Simple synthesis of novel acyclic (E)-bromovinyl nucleosides as potential antiviral agents

Article abstract of DOI:10.1080/15257770600793877

In these study, novel acyclic (E)-bromovinyl nucleosides were synthesized as potential antiviral agents. The coupling of the allylic bromide 9 with bases (thymine, uracil, 5-fluorouracul, 5-iodouracil, cytosine, adenine) afforded a series of novel acyclic

Full text of DOI:10.1080/15257770600793877

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Simple Synthesis of Novel Acyclic (E)-
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Antiviral Agents
Jin Woo Kim a & Joon Hee Hong a
a College of Pharmacy, Chosun University, Kwangju, Republic of
Korea
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To cite this article: Jin Woo Kim & Joon Hee Hong (2006): Simple Synthesis of Novel Acyclic (E)-
Bromovinyl Nucleosides as Potential Antiviral Agents, Nucleosides, Nucleotides and Nucleic Acids,
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Nucleosides, Nucleotides, and Nucleic Acids, 25:879–887, 2006
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770600793877
SIMPLE SYNTHESIS OF NOVEL ACYCLIC (E)-BROMOVINYL
NUCLEOSIDES AS POTENTIAL ANTIVIRAL AGENTS
Jin Woo Kim and Joon Hee Hong
College of Pharmacy, Chosun University,
2
Kwangju, Republic of Korea
In these study, novel acyclic (E)-bromovinyl nucleosides were synthesized as potential antiviral
2
agents. The coupling of the allylic bromide 9 with bases (thymine, uracil, 5-fluorouracul,
5-iodouracil, cytosine, adenine) afforded a series of novel acyclic nucleosides. The synthesized
compounds were evaluated for their antiviral activity against various viruses such as HIV-1,
HSV-1, HSV-2, and HCMV. 5-Iodouracil analogue 19 showed weak anti-HIV-1 activity.
Keywords Antiviral Agents; Neplanocin A; Acyclovir; Penciclovir
INTRODUCTION
A number of carbocyclic adenosine analogues are assumed to exert their
antiviral action through inhibition of SAH hydrolase. Recently, neplanocin
A (NPA, 1),[1] which is a novel cyclic carba analogue of adenosine with a
cyclopentene ring, has generated considerable attention both synthetically
and biologically due to the effect of the double bond on the compound
activity and potency.[2] NPA mediated inhibition of S-adenosylhomocysteine
hydrolase is responsible for its biological activity, which is the key enzyme in
the regulation of S-adenosyl-methionine–dependent methylation rections
during mRNA replication cycles.[3] Because of the unusual presence of
a double bond in neplanocin A, this compound has stimulated extensive
research in the synthesis of new olefinic nucleoside analogues that mimic
the sugar portion of naturally occurring neplanocin A. However, with
relatively few exceptions, the activity of most conventional carbocyclic
nucleosides has been poorer than those of the corresponding ribosides.
The loss of the furan oxygen in the carba nucleosides is believed to have a
critical effect on their antiviral activity. The incorporation of halogen atoms
into organic molecules has often been associated with profound changes
Received 23 March 2006; accepted 3 May 2006.
Address correspondence to Dr. Joon Hee Hong, College of Pharmacy, Chosun University, Kwangju
501-759, Republic of Korea . E-mail: hongjh@chosun.ac.kr
879

880
J. W. Kim and J. H. Hong
FIGURE 1 Synthesis rationale of the target compounds.
in the biological profiles of the halogenated analogues compared to their
hydrocarbon counterparts.
More recently, (E)-5-(2-bromovinyl)uracil analogues, such as (E)-5-
(2-bromovinyl)-2ꢁ-deoxyuridine (BVDU, 2)[4] and 1(β-d-arabinofuranosyl)-
(E)-5-(2-bromovinyl)uracil (BVAU, 3),[5] have been found to exhibit potent
anti-VZV activity in vitro as well as in vivo.[6] However, metabolic instability
of BVDU by pyrimidine nucleosides phosphiorylase as well as the drug
interaction of BVAU with 5-FU limited their use (Figure 1).
Motivated by these facts, the present investigation was directed toward
the synthesis of hybrid compounds that comprise both olefinic nucleoside
moiety and the aforementioned bromovinyl nucleosides. Such hybridization
was elaborated to obtain synergistic chemotherapeutic activity with higher
selectivity and less toxicity.
RESULTS AND DISCUSSION
As shown in Scheme 1, the target nucleosides were from the
protected ketone derivative 4, which was readily synthesized from 2-
hydroxyacetophenon by using the previously reported procedure.[7] Ketone
derivative was subjected to Horner-Wadsworth-Emmons (HWE) reaction
to give the α,β-unsaturated ethyl ester 5(E) and 5(Z), which are readily
separated as well as characterized by NOE study. For the synthesis of
desired (E)-bromovinyl nucleosides, ester 5(Z) was treated with Br2 and
Et3N in CH2Cl2 solvent produced the dibrominated product 6, which was
converted to bromovinyl 7 using the K2CO3 in DMF. The bromovinyl 7 was

(E)-Bromovinyl Nucleosides
881
SCHEME 1 Synthesis of acyclic bromovinyl nucleosides.
reduced with DIBAL-H to provide allylic alcohol 8. Conversion of allylic
alcohols 8 to the allylic bromide 9 was accomplished by the sequential
addition of NBS to a solution of the alcohol and triphenylphosphine in
CH2Cl2 in high yield.[8] The coupling of the allylic bromide 9 with bases
(thymine, uracil, 5-fluorouracil, 5-iodouracil, cytosine, adenine) in DMF
with cesium carbonate (CsCO3) as a basic catalyst provided the nucleoside
derivatives 10–15. The desired acyclic bromovinyl nucleosides 16–21 was
synthesized by removing of the t-butyldimethylsilyl group (TBDMS) using
tetrabutylammonium fluoride (TBAF) in tetrahydrofuran (THF).
The antiviral assays against several viruses such as HIV-1 (MT-4 cells),
HSV-1 (CCL81 cells), HSV-2 (CCL-81 cells), and HCMV (AD-169) were
performed. As shown in Table 1, none of the tested compounds showed

882
J. W. Kim and J. H. Hong
TABLE 1 Antiviral Activity of the Synthesized Compounds
HIV-1
HSV-1
HSV-2
HCMV
Cytotoxicity
EC50 (µM)
EC50 (µM)
EC50 (µM)
EC50 (µM)
CC50 (µM)
16
17
18
19
20
21
AZT
GCV
ACV
>100
51.82
>100
28.20
>100
>100
0.0002
ND
>100
>100
>100
>100
>100
45.32
ND
>100
>100
>100
>100
>100
>100
ND
56.81
>100
>100
77.26
>100
>100
ND
>100
>100
>100
>100
>100
>100
2.0
ND
0.4
ND
ND
1.0
ND
>10
>100
ND
AZT: azidothymidine; GCV: ganciclovir; ACV: acyclovir.
ND: Not determined.
EC50 (µM): Concentration required to inhibit 50% of virus-induced cytopathicity.
CC50 (µM): Concentration required to reduce cell viability by 50%.
See De Clercq[2] and Borchardt et al.[9] for the anitviral activity of neplanocin A.
good antiviral activity except for the 5-iodouracil 19, which exhibited
moderate anti-HIV-1 activity (EC50 = 28.20 µmol) without any cytotoxicity
up to 100 µM.
In conclusion, a very simple synthetic method for novel acyclic ne-
planocin A analogues from a ketone derivative was developed in this study.
When the synthesized compounds were tested against several viruses, only
iodouracil derivative 19 showed weak anti-HIV-1 activity. Although we could
not find good antiviral agents, the information obtained in the present study
will be useful for the development of a novel nucleoside antiviral agent.
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 Ar using distilled dry solvents. The melting points were de-
termined using a Mel-temp II laboratory device and were uncorrected. The
NMR spectra were recorded on a JEOL 300 Fourier transform 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 analysis was performed using an
Elemental Analyzer System (Profile HV-3). TLC was performed on Uniplates
(silica gel) purchased from Analtech Co.
(E)-4-(t-Butyldimethylsilyloxy)-3-phenyl-but-2-enoic acid ethyl ester (5E) and (Z)-
4-(t-butyldimethylsilyloxy)-3-phenyl-but-2-enoic acid ethyl ester (5Z). To a suspen-
sion of sodium hydride (60% in mineral oil, 0.74 g, 18.5 mmol) in distilled
THF at 0◦C, triethyl phosphonoacetate (2.81 mL, 18.5 mmol) was added

(E)-Bromovinyl Nucleosides
883
dropwise and with constant stirring at room temperature for 1 h. The ketone
4 (4.6 g, 18.5 mmol) was added to this mixture and stirred for 1 h. The
solution was neutralized with AcOH and extracted with EtOAc. The organic
layer was washed with brine and dried over anhydrous MgSO4, filtered, and
evaporated. The residue was purified by silica gel column chromatography
(EtOAc/hexane, 1:15) to give 5(Z) (2.64 g, 45%) and 5(E) (2.24 g, 38%),
respectively. Compound 5(E): 1H NMR (CDCl3, 300 MHz) δ 7.25–7.22 (m,
2H), 7.07–7.04 (m, 3H), 5.17 (s, 1H), 4.23 (d, J = 2.1 Hz, 2H), 3.90 (q, J =
6.5 Hz, 2H), 0.95 (t, J = 6.5 Hz, 3H), 0.83 (s, 9H), 0.02 (s, 6H); 13C NMR
(CDCl3) δ 166.19, 157.56, 137.46, 127.89, 127.30, 115.18, 66.77, 59.71, 25.82,
18.33, 13.88, -5.51; Compound 5(Z): 1H NMR (CDCl3, 300 MHz) δ 7.50–7.46
(m, 2H), 7.35–7.33 (m, 3H), 6.04 (s, 1H), 5.19 (s, 2H), 4.23 (q, J = 6.9 Hz,
2H), 1.32 (t, J = 6.9 Hz, 3H), 0.75 (s, 9H), 0.01 (s, 6H); 13C NMR (CDCl3)
δ 166.10, 158.56, 139.13, 128.64, 127.97, 127.69, 117.65, 60.17, 59.64, 25.66,
18.08, 14.29, −5.38.
Ethyl-2,3-dibromo-4 - (tert - butyldimethylsilanyloxy) - 3-phenyl-but - 2-enoic acid
ethyl ester (6). To a solution of compound 5(Z) (419.8 mg, 1.31 mmol) in
CCl4 under nitrogen was added bromine (0.06 mL, 1.443 mmol) followed
by slow addition of triethylamine (0.27 mL, 1.965 mmol) at ice bath. The
reaction mixture was stirred for 5 h at 0◦C, filtered, and washed with CCl4.
The filtrate was washed with 2 N HCl and then sodium bicarbonate, dried
with anhydrous MgSO4, and concentrated. The residue was purified by silica
gel column chromatography (EtOAc/hexane, 1:30) to give compound 5
1
(339 mg, 54%) as a colorless oil: H NMR (CDCl3, 300 MHz) δ 7.76–7.69
(m, 2H), 7.34–7.27 (m, 3H), 5.13 (s, 2H), 4.57 (d, J = 11.1 Hz, 1H), 4.35
(d, J = 11.1 Hz, 1H), 4.16 (q, J = 6.9 Hz, 2H), 1.17 (t, J = 6.9 Hz, 3H), 0.87
(s, 9H), 0.02 (s, 6H); 13C NMR (CDCl3) δ 167.10, 138.99, 129.54, 128.93,
128.56, 127.89, 127.59, 70.79, 61.99, 51.44, 25.75, 18.85, 13.74, −5.52.
(E)-2-Bromo-4-(tert-butyl-dimethyl-silanyloxy)-3-phenyl-but-2-enoic acid ethyl
ester (7). Ester 6 (576 mg, 1.2 mmol) was dissolved in DMF (15 mL)
and treated with K2CO3 (248 mg, 1.8 mmol). The mixture was stirred
over night and quenched with water and extracted with diethyl ether.
Organic layer was dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by silica gel column
chromatography (EtOAc/hexane, 1:30) to give compound 7 (479 mg,
1
65%) as a colorless oil: H NMR (CDCl3, 300 MHz) δ 7.44–7.22 (m, 5H),
4.72 (s, 2H), 4.01 (q, J = 7.5 Hz, 2H), 1.00 (t, J = 7.5 Hz, 3H), 0.82 (s, 9H),
0.02 (s, 6H); 13C NMR (CDCl3) δ 164.62, 148.73, 137.87, 128.12, 127.92,
110.34, 66.25, 61.85, 25.69, 18.11, 13.41, −5.50.
(E)-2-Bromo-4-(tert-butyl-dimethyl-silanyloxy)-3-phenyl-but-2-en-1-ol (8). To a
solution of compound 7 (3.77 g, 9.45 mmol) in CH2Cl2 (100 mL), DIBAL-H
(8.3 mL, 1.0 M solution in hexane) was added slowly at −20◦C, and stirred
for 2 h at the same temperature. To the resulting mixture, methanol (10
mL) was slowly added. The mixture was stirred at room temperature for

884
J. W. Kim and J. H. Hong
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, 1:12) to give the allylic alcohol 8
(3.24 g, 96%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 7.43–7.23 (m,
5H), 4.69 (s, 2H), 4.25 (d, J = 5.7 Hz, 2H), 0.85 (s, 9H), 0.03 (s, 6H); 13C
NMR (CDCl3) δ 142.76, 137.70, 128.75, 128.07, 127.68, 125.10, 67.05, 65.52,
25.76, 18.64, −5.43.
(E)-tert-Butyl-(3,4-dibromo-2-phenyl-but-2-enyloxy)-dimethylsilane (9). To a
solution of compound 8 (1.44 g, 4.03 mmol) and triphenylphosphine (1.16
g, 4.44 mmol) in CH2Cl2 (40 mL), N -bromosuccinimide (768 mg, 4.32
mmol) was added slowly at 0◦C, stirred for 4 h at room temperature, and
diluted with CH2Cl2. The organic layer was washed with water and brine,
dried over anhydrous magnesium sulfate, and filtered through a Celite pad.
The filtrate was concentrated under vacuum and the residue was purified
by quick flash silica gel column chromatography (EtOAc/hexane, 1:30) to
1
give the allylic bromide 9 (999 mg, 59%) as a yellow oil: H NMR (CDCl3,
300 MHz) δ 7.47–7.27 (m, 5H), 4.64 (s, 2H), 3.53 (s, 2H), 0.81 (s, 9H), 0.02
(s, 6H); 13C NMR (CDCl3) δ 145.23, 137.26, 128.19, 127.92, 119.98, 67.15,
37.40, 25.73, 18.11, −5.50; Anal calc for C16H24Br2OSi: C, 45.73; H, 5.76.
Found: C, 45.61; H, 5.82.
(E)-1-[2-Bromo-4-(tert-butyldimethylsilanyloxy)-3-phenyl-but-2-enyl]thymine
(10). A solution of the allylic bromide 9 (307 mg, 0.732 mmol), thymine
(297 mg, 2.364 mmol), and sodiume hydride (90 mg, 2.364 mmol) in
anhydrous DMF (15 mL) was stirred overnight at room temperature.
The mixture was quenched by the addition of water and diluted with
ethylacetate. The organic layer was separated and washed with brine, dried
over anhydrous magnesium sulfate, filtered, and concentrated. The residue
was purified by silica gel column chromatography (EtOAc/hexane, 4:1) to
give compound 10 (150 mg, 44%) as a solid: 1H NMR (CDCl3, 300 MHz) δ
8.56 (br s, 1H), 7.49–7.25 (m, 5H), 6.84 (s, 1H), 4.68 (s, 2H), 4.60 (s, 2H),
1.97 (s, 3H), 0.86 (s, 9H), 0.02 (s, 6H); 13C NMR (CDCl3) δ 163.64, 150.49,
146.13, 138.93, 137.27, 128.55, 128.13, 118.35, 110.92, 67.03, 51.10, 25.64,
18.76, 12.47, −5.53.
(E)-1-[2-Bromo-4-(tert-butyldimethylsilanyloxy)-3-phenyl-but-2-enyl] uracil (11).
Compound 11 was synthesized from 9 using the procedure as described
1
for 10: yield 39%; H NMR (CDCl3, 300 MHz) δ 8.45 (br s, 1H), 7.30–7.17
(m, 5H), 6.54 (d, J = 5.4 Hz, 1H), 5.99 (d, J = 5.7 Hz, 1H), 3.73 (dd, J =
19.8, 9.6 Hz, 2H), 2.90 (d, J = 14.4 Hz, 1H), 2.70 (d, J = 14.4 Hz, 1H), 0.87
(s, 9H), 0.02 (s, 6H); 13C NMR (CDCl3) δ 163.70, 150.84, 146.22, 144.11,
141.01, 128.56, 127.91, 120.51, 102.27, 64.26, 51.62, 25.76, 18.20, −5.56.
(E)-1-[2-Bromo-4-(tert-butyldimethylsilanyloxy)-3-phenyl-but-2-enyl]
5-fluorouracil (12). Compound 12 was synthesized from 9 using the
1
procedure as described for 10: yield 34%; H NMR (CDCl3, 300 MHz) δ

(E)-Bromovinyl Nucleosides
885
8.89 (br s, 1H), 7.49 (d, J = 5.4 Hz, 1H), 7.40–7.25 (m, 5H), 4.67 (s, 2H),
4.45 (s, 2H), 0.85 (s, 9H), 0.03 (s, 6H); 13C NMR (CDCl3) δ 165.27, 153.62,
145.78, 142.83, 137.54, 128.45, 127.89, 118.62, 101.34, 67.54, 51.62, 25.54,
18.34, −5.62.
(E)-1-[2-Bromo-4-(tert-butyldimethylsilanyloxy)-3-phenyl-but-2-enyl]
5-iodouracil (13). Compound 13 was synthesized from 9 using the
1
procedure as described for 10: yield 42%; H NMR (CDCl3, 300 MHz)
δ 9.01 (br s, 1H), 7.59 (s, 1H), 7.46–7.23 (m, 5H), 4.68 (s, 2H), 4.53 (s,
2H), 0.80 (s, 9H), 0.02 (s, 6H); 13C NMR (CDCl3) δ 162.02, 151.78, 146.78,
144.56, 138.32, 129.71, 128.98, 127.52, 120.62, 116.34, 67.65, 52.44, 25.50,
18.91, −5.65.
(E)-1-[2-Bromo-4 - (tert - butyldimethylsilanyloxy) - 3- phenyl-but -2-enyl] cytosine
(14). Compound 14 was synthesized from 9 using the procedure as de-
1
scribed for 10: yield 36%; H NMR (CDCl3, 300 MHz) δ 7.55 (d, J = 7.4
Hz, 1H), 7.42–7.22 (m, 5H), 5.74 (d, J = 7.4 Hz, 1H), 4.76 (s, 2H), 4.49
(s, 2H), 0.83 (s, 9H), 0.02 (s, 6H); 13C NMR (CDCl3) δ 166.21, 150.33,
146.71, 145.65, 138.38, 128.50, 127.62, 119.77, 92.90, 67.67, 51.23, 25.60,
18.39, −5.59.
(E) - 9-[2 - Bromo - 4- (tert -butyldimethylsilanyloxy)-3-phenyl-but-2-enyl] adenine
(15). Compound 15 was synthesized from 9 using the procedure as de-
1
scribed for 10: yield 43%; H NMR (CDCl3, 300 MHz) δ 8.40 (s, 1H), 8.12
(s, 1H), 7.39–7.19 (m, 5H), 4.79 (s, 2H), 4.54 (s, 2H), 0.80 (s, 9H), 0.02
(s, 6H); 13C NMR (CDCl3) δ 155.72, 152.56, 150.84, 146.65, 140.34, 137.76,
128.50, 127.89, 120.45, 118.65, 67.76, 50.98, 25.67, 18.71, −5.65.
(E)-1-(2-Bromo-4-hydroxy-3-phenyl-but-2-enyl) thymine (16). To a solution of
compound 10 (200 mg, 0.432 mmol) in THF (10 mL), TBAF (0.65 mL,
1.0 M solution in THF) at 0◦C was added. The mixture was stirred at room
temperature for 5 h and concentrated. The residue was purified by silica
gel column chromatography (MeOH/CH2Cl2, 1:7) to give compound 16
(91 mg, 60%) as a white solid: mp 160–163◦C; UV (H2O) λmax 267.5 nm;
1H NMR (DMSO-d6, 300 MHz) δ 11.25 (br s, 1H), 7.55–7.28 (m, 5H), 7.17
(s, 1H), 4.98 (t, J = 6.0 Hz, 1H), 4.39 (m, 4H), 1.72 (s, 3H); 13C NMR
(DMSO-d6) δ 163.99, 151.85, 146.69, 142.56, 138.78, 128.13, 127.45, 119.45,
110.56, 64.54, 51.39, 12.87; Anal calc for C15H15BrN2O3: C, 51.30; H, 4.31;
N, 7.98. Found: C, 51.15; H, 4.27; N, 8.19.
(E)-1-(2-Bromo-4-hydroxy-3-phenyl-but-2-enyl) uracil (17). Uracil nucleoside
17 was synthesized from 11 using the procedure as described for 16: yield
1
67%; mp 165–168◦C; UV (H2O) λmax 263.0 nm; H NMR (DMSO-d6, 300
MHz) δ 11.28 (br s, 1H), 7.55–7.24 (m, 6H), 5.73 (d, J = 8.1 Hz, 1H), 5.33 (t,
J = 5.7 Hz, 1H), 4.53–4.37 (m, 4H); 13C NMR (DMSO-d6) δ 163.71, 151.36,
148.77, 145.98, 138.39, 128.61, 128.32, 127.89, 120.54, 102.61, 65.46, 51.69;
Anal calc for C14H13BrN2O3: C, 49.87; H, 3.89; N, 8.31. Found: C, 49.75; H,
4.08; N, 8.47.

886
J. W. Kim and J. H. Hong
(E)-1-(2-Bromo-4-hydroxy-3-phenyl-but-2-enyl)-5-fluorouracil (18). Compo-
und 18 was synthesized from 12 using the procedure as described for 16:
1
yield 69%; mp 155–158◦C; UV (H2O) λmax 271.0 nm; H NMR (DMSO-d6,
300 MHz) δ 11.83 (br s, 1H), 7.77 (d, J = 5.6 Hz, 1H), 7.41–7.22 (m, 5H),
5.01 (t, J = 5.4 Hz, 1H), 4.70 (s, 2H), 4.43 (d, J = 5.8 Hz, 2H); 13C NMR
(DMSO-d6) δ 165.69, 154.21, 146.12, 143.78, 138.11, 127.98, 127.21, 119.69,
108.34, 67.61, 51.42; Anal calc for C14H12BrFN2O3: C, 47.34; H, 3.41; N,
7.89. Found: C, 47.56; H, 3.27; N, 7.66.
(E)-1-(2-Bromo-4-hydroxy-3-phenyl-but-2-enyl)-5-iodouracil (19). Compound
19 was synthesized from 13 using the procedure as described for 16: yield
1
70%; mp 167–170◦C; UV (H2O) λmax 285.0 nm; H NMR (DMSO-d6, 300
MHz) δ 11.39 (br s, 1H), 7.50 (s, 1H), 7.41–7.21 (m, 5H), 5.09 (t, J = 5.8
Hz, 1H), 4.65 (s, 2H), 4.50 (s, 2H); 13C NMR (DMSO-d6) δ 161.89, 152.23,
147.70, 145.21, 138.31, 128.70, 128.65, 127.52, 120.62, 70.56, 67.54, 51.87;
Anal calc for C14H12BrIN2O3: C, 36.31; H, 2.61; N, 6.05. Found: C, 36.50; H,
2.56; N, 5.85.
(E)-1-(2-Bromo-4-hydroxy-3-phenyl-but-2-enyl) cytosine (20). Cytosine deriva-
tive 20 was synthesized from 14 using the procedure as described for 16:
1
yield 60%; mp 168–170◦C; UV (H2O) λmax 272.0 nm; H NMR (DMSO-d6,
300 MHz) δ 7.72 (d, J = 7.0 Hz, 1H), 7.42–7.22 (m, 5H), 5.71 (d, J = 70
Hz, 1H), 4.99 (t, J = 5.4 Hz, 1H), 4.74 (s, 2H), 4.54 (s, 2H); 13C NMR
(DMSO-d6) δ 166.76, 153.23, 147.71, 138.87, 128.32, 127.72, 121.78, 100.47,
65.64, 52.45; Anal calc for C14H14BrN3O2: C, 50.02; H, 4.20; N, 12.50.
Found: C, 49.87; H, 4.15; N, 12.68.
(E)-9-(2-Bromo-4-hydroxy-3-phenyl-but-2-enyl) adenine (21). Adenine nucle-
oside 21 was synthesized from 15 using the procedure as described for 16:
1
yield 68%; mp 180–181◦C; UV (H2O) λmax 262.5 nm; H NMR (DMSO-d6,
300 MHz) δ 8.52 (s, 1H), 8.09 (s, 1H), 7.48–7.19 (m, 5H), 5.05 (t, J = 5.4
Hz, 1H), 4.70 (s, 2H), 4.64 (s, 2H); 13C NMR (DMSO-d6) δ 155.74, 153.72,
150.76, 147.51, 141.71, 137.90, 128.89, 128.32, 127.39, 120.32, 119.54, 64.23,
51.51; Anal calc for C15H14BrN5O: C, 50.02; H, 3.92; N, 19.44. Found: C,
50.19; H, 4.12; N, 19.58.
REFERENCES
1. Yaginuma, S.; Muto, N.; Tsujino, M.; Sudate, Y.; Hayashi, M.; Otani, M. Studies on Neplanocin A, New
Antitumor Antibiotics. I. Producing Organism, Isolation and Characterization. Journal of Antibiotics
1981, 34, 359–366.
2. De Clercq, E. Antiviral and Antimetabolic Activities of Neplanocins. Antimicrobial Agents in Chemother-
apy 1985, 28, 84–89.
3. Wolfe, M.S.; Borchart, R.T. S-Adenosylhomocysteine Hydrolase as Target for Chemotherapy. Journal
of Medicinal Chemistry 1991, 34, 1521–1530.
4. De Clercq, E.; Descamps, J.; De Somer, P.; Barr, P.J.; Jones, A.S.; Walker, R.T. (E)-5-(2-Bromovinyl)-2ꢁ-
deoxyuridine: A Potent and Selective Anti-Herpes Agent. Proceedings of the National Academy of Sciences
USA 1979, 76, 2947–2951.

(E)-Bromovinyl Nucleosides
887
5. Machida, H.; Sakata, S.; Kuninaka, A.; Yoshino, H. Antiherpes Viral and Anticellular Effect of 1-β-d-
Arabinofuranosyl-E-5-(2-Halogenovinyl)Uracils. Antimicrobial Agents in Chemotherapy 1981, 20, 47–52.
6. Desgranges, C.; Razaka, G.; Rabaud, M.; Bricaud, H.; Balzarini, J.; De Clercq, E. Phospholysis of (E)-(2-
Bromovinyl)-2ꢁ-Deoxy-Uridine (BVDU) and Other 5-Substituted-2ꢁ-Deoxyuridine by Purified Human
Thymidine Phosphorylase and Intact Blood Platelets. Biochemical Pharmacology 1983, 32, 3583–3590.
7. Hong, J.H.; Ko, O.H. Synthesis of 4ꢁα-C Phenyl Branched Carbocyclic Nucleoside Using Ring Closing
Metathesis. Bulletin of the Korean Chemical Society 2003, 24, 1289–1292.
8. Borcherding, D.R.; Narayanan, S.; Hasobe, M.; McKee, J.G.; Keller, B.T.; Borchardt, R.T. Potential
Inhibitors of S-Adenosylmethionine-Dependent Methyltransferases: Molecular Dissections of Ne-
planocin A as Potential Inhibitors of S-Adenosylhomocysteine Hydrolase. Journal of Medicinal Chemistry
1988, 31, 1729–1738.