Figure 1).
therapy. The recent discovery of olefinic carbocyclic
nucleosides such as abacavir 5 [7] and entecavir 6 [8]
as potential antiviral agents has given a strong im-
petus to the search for novel nucleosides in this class
of compounds. Carbocyclic nucleosides are also be-
lieved to be potent inhibitors of the cellular enzyme S-
adenosyl-L-homocysteine (AdoHcy) hydrolase, which
is very important for regulating the S-adenosylmeth-
ionine (SAM)-dependent methylation reactions and
has emerged as a specific target for the reversible hy-
drolysis of the AdoHcy linkage to adenosine and
homocysteine [9]. The inhibition of this enzyme on in-
tact cellular systems results in the accumulation of
AdoHcy. A higher concentration of AdoHcy sup-
presses the enzyme activity by acting as a product in-
hibitor of the AdoMet-dependent methylation reaction
[10]. Methyltransferases are essential for the matu-
ration of mRNA. Therefore, inhibiting the methyl trans-
ferases by blocking the AdoHcy metabolism can dis-
rupt the maturation of viral mRNA. AdoHcy inhibitors
usually display a broad spectrum of antiviral activities.
In addition, this mechanism might be exploited in
some form of a combination therapy, with the nucleo-
sides having a different mechanism of action.
More fundamental modifications of the pentofuranose
moiety, such as carbocyclic nucleosides, have been
reported to be compatible with their antiviral activities.
Carbocyclic nucleosides [5] are a group of compounds
that are structurally similar to the natural nucleosides
where the furanose oxygen is replaced by a methylene
group. The replacement of the oxygen on the furanose
ring by carbon is of particular interest because the re-
sulting carbocyclic nucleosides possess a greater
metabolic stability to phosphorylase [6], which cleaves
the glycosidic bond of nucleosides. Since the cyclo-
pentane ring of the carbocyclic nucleosides can emu-
late the furanose moiety, a number of these com-
Encouraged by these interesting structures and the
biological activities of branched nucleosides as well as
of olefinic carbocyclic nucleosides, a novel class of
nucleosides comprising branched carbocyclic nucleo-
Correspondence: Joon Hee Hong, College of Pharmacy,
Chosun University, Kwangju 501-759, Republic of Korea.
Phone: +82 62 230-6378, Fax: +82 62 222-5414, e-mail:
hongjh@chosun.ac.kr
© 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

580 Hong et al.
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 579−586
Figure 1. Structures of olefinic carbocyclic nucleosides, branched furanose nucleosides and target nucleosides.
sides with additional branches at the 2Ј-, 3Ј- and 4Ј-
CH2=C(CH3)MgBr to yield the bis-olefins 19 and 20 as
position was synthesized.
stereoisomeric mixtures.
The bis-olefins 19 and 20 were subjected to the well-
known ring-closing metathesis conditions [12] using a
Grubbs’ catalyst II [(Im)Cl2PCy3RuCHPh], giving the
compound 21 and the stereoisomers 22 and 23 in al-
most equal amounts. The relative stereochemistry of
compounds 22 and 23 was unambiguously deter-
mined based on the NOE correlations between the
proximal hydrogen and the methylene group (H-1 vs.
H-5). Unlike compound 22, a strong NOE correlation
was observed between the H-1 vs. H-5 of compound
23 (2.2% NOE) (Figure 2).
Chemistry
As shown in Scheme 1, the α,β-unsaturated ester de-
rivatives 9 and 10, which were readily synthesized
from 1,3-dihydroxy acetone and 2-hydroxy aceto-
phenone, respectively, by
a previously reported
method (Scheme 1), were selected as the starting
compounds for the synthesis of the 2Ј,3Ј,4Ј-triply
branched target nucleosides [11].
Without separation, the esters 9 and 10 were reduced
using diisobutylaluminum hydride (DIBALH), and the
resulting allylic alcohols 11 and 12 were subjected to
a [3,3]-sigmatropic rearrangement using triethylortho-
acetate to give the γ,δ-unsaturated esters 13 and 14
at a high yield. The addition of DIBALH to a solution
of the esters 13 and 14 in CH2Cl2 at 0°C gave the
alcohols 15 and 16, which were subjected to oxidation
conditions using PCC. The resulting aldehydes 17
and 18 were subjected to a Grignard reaction with
In order to couple the cyclopentenol with the bases
(A = adenine, C = cytosine) using a simple nucleophilic
substitution-type reaction, compounds 21 and 23 were
subjected to a mesylation reaction (MsCl, TEA,
CH2Cl2). Unexpectedly, the reactions had a low yield,
and the results were not reproducible. Therefore, at-
tention was turned to a palladium(0)-catalyzed reac-
tion procedure [13].
© 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Pharm. Med. Chem. 2004, 337, 579−586
Triply Branched Carbocyclic Nucleosides as Antiviral Agents 581
Scheme 1. Synthesis of key intermediates 17 and 18.
any cytotoxicity when tested at up to 100 µg/mL. How-
ever, the adenine analogue 30 did show moderate
antiviral activity against HCMV (Table 1), indicating
that this virus might allow the sugar moiety for phos-
phorylation as well as for DNA polymerase, which is
different from other viruses. In addition, the adenine
analogue 32 also had weak antiviral activity against
HIV-1 (MT-4 cells). The HCMV strains AD-169
(ATTCC VR-583) and Davis (ATCC VR-807) were
used to evaluate the anti-HCMV activity, and a stand-
ard CPE inhibition assay was used. HEL 299 (human
embryonic lung fibroblast) cells were used for the cyto-
toxicity assay.
Figure 2. NOE study of compound 22 and 23.
The cyclopentenols 21 and 22 were transformed to the
ethoxycarbonyl derivatives 24 and 25 using ethyl
chloroformate. Compounds 24 and 25 were coupled
with the adenine and cytosine anion generated by
NaH/DMSO with the [tris(dibenzylidene-acetone)-di-
palladium(0)-chloroform] adduct to give the com-
pounds 26Ϫ29 (Scheme 2). The required stereochem-
istry of the nucleosides 28 and 29 was successfully
controlled from the b-configuration of compound 25 via
a Pd(0)-catalyzed πϪallyl complex mechanism. Com-
pounds 26Ϫ29 were desilylated by treating them with
tetrabutylammonium fluoride (TBAF) to give the final
nucleosides 30Ϫ33 at high yields.
In summary, a novel synthetic method for 2Ј,3Ј,4Ј-triply
branched carbocyclic nucleosides from simple α-
hydroxy carbonyl derivatives was developed. When
the synthesized compounds were tested against sev-
eral viruses such as HIV-1, HSV-1, HSV-2 and HCMV,
only the adenosine analogue 30 exhibited moderate
antiviral activity against HCMV. The lack of antiviral ac-
tivity of these racemic compounds is presumably as-
sociated with their unfavorable conformations for the
phosphorylation occurring during the nucleotide acti-
vation process. However, the information obtained in
the present study will be useful for the development of
a novel carbonucleoside. Studies toward this end and
to clarify the mechanism are underway.
Antiviral activity studies
The synthesized compounds 30, 31, 32 and 33 were
tested against several viruses, such as HIV (MT-4
cells), HSV-1 (CCL81 cells), HSV-2 (CCL81 cells), and
HCMV (AD-169, Davis cells). All the compounds syn-
thesized showed neither excellent antiviral activity nor
Acknowledgments
The authors wish to acknowledge Dr. C.-K. Lee (Korea
Research Institute of Chemical Technology) for the
antiviral assays.
© 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

582 Hong et al.
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 579−586
Scheme 2. Synthesis of targeted nucleosides.
Table 1. The antiviral activities of the synthesized compounds.
compound
HIV-1
HSV-1
HSV-2
HCMV
cytotoxicity
EC50 (µg/mL)
EC50 (µg/mL)
EC50 (µg/mL)
EC50 (µg/mL)
IC50 (µg/mL)
30
31
32
33
>100
>100
61.0
>100
0.001
ND
>100
>100
78.5
>100
ND
>100
>100
>100
>100
ND
30.1
>100
>100
>100
ND
>100
>100
>100
>100
1.17
AZT
Ganciclovir
Ribavirin
2.10
ND
2.10
ND
ND
12.60
>10
300.00
ND
ND: not determined.
© 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Pharm. Med. Chem. 2004, 337, 579−586
Triply Branched Carbocyclic Nucleosides as Antiviral Agents 583
(CDCl3, 300 MHz) δ 7.51Ϫ7.24 (m, 5H), 5.09 (s, 1H), 4.94
(s, 1H), 4.29 (d, J = 9.0 Hz, 1H), 4.10 (d, J = 9.0 Hz, 1H),
4.05 (q, J = 6.9 Hz, 1H), 3.22 (d, J = 6.9 Hz, 2H), 2.95 (d, J =
6.9 Hz, 1H), 1.61 (s, 3H), 1.20 (t, J = 6.9 Hz, 3H), 0.87 (s,
9H), 0.03 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 171.78,
147.14, 143.40, 127.85, 126.48, 126.19, 112.04, 65.84,
59.87, 51.38, 37.91, 25.67, 18.47, 17.84, 14.12, Ϫ5.83; Anal.
calc. for C21H34O3Si: C 69.56; H 9.45. Found: C 69.31; H
9.50.
Experimental
All the chemicals were of reagent grade and were used with-
out further purification. All the moisture-sensitive reactions
were performed in an inert atmosphere with either N2 or Ar,
using distilled dry solvents. The melting points were deter-
mined using a Mel-temp II laboratory device and were uncor-
rected. The NMR spectra were recorded on a JEOL JNM-LA
300 spectrometer. The chemical shifts are reported in parts
per million (δ), 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 (Profile HV-3).
TLC was performed on Uniplates (silica gel) purchased from
Analtech Co. The dry THF was obtained by distillation from
Na and benzophenone when the solution became purple.
3,3Ј-Bis-(t-butyldimethylsilyloxymethyl)-4-methyl-pent-4-enol
(15)
To a solution of compound 13 (8.5 g, 19.73 mmol) in CH2Cl2
(300 mL), DIBALH (41.43 mL, 1.0 M solution in hexane) was
added slowly at 0°C and stirred for 30 min at the same tem-
perature. To the resulting mixture, methanol (40 mL) was ad-
ded. The mixture was then stirred at room temperature for 2
h, and the resulting solid was filtered through a Celite pad.
The filtrate was concentrated under vacuum, and the residue
was purified by silica gel column chromatography (EtOAc/
hexane, 1 : 25) to give compound 15 (7.09 g, 96%) as a
4,4Ј-Bis-(t-butyldimethylsilyloxy)-2-methyl-but-2-en-1-ol (11)
To a solution of compound 9 (10 g, 24.83 mmol) in CH2Cl2
(300 mL), DIBALH (52.1 mL, 1.0 M solution in hexane) was
added slowly at Ϫ50°C and stirred for 2 h at the same tem-
perature. To the resulting mixture, methanol (50 mL) was ad-
ded. The mixture was stirred at room temperature for 2 h,
and the resulting solid was filtered through a Celite pad. The
filtrate was concentrated under vacuum, and the residue was
purified by silica gel column chromatography (EtOAc/hexane,
1 : 7) to give the alcohol 11 (8.68 g, 97%) as a colorless oil:
1H NMR (CDCl3, 300 MHz) δ 4.25 (s, 4H), 4.17 (s, 2H), 1.71
(s, 3H), 0.93 (s, 18H), 0.05 (s, 12H); 13C NMR (CDCl3, 75
MHz) δ 141.21, 125.39, 64.85, 59.40, 58.70, 25.83, 20.34,
18.24, Ϫ5.35; Anal. calc. for C18H40O3Si2: C 59.94; H 11.18.
Found: C 59.77; H 11.21.
1
colorless oil: H NMR (CDCl3, 300 MHz) δ 4.82 (s, 1H), 4.62
(s, 1H), 3.57 (dd, J = 12.9, 9.6 Hz, 6H), 1.69 (s, 3H), 1.64
(dd, J = 6.0, 3.6 Hz, 2H), 0.87 (s, 18H), 0.04 (s, 12H); 13C
NMR (CDCl3, 75 MHz) δ 146.45, 112.24, 63.41, 59.16, 47.99,
33.63, 25.81, 20.30, 18.16, Ϫ5.57; Anal. calc. for
C20H44O3Si2: C 61.79; H 11.41. Found: C 61.52; H 11.55.
( )-3-(t-Butyldimethylsilyloxymethyl)-3-phenyl-4-methyl-pent-
4-enol (16)
Compound 16 was prepared from compound 14 using the
method described for compound 15: yield 98%; 1H NMR
(CDCl3, 300 MHz) δ 7.46Ϫ7.34 (m, 5H), 5.25 (s, 1H), 5.14
(s, 1H), 4.21 (d, J = 9.3 Hz, 1H), 4.02 (d, J = 9.3 Hz, 1H),
3.80 (dd, J = 6.9, 6.6 Hz, 2H), 2.61 (dd, J = 13.5, 6.9 Hz, 1H),
2.38 (dd, J = 13.2, 6.6 Hz, 1H), 1.68 (s, 3H), 1.00 (s, 9H),
0.01 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 147.59, 144.17,
127.93, 127.06, 126.05, 112.46, 67.53, 59.58, 51.29, 35.42,
25.69, 20.61, 18.06, Ϫ5.90; Anal. calc. for C19H32O2Si: C
71.19; H 10.06. Found: C 70.98; H 9.89.
(E)- and (Z)-4-(t-Butyldimethylsilyloxy)-2,3-dimethyl-but-2-en-
1-ol (12)
Compound 12 was prepared from compound 10 using the
method described for compound 11: yield 91%; 1H NMR
(CDCl3, 300 MHz) δ 7.44Ϫ7.02 (m, 5H), 4.51 (d, J = 5.4, 2H),
4.36 (d, J = 4.2 Hz, 1H), 4.02 (s, 1H), 0.89 (s, 9H), 0.04 (s,
6H); Anal. calc. for C17H28O2Si: C 69.81; H 9.65. Found: C
69.61; H 9.54.
3,3Ј-Bis-(t-butyldimethylsilyloxymethyl)-4-methyl-pent-4-enal
(17)
3,3Ј-Bis-(t-butyldimethylsilyloxymethyl)-4-methyl-pent-4-
enoic acid ethyl ester (13)
To a solution of compound 15 (5.0 g, 12.86 mmol) in CH2Cl2
˚
(100 mL), 4-A molecular sieves (7.5 g) and PCC (6.93 g,
A solution of the allylic alcohol 11 (15 g, 41.58 mmol) in tri-
ethyl orthoacetate (300 mL) and 1.5 mL of propionic acid was
heated at 140°C overnight with constant stirring to allow for
the removal of ethanol. An excess of triethyl orthoacetate was
removed by distillation, and the residue was purified by silica
gel column chromatography (EtOAc/hexane, 1 : 50) to give
compound 13 (15.22 g, 85%) as a colorless oil: 1H NMR
(CDCl3, 300 MHz) δ 4.87 (s, 1H), 4.62 (s, 1H), 4.05 (q, J =
7.5 Hz, 2H), 3.65 (dd, J = 15.6, 9.0 Hz, 4H), 2.41 (s, 2H),
1.61 (s, 3H), 1.12 (t, J = 7.5 Hz, 3H), 0.94 (s, 18H), 0.02 (s,
12H); 13C NMR (CDCl3, 75 MHz) d 171.92, 139.76, 114.48,
64.67, 59.88, 45.98, 36.84, 25.85, 20.34, 18.25, 14.25,
Ϫ5.26; Anal. calc. for C22H46O4Si2: C 61.34; H 10.76. Found:
C 61.12; H 10.60.
32.15 mmol) were added slowly at 0°C and stirred for 4 h at
room temperature. To the resulting mixture, excess diethyl
ether (500 mL) was added. The mixture was then vigorously
stirred for 2 h at the same temperature, and the resulting solid
was filtered through a short silica gel column. The filtrate was
concentrated under vacuum, and the residue was purified by
silica gel column chromatography (EtOAc/hexane, 1 : 50) to
1
give compound 17 (4.47 g, 90%) as a colorless oil: H NMR
(CDCl3, 300 MHz) δ 9.65 (m, 1H), 4.96 (s, 1H), 4.75 (s, 1H),
3.64 (dd, J = 13.5, 9.3 Hz, 4H), 2.43 (s, 2H), 1.76 (s, 3H),
0.84 (s, 18H), 0.04 (s, 12H); 13C NMR (CDCl3, 75 MHz) δ
202.89, 145.02, 113.28, 65.01, 48.62, 45.44, 25.79, 20.42,
18.17, Ϫ5.67; Anal. calc. for C20H42O3Si2: C 62.12; H 10.95.
Found: C 62.33; H 10.81.
( )-3-(t-Butyldimethylsilyloxymethyl)-3-phenyl-4-methyl-pent-
4-enoic acid ethyl ester (14)
( )-3-(t-Butyldimethylsilyloxymethyl)-3-phenyl-4-methyl-pent-
4-enal (18)
Compound 14 was prepared from compound 12 using the
method described for compound 13: yield 78%; 1H NMR
Compound 18 was prepared from compound 16 using the
method described for compound 17: yield 82%; 1H NMR
© 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

584 Hong et al.
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 579−586
(CDCl3, 300 MHz) δ 9.64 (m, 1H), 7.35Ϫ7.21 (m, 5H), 5.15
(d, J = 2.4 Hz, 1H), 5.09 (s, 1H), 4.05 (d, J = 9.6 Hz, 1H),
3.90 (d, J = 9.6 Hz, 1H), 2.99 (dd, J = 13.2, 3.0 Hz, 1H), 2.84
(dd, J = 13.2, 3.2 Hz, 1H), 1.55 (s, 3H), 0.84 (s, 9H), 0.01 (s,
6H); 13C NMR (CDCl3, 75 MHz) δ 203.05, 146.09, 142.60,
127.88, 126.77, 113.53, 68.58, 51.45, 47.38, 25.76, 20.39,
18.17, Ϫ5.84; Anal. calc. for C19H30O2Si: C 71.64; H 9.49.
Found: C 71.44; H 9.40.
(rel)-(1R,4R)-4-(t-Butyldimethylsilyloxymethyl)-4-phenyl-2,3-
dimethyl-cyclopent-2-ene (22) and (rel)-(1S,4R)-4-(t-butyldi-
methylsilyloxymethyl)-4-phenyl-2,3-dimethyl-cyclopent-2-
ene (23)
Compounds 22 and 23 were prepared from compound 20
using the method described for compound 21: yield for 22
(42%) and for 23 (41%). Compound 22; 1H NMR (CDCl3,
300 MHz) δ 7.17Ϫ6.94 (m, 5H), 4.28 (dd, J = 10.8, 7.2 Hz,
1H), 3.95 (d, J = 9.0 Hz, 1H), 3.81 (d, J = 9.6 Hz, 1H), 2.75
(d, J = 10.8 Hz, 1H), 2.17 (dd, J = 14.1, 7.2 Hz, 1H), 1.67 (s,
3H), 1.23 (s, 3H), 0.79 (s, 9H), Ϫ0.02 (s, 6H); 13C NMR
(CDCl3, 75 MHz) δ 145.94, 138.74, 136.13, 128.41, 126.17,
78.66, 65.29, 59.63, 49.06, 25.93, 18.44, 11.84, 10.61,
Ϫ5.59; Anal. calc. for C20H32O2Si: C 72.23; H 9.70. Found:
C 72.38; H 9.58. Compound 23; 1H NMR (CDCl3, 300 MHz)
δ 7.25Ϫ7.08 (m, 5H), 4.55 (s, 1H), 3.99 (d, J = 9.3 Hz, 1H),
3.77 (d, J = 9.3 Hz, 1H), 2.61 (dd, J = 13.8, 7.5 Hz, 1H), 1.71
(s, 3H), 1.65 (dd, J = 13.5, 3.9 Hz, 1H), 1.35 (s, 3H), 0.80 (s,
9H), 0.02 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 146.23,
137.78, 136.91, 128.20, 127.47, 112.50, 79.43, 66.23, 58.97,
47.65, 25.49, 18.09, 11.48, 11.15, Ϫ5.48; Anal. calc. for
(rel)-(3R and 3S,5S)-5,5Ј-Bis-(t-butyldimethylsilyloxymethyl)-
2,6-dimethyl-hepta-1,6-dien-3-ol (19)
To a solution of compound 17 (6.0 g, 15.5 mmol) in dry THF
(150 mL), isopropenyl magnesiumbromide (23.27 mL, 1.0 M
solution in THF) was added slowly at Ϫ78°C. After 3 h, a
saturated NH4Cl solution (20 mL) was added, and the reac-
tion mixture was then slowly warmed to room temperature.
The mixture was extracted with EtOAc (2 ϫ 250 mL). The
combined organic layer was dried over MgSO4, filtered and
evaporated. The residue was purified by silica gel column
chromatography (EtOAc/hexane, 1 : 45) to give compound
19 (5.25 g, 79%) as a colorless oil: as a diastereomeric mix-
ture for 1H NMR (CDCl3, 300 MHz) δ 4.93 (d, J = 8.4 Hz, 2H),
4.71 (d, J = 10.8 Hz, 2H), 4.10 (d, J = 11.1 Hz, 1H), 3.80 (d,
J = 9.9 Hz, 1H), 3.71 (d, J = 9.9 Hz, 1H), 3.57 (d, J = 9.9 Hz,
1H), 3.49 (d, J = 9.9 Hz, 1H), 3.47 (s, 1H), 1.71 (s, 3H), 1.68
(s, 3H), 1.55 (m, 2H), 0.86 (s, 18H), 0.04 (s, 12H); 13C NMR
(CDCl3, 75 MHz) δ 148.35, 146.47, 112.85, 109.81, 64.32,
63.49, 48.37, 37.47, 25.82, 20.39, 18.17, 17.86, Ϫ5.58; Anal.
calc. for C23H48O3Si2: C 64.42; H 11.28. Found: C 64.60; H
11.39.
C20H32O2Si: C 72.23; H 9.70. Found: C 72.08; H 9.77.
(rel)-(1R,4R)-1-Ethoxycarbonyloxy-4,4Ј-(t-butyldimethyl-
silyloxymethyl)-2,3-dimethyl-cyclopent-2-ene (24)
To a solution of compound 21 (3.0 g, 7.48 mmol) in anhy-
drous pyridine (15 mL), ethyl chloroformate (1.72 mL, 11.22
mmol) and DMAP (110 mg, 0.9 mmol) were added. The reac-
tion mixture was stirred overnight at room temperature. The
reaction mixture was quenched using a saturated NaHCO3
solution (1 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 : 30) to give compound
24 (3.1 g, 88%) as a colorless syrup: 1H NMR (CDCl3, 300
MHz) d 5.64 (dd, J = 7.0, 4.6 Hz, 1H), 4.16 (q, J = 7.6 Hz,
2H), 3.54 (m, 4H), 2.92 (dd, J = 13.6, 7.6 Hz, 1H), 1.78 (s,
3H), 1.68 (d, J = 13.6 Hz, 1H), 1.51 (s, 3H), 1.33 (t, J = 7.6
Hz, 3H), 0.86 (s, 18H), 0.05 (s, 12H); 13C NMR (CDCl3, 75
MHz) d 155.32, 137.43, 134.76, 83.56, 67.45, 65.11, 63.21,
58.32, 40.91, 25.78, 18.44, 14.78, 11.67, 10.34, Ϫ5.54; Anal.
calc. for C24H48O5Si2: C 60.97; H 10.23. Found: C 61.21; H
10.06.
(rel)-(3R and 3S,5S)-5-(t-Butyldimethylsilyloxymethyl)-5-
phenyl-2,6-dimethyl-hepta-1,6-dien-3-ol (20)
Compound 20 was prepared from compound 18 using the
method described for compound 19: yield 83%; as a dia-
stereomeric mixture for 1H NMR (CDCl3, 300 MHz) δ 7.28 (m,
5H), 5.11 (s, 1H), 5.01 (s, 1H), 4.96 (s, 1H), 4.80 (s, 1H), 4.16
(d, J = 6.3 Hz, 1H), 4.1 (d, J = 10.5 Hz, 1H), 2.78 (d, J = 2.7
Hz, 1H), 2.41 (dd, J = 14.4, 2.4 Hz, 1H), 2.19 (dd, J = 14.4,
8.1 Hz, 1H), 1.74 (s, 3H), 1.58 (s, 3H), 0.85 (s, 9H), 0.09 (s,
6H); 13C NMR (CDCl3, 75 MHz) δ 149.36, 148.34, 143.91,
128.00, 127.18, 126.14, 112.32, 109.84, 77.19, 72.50, 66, 32,
51.46, 39.86, 25.71, 20.96, 18.10, 17.92, Ϫ5.85; Anal. calc.
for C22H36O2Si: C 73.28; H 10.06. Found: C 70.41; H 10.32.
(rel)-(1R,4R)-1-Ethoxycarbonyloxy-4-(t-butyldimethylsilyl-
oxymethyl)-4-phenyl-2,3-trimethyl-cyclopent-2-ene (25)
Compound 25 was prepared from compound 22 using the
method described for compound 24: yield 87%; 1H NMR
(CDCl3, 300 MHz) δ 7.17Ϫ6.98 (m, 5H), 5.57 (dd, J = 7.2,
4.6 Hz, 1H), 4.18 (q, J = 7.8 Hz, 2H), 3.82 (d, J = 9.4 Hz,
1H), 3.70 (d, J = 9.3 Hz, 1H), 2.61 (dd, J = 14.2, 7.6 Hz, 1H),
1.87 (d, J = 14.2 Hz, 1H), 1.65 (s, 3H), 1.34 (t, J = 7.8 Hz,
3H), 1.30 (s, 3H), 0.85 (s, 9H), 0.06 (s, 6H); 13C NMR (CDCl3,
75 MHz) δ 155.36, 145.71, 138.89, 136.76, 128.25, 127.41,
112.54, 83.13, 66.20, 63.65, 59.23, 48.65, 25.59, 18.19,
14.21, 11.68, 11.12, Ϫ5.65; Anal. calc. for C23H36O4Si: C
68.27; H 8.97. Found: C 68.34; H 9.09.
( )-4,4Ј-Bis-(t-butyldimethylsilyloxymethyl)-2,3-dimethyl-
cyclopent-2-enol (21)
To a solution of compound 19 (2.5 g, 5.8 mmol) in dry ben-
zene (5 mL), Grubbs’ catalyst II (51 mg, 0.06 mmol) was ad-
ded. The reaction mixture was refluxed overnight and then
concentrated. The residue was purified by silica gel column
chromatography (EtOAc/hexane, 1 : 15) to give the cyclo-
pentenol 21 (1.99 g, 86%) as colorless oil. 1H NMR (CDCl3,
300 MHz) d 4.20 (dd, J = 10.8, 7.2 Hz, 1H), 3.62 (d, J = 9.3
Hz, 1H), 3.50 (dd, J = 9.9, 5.4 Hz, 2H), 3.40 (d, J = 9.9 Hz,
1H), 2.74 (d, J = 10.2 Hz, 1H), 1.95 (dd, J = 14.1, 7.5 Hz,
1H), 1.67 (s, 3H), 1.51 (s, 3H), 0.85 (s, 18H), 0.04 (s, 12H);
13C NMR (CDCl3, 75 MHz) d 137.10, 135.24, 77.87, 67.19,
64.93, 57.13, 41.07, 25.71, 18.07, 11.56, 10.42, Ϫ5.67; Anal.
calc. for C21H44O3Si2: C 62.94; H 11.07. Found: C 63.11; H
10.92.
(rel)-(1ЈR,4ЈR)-9-[4,4Ј-Bis-(t-butyldimethylsilyloxymethyl)-2,3-
dimethyl-cyclopent-2-en-1-yl] adenine (26)
To pure NaH (70.2 mg, 2.92 mmol) in anhydrous DMSO (10.0
mL), adenine (402 mg, 2.94 mmol) was added. The reaction
mixture was stirred for 30 min at 50Ϫ55°C and cooled to
© 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Pharm. Med. Chem. 2004, 337, 579−586
Triply Branched Carbocyclic Nucleosides as Antiviral Agents 585
room temperature. Simultaneously, P(O-i-Pr)3 (1.44 mL, 3.3
mmol) was added to a solution of Pd2(dba)3·CHCl3 (69 mg,
37.5 µmol) in anhydrous THF (10.0 mL), which was stirred
for 40 min. To the adenine solution in DMSO, a catalyst solu-
tion of THF and compound 24 (1.24 g, 2.64 mmol) dissolved
in anhydrous THF (9 mL) were added slowly. The reaction
mixture was stirred overnight at a refluxing temperature and
quenched with water (5 mL). The reaction solvent was re-
moved under reduced pressure. The residue was purified by
silica gel column chromatography (MeOH/CH2Cl2, 1 : 15) to
give compound 26 (478 mg, 35%) as a white solid: mp
186Ϫ188°C; UV (MeOH) λmax 260.5 nm; 1H NMR (CDCl3,
300 MHz) δ 8.27 (s, 1H), 7.97 (s, 1H), 5.67 (dd, J = 8.6, 4.6
Hz, 1H), 3.71 (m, 4H), 2.63 (dd, J = 13.8, 7.8 Hz, 1H), 1.92
(d, J = 13.8, 1H), 1.77 (d, 3H), 1.51 (s, 3H), 0.86 (s, 18H),
0.06 (s, 12H); 13C NMR (CDCl3, 75 MHz) δ 155.46, 152.90,
142.44, 138.82, 136.36, 68.45, 67.31, 59.45, 57.13, 39.17,
25.89, 18.32, 11.61, 10.67, Ϫ5.51; Anal. calc. for
C26H47N5O2Si2: C 60.30; H 9.15; N 13.52. Found: C 60.54;
H 9.31; N 13.44.
10.09, Ϫ5.42; Anal. calc. for C24H35N3O2Si: C 67.72; H 8.29;
N 9.87. Found: C 67.91; H 8.02; N 9.92.
(rel)-(1ЈR,4ЈR)-9-Bis-[4,4Ј-(hydroxymethyl)-2,3-dimethyl-
cyclopent-2-en-1-yl] adenine (30)
To a solution of compound 26 (200 mg, 0.386 mmol) in THF
(5 mL), TBAF (0.58 mL, 1.0 M solution in THF) at 0°C was
added. The mixture was stirred at room temperature for 4 h
and concentrated. The residue was purified by silica gel col-
umn chromatography (MeOH/CH2Cl2, 1 : 5) to give com-
pound 30 (89 mg, 80%) as a white solid: mp 186Ϫ188°C;
UV (H2O) λmax 261.5 nm; 1H NMR (DMSO-d6, 300 MHz) δ
8.24 (s, 1H), 8.07 (s, 1H), 7.20 (br s, 2H D2O exchangeable),
5.62 (br s, 2H), 4.83 (br s, 2H D2O exchangeable), 3.82 (dd,
J = 13.6, 6.6 Hz, 2H), 3.35 (d, J = 8.6 Hz, 2H), 2.71 (dd, J =
13.6, 8.0 Hz, 1H), 2.12 (d, J = 13.6 Hz, 1H), 1.72 (s, 3H),
1.11 (s, 3H); 13C NMR (DMSO-d6, 75 MHz) δ 155.71, 153.10,
143.76, 139.06, 135.63, 67.61, 66.21, 58.41, 55.78, 38.12,
11.12, 10.07; Anal. calc. for C14H19N5O2: C 58.12; H 6.62; N
24.21. Found: C 58.34; H 6.60; N 24.29.
(rel)-(1ЈR,4ЈR)-1-[4,4Ј-Bis-(t-butyldimethylsilyloxymethyl)-2,3-
dimethyl-cyclopent-2-en-1-yl] cytosine (27)
(rel)-(1ЈR,4ЈR)-1-Bis-[4,4Ј-(hydroxymethyl)-2,3-dimethyl-
cyclopent-2-en-1-yl] cytosine (31)
Compound 27 was prepared from compound 24 using the
method described for synthesizing compound 26: yield 31%;
mp 176Ϫ178°C; UV (MeOH) λmax 271.0 nm; 1H NMR
(CDCl3, 300 MHz) δ 7.72 (d, J = 7.4 Hz, 1H), 5.72 (dd, J =
7.8, 4.6 Hz, 1H), 5.62 (d, J = 7.4 Hz, 1H), 3.72 (dd, J = 13.6,
7.2 Hz, 1H), 3.44 (d, J = 8.6 Hz, 1H), 3.21 (d, J = 8.6 Hz,
1H), 2.64 (dd, J = 14.2, 7.6 Hz, 1H), 2.12 (d, J = 14.2 Hz,
1H), 1.73 (s, 3H), 1.41 (s, 3H), 0.87 (s, 18H), 0.05 (s, 12H);
13C NMR (CDCl3, 75 MHz) δ 165.42, 155.45, 143.67, 144.78,
132.45, 93.81, 68.32, 67.45, 61.18, 58.62, 35.80, 25.40,
18.76, 11.71, 10.78, Ϫ5.66; Anal. calc. for C25H47N3O3Si2: C
60.80; H 9.59; N 8.51. Found: C 60.67; H 9.41; N 8.40.
Compound 31 was prepared from compound 27 using the
method described for synthesizing compound 30: yield 82%;
mp 171Ϫ174°C; UV (H2O) λmax 271.5 nm; H NMR (DMSO-
1
d6, 300 MHz) d 7.76 (d, J = 7.2 Hz, 1H), 7.14 (br d, 2H D2O
exchangeable), 5.70 (br s, 1H), 5.61 (d, J = 7.2 Hz, 1H), 4.83
(br s, 2H D2O exchangeable), 3.80 (d, J = 14.2, 6.6 Hz, 1H),
3.47 (d, J = 14.2 Hz, 1H), 3.33 (dd, J = 13.2, 7.6 Hz, 2H),
2.74 (dd, J = 12.2, 7.8 Hz, 1H), 2.32 (d, J = 12.4 Hz, 1H),
1.68 (s, 3H), 1.32 (s, 3H); 13C NMR (DMSO-d6, 75 MHz) δ
165.77, 155.67, 144.78, 142.78, 132.25, 93.78, 67.90, 68.12,
61.22, 58.25, 35.45, 11.23, 11.02; Anal. calc. for C13H19N3O3:
C 58.85; H 7.22; N 15.84. Found: C 58.67; H 7.31; N 15.60.
(rel)-(1ЈR,4ЈR)-9-[4-(t-Butyldimethylsilyloxymethyl)-4-phenyl-
2,3-dimethyl-cyclopent-2-en-1-yl] adenine (28)
(rel)-(1ЈR,4ЈR)-9-[4-(t-Hydroxymethyl)-4-phenyl-2,3-trimethyl-
cyclopent-2-en-1-yl] adenine (32)
Compound 28 was prepared from compound 25 using the
method described for synthesizing compound 27: yield 32%;
mp 194Ϫ196°C; UV (MeOH) λmax 261.5 nm; 1H NMR
(CDCl3, 300 MHz) δ 8.36 (s, 1H), 8.12 (s, 1H), 7.26Ϫ6.99 (m,
5H), 5.70 (dd, J = 8.8, 6.2 Hz, 1H), 3.85 (d, J = 8.6 Hz, 1H),
3.64 (d, J = 8.6 Hz, 1H), 2.65 (dd, J = 13.8, 6.8 Hz, 1H), 2.15
(d, J = 13.8 Hz, 1H), 1.71 (s, 3H), 1.26 (s, 3H), 0.83 (s, 9H),
0.04 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 155.76, 152.81,
146.22, 141.54, 139.21, 137.32, 136.65, 129.43, 126.21,
66.45, 59.60, 49.12, 25.72, 18.21, 11.45, 10.31, Ϫ5.40; Anal.
calc. for C25H35N5OSi: C 66.78; H 7.85; N 15.57. Found: C
66.80; H 7.78; N 15.42.
Compound 32 was prepared from compound 28 using the
method described for synthesizing compound 31: yield 85%;
mp 190Ϫ192°C; UV (H2O) λmax 261.5 nm; H NMR (DMSO-
1
d6, 300 MHz) δ 8.30 (s, 1H), 8.07 (s, 1H), 7.26Ϫ6.99 (m, 5H),
7.12 (br s, 2H D2O exchangeable), 5.77 (dd, J = 8.6, 4.2 Hz,
1H), 4.81 (br s, 1H D2O exchangeable), 3.81 (d, J = 8.8 Hz,
1H), 3.54 (d, J = 8.8 Hz, 1H), 2.68 (dd, J = 13.8, 8.6 Hz, 1H),
2.25 (d, J = 13.8 Hz, 1H), 1.79 (s, 3H), 1.34 (s, 3H); 13C
NMR (DMSO-d6, 75 MHz) δ 155.61, 153.13, 146.28, 141.92,
138.12, 137.45, 135.10, 129.43, 125.91, 67.467, 58.54,
48.21, 11.40, 10.23; Anal. calc. for C19H21N5O: C 68.04; H
6.31; N 20.88. Found: C 67.88; H 6.41; N 20.91.
(rel)-(1ЈR,4ЈR)-1-[4-(t-Butyldimethylsilyloxymethyl)-4-phenyl-
2,3-dimethyl-cyclopent-2-en-1-yl] cytosine (29)
(rel)-(1ЈR,4ЈR)-1-[4-(t-Butyldimethylsilyloxymethyl)-4-phenyl-
2,3-dimethyl-cyclopent-2-en-1-yl] cytosine (33)
Compound 29 was prepared from compound 25 using the
method described for synthesizing compound 28: yield 29%;
mp 182Ϫ184°C; UV (MeOH) λmax 271.5 nm; 1H NMR
(CDCl3, 300 MHz) δ 7.52 (d, J = 7.2 Hz, 1H), 7.27Ϫ7.04 (m,
5H), 5.85 (br s, 1H), 5.52 (d, J = 7.2 Hz, 1H), 3.89 (d, J = 8.6
Hz, 1H), 3.62 (d, J = 8.6 Hz, 1H), 2.76 (dd, J = 13.8, 7.8 Hz,
1H), 2.13 (d, J = 13.8 Hz, 1H), 1.76 (s, 3H), 1.33 (s, 3H), 0.83
(s, 9H), 0.03 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 165.12,
155.72, 146.20, 144.667, 138.80, 137.34, 128.19, 127.02,
112.51, 93.74, 66.23, 58.97, 47.65, 25.49, 18.09, 11.53,
Compound 33 was prepared from compound 29 using the
method described for synthesizing compound 32: yield 81%;
mp 178Ϫ181°C; UV (H2O) λmax 272.0 nm; H NMR (DMSO-
d6, 300 MHz) δ 7.59 (d, J = 7.4 Hz, 1H), 7.29Ϫ7.08 (m, 5H),
5.81 (dd, J = 8.6, 4.5 Hz, 1H), 5.52 (d, J = 7.4 Hz, 1H), 3.73
(d, J = 8.4 Hz, 1H), 3.52 (d, J = 8.4 Hz, 1H), 2.66 (dd, J =
14.2, 7.2 Hz, 1H), 2.13 (d, J = 14.2 Hz, 1H), 1.82 (s, 3H),
1.38 (s, 3H), 0.88; 13C NMR (DMSO-d6, 75 MHz) δ 165.70,
154.99, 146.28, 144.61, 137.34, 136.41, 128.65, 126.81,
112.88, 93.31, 66.90, 59.05, 48.54, 11.571, 10.21; Anal. calc.
1
© 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

586 Hong et al.
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 579−586
for C18H21N3O2: C 69.43; H 6.80; N 13.49. Found: C 69.29;
H 6.72; N 13.52.
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© 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim