Novel synthesis and anti-HIV activity of 4′-branched exomethylene carbocyclic nucleosides using a ring-closing metathesis of triene

Article abstract of DOI:10.1080/15257770802458246

The exomethylene of 6 was successfully constructed from the aldehyde 5 using Eschenmoser′s reagents. A triene compound 7 was cyclized successfully using Grubbs′ II catalyst to give an exomethylene carbocycle nucleus for the target compound. A Mitsunobu reaction was successfully used to condense the natural bases (adenine, thymine, uracil, and cytosine). The synthesized cytosine analogue 20 showed moderate anti-HIV activity (EC50 = 10.67 μM). Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/15257770802458246

Nucleosides, Nucleotides and Nucleic Acids, 27:1238–1249, 2008
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770802458246
NOVEL SYNTHESIS AND ANTI-HIV ACTIVITY OF 4ꢀ-BRANCHED
EXOMETHYLENE CARBOCYCLIC NUCLEOSIDES USING A
RING-CLOSING METATHESIS OF TRIENE
Hua Li, Jin Cheol Yoo, and Joon Hee Hong
BK-21 Project Team, College of Pharmacy, Chosun University, Kwangju, Republic of Korea
The exomethylene of 6 was successfully constructed from the aldehyde 5 using Eschenmoser’s
2
reagents. A triene compound 7 was cyclized successfully using Grubbs’ II catalyst to give an
exomethylene carbocycle nucleus for the target compound. A Mitsunobu reaction was successfully
used to condense the natural bases (adenine, thymine, uracil, and cytosine). The synthesized cytosine
analogue 20 showed moderate anti-HIV activity (EC50 = 10.67 µM).
Keywords Quaternary carbon; triene; ring-closing metathesis; Mitsunobu reaction
INTRODUCTION
The carbocyclic nucleosides[1] can potently inhibit viral infection. Due
to the absence of a true glycosidic bond, carbocyclic nucleoside analogues
are chemically more stable and not subject to the enzymatic degradation
that occurs in conventional nucleosides.[2] The recent discovery of olefinic
carbocyclic nucleosides, such as carbovir 1[3] and entecavir 2,[4], as potential
antiviral agents has attracted considerable attention in the search for novel
nucleosides of this class. Recently, a number of 4ꢁα-substituted nucleoside[5]
analogues showed significant antitumor or antiviral activities. Among
them, 4ꢁ-methyl-2ꢁ-deoxycytidine,[6] 4ꢁ-fluoromethyl-2ꢁ-deoxycytidine,[7] 4ꢁ-
hydroxymethylthymidine,[8] and 4ꢁ-azidomethylthymidine[9] demonstrated
very potent biological activities, but their high toxicity rendered them
ineffectual as drugs.
Based on these results and as part of our drug discovery program, we
have designed novel 4ꢁ-branched exomethylene carbocyclic nucleosides that
Received 6 May 2008; accepted 4 September 2008.
Address correspondence to Joon Hee Hong, College of Pharmacy, Chosun University, Kwangju
501–759, Republic of Korea. E-mail: hongjh@chosun.ac.kr
1238

Exomethylene Carbocyclic Nucleosides
1239
SCHEME 1 Synthesis of exomethylene cyclopentene intermediate 8
mimic the properties of potent olefinic carbocyclic nucleosides, as well as
biologically active 4ꢁ-branched furanose nucleosides. Herein, we disclose
their de novo synthetic routes that employed a versatile three-step sequence
([3,3]-sigmatropic rearrangement, Eschenmoser’s methylenation, Grubbs
ring closing metathesis) from a simple acyclic precursor, 1,3-dihydroxyl
acetone.
RESULTS AND DISCUSSION
The synthetic route for the key intermediate 8 in the synthesis of
the target nucleosides is illustrated in Scheme 1. The quaternary car-
bon of γ ,δ-unsaturated ester 4 was constructed successfully from the 1,3-
dihydroxyacetone using a previously reported procedure.[10] The addition
of one equivalent of DIBALH to a solution of the ester 4 in anhydrous
toluene at –78◦C produced the aldehyde 5. The treatment of carbonyl
5 with Eschenmoser’s salt (methylene-N,N -dimethylammonium iodide)[11]
gave exomethylene acyclic divinyl derivative 6. We next turned our attention
to the construction of a triene system for the metathesis cyclization reaction.
Thus, the addition of vinylmagnesium bromide to the divinyl aldehyde 6
furnished the desired acyclic triene 7, which was subjected to standard ring-
closing metathesis conditions using a second-generation Grubbs’ catalyst
[(Im)Cl2PCy3RuCHPh][12] to provide the required exomethylene cyclopen-
tenol 8 (Scheme 1).
We initially hypothesized that palladium(0)-catalyzed reactions[13] could
introduce functional groups into allylic positions of synthetic organic com-
pounds, including the exomethylene cyclopentene derivative 8, through an
ethyl formate analogue. To our surprise, we could not find any nucleoside
analogues and therefore needed an alternative coupling method. The

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H. Li et al.
SCHEME 2 Synthesis of adenine nucleoside analogue 11
Mitsunobu reactions can couple a cyclopentenol or cyclopentanol with
nucleosidic bases, allowing us to synthesize our target nucleosides with the
desired regio- and stereochemistry.[14] The success of a Mitsunobu reaction
in the synthesis of nucleoside analogues depends on the reaction condi-
tions, such as the solvent system, temperature, and addition procedure,
to control the regiochemistry of the desired nucleosides. Instead of THF
only, a 2:1 cosolvent mixture of dioxane/DMF was used for the coupling
of the cyclopentenol 8 with the nucleobases; the heterocyclic bases had
better solubility in the dioxane-DMF mixture, resulting in better yields.[15]
The slow addition of diisopropylazodicarboxylate (DIAD) to a mixture of
cyclopentenol 8, triphenylphosphine, and the corresponding purine base
in an anhydrous solvent produced a yellow solution, which was then stirred
for 2 hours at –20◦C to yield the 6-chloropurine analogue 9 without the
formation of N -7 isomers. The N -9 isomer of the coupling was confirmed
by UV spectra data [λmax (MeOH) 264 nm].[16] The desilylated nucleoside
10 was obtained from the corresponding nucleoside 9 by treatment with
tetrabutylammonium fluoride (TBAF) in a THF/CH3CN (1/1) co-solvent
system. The target adenosine analogue 11 was synthesized from the corre-
sponding nucleoside analogue 10 by treatment with a saturated solution of
methanolic ammonia in a steel bomb at 90–95◦C overnight (Scheme 2).
To synthesize the pyrimidine nucleoside analogues, that is, the N 3 or
N 4-benzoyl bases, we used a similar Mitsunobu procedure on the thymine,
uracil and cytosine bases to give the protected nucleoside analogues 12,
13, and 18. The regioisomers were easily confirmed by comparison of the
UV literature data.[16] The desilylations of the nucleoside intermediates

Exomethylene Carbocyclic Nucleosides
1241
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)
11
16
55.5
66
70.4
99
99
99
99
95
99
99
17
58
84
49
99
99
20
10.67
0.009
ND
50.5
ND
ND
0.2
95
41.5
ND
0.6
ND
95
AZT
GCV
ACV
ND
ND
ND
1.17
>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%.</tfn1>
were performed similarly to that for adenine nucleoside 10 to produce
pyrimidine the nucleosides 14, 15, and 19, which were debenzoylated by
treatment with sodium methoxide in methanol to produce nucleosides 16,
17, and 20.
The antiviral activity against HIV-1, HSV-1, HSV-2, and HCMV was
measured. The synthesized cytosine analogue 20 showed moderate anti-HIV
activity (EC50 = 10.67 µM, MT-4 cell lines) without any cytotoxicity up to 100
µM (Table 1).
The rigid arrangement in the exomethylene carbocyclic cytosine nucleo-
side analogue 20 may be conformationally similar to carbovir and entecavir.
Hence, this arrangement will enhance the level of phosphorylation by
kinase to produce the active monophosphate form.[17]
In summary, we developed a convenient method for synthesizing ex-
omethylene carbocyclic nucleoside analogues via the triene intermediate 7.
Based on this strategy, the syntheses of other nucleosides such as branched
carbocyclic nucleosides with different nucleobases are currently underway.
EXPERIMENTAL SECTION
Melting points were determined on a Mel-temp II laboratory device
and are uncorrected. NMR spectra were recorded on a JEOL 300 Fourier
transform spectrometer (JEOL, Tokyo, Japan); chemical shifts are reported
in parts per million (δ) and signals are reported as s (singlet), d (doublet),
t (triplet), q (quartet), m (multiplet), and dd (doublet of doublets). UV
spectra were obtained on a Beckman DU-7 spectrophotometer (Beckman,
South Pasadena, CA, USA). The elemental analyses were performed using a
Perkin-Elmer 2400 analyzer (Perkin-Elmer, Norwalk, CT, USA). Mass spectra
were measured with FAB-MS modified Finninggan MAT 312 spectrometer
(Arcade, NY 14009, USA). All reactions were carried out under an atmo-
sphere of nitrogen unless specified. Dry dichloromethane, benzene, and

1242
H. Li et al.
pyridine were obtained by distillation from CaH2. Dry THF was obtained by
distillation from Na and benzophenone immediately prior to use.
( )-3,3-Bis-(tert-butyldimethylsilanyloxymethyl)-pent-4-enal (5): To a so-
lution of 4 (3.5 g, 8.39 mmol) in toluene (100 mL), DIBALH (6.16 mL, 1.5
M solution in toluene) was added slowly at −78◦C, and stirred for 10 minutes
at the same temperature. Methanol (10 mL) was then added to the mixture.
The mixture was stirred at room temperature for 2 hours, 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
1
(EtOAc/hexane, 1:15) to give 5 (4.4 g, 69%) as a colorless oil: H NMR
(CDCl3, 300 MHz) δ 8.78 (s, 1H), 5.67 (dd, J = 17.7, 11.1 Hz, 1H), 5.21
(d, J = 11.1 Hz, 1H), 5.14 (d, J = 17.7 Hz, 1H), 3.58 (dd, J = 17.7, 10.2
Hz, 2H), 2.45 (s, 1H), 0.87 (m, 18H), 0.02 (m, 12H); 13C NMR (CDCl3) δ
202.68, 139.65, 115.45, 65.74, 46.79, 46.61, 25.81, 18.22, -5.62; MS (FAB+)
m/z 273 (M+H)+.
( )-3,3-Bis-(tert-butyldimethylsilanyloxymethyl)-2-methylene-pent-4-
enal (6): Eschenmoser’s salt, methylene-N ,N -dimethylammonium iodide,
(2.18 g, 11.82 mmol) was added to a solution of aldehyde 5 (2.2 g, 5.91
mmol) and triethylamine (2.46 mL, 17.73 mmol) in CH2Cl2 at room
temperature. The mixture was stirred overnight at room temperature.
After adding saturated aq. NaHCO3 solution, the mixture was extracted
with CH2Cl2, washed with brine, dried over MgSO4, and concentrated
under reduced pressure. The residue was purified by silica gel column
chromatography (EtOAc/n-hexane, 1:30) to give compound 6 (1.25 g,
55%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 9.12 (s, 1H), 6.09 (d,
J = 0.6 Hz, 1H), 5.80 (d, J = 0.8 Hz, 1H), 5.60–5.52 (m, 1H), 5.06–4.98
(m, 2H), 3.61 (d, J = 10.8 Hz, 1H), 3.52 (d, J = 10.8 Hz, 1H), 0.89 (m,
18H), 0.01 (m, 12H); 13C NMR (CDCl3) δ 202.86, 154.42, 136.78, 133.72,
109.71, 66.32, 52.43, 25.43, 18.39, −5.54; MS (FAB+) m/z 385 (M+H)+;
Anal. calcd. for C20H40O3Si2: C, 62.44; H, 10.48. Found: C, 62.58; H, 10.39.
( )-5,5-Bis-(tert-butyldimethylsilanyloxymethyl)-4-methylene-hepta-1,6-
dien-3-ol (7): Vinyl magnesium bromide (7.8 mL, 1.0 M solution in THF)
was added slowly to a solution of compound 6 (2.5 g, 6.5 mmol) in dry THF
(100 mL) at −78◦C. After 2 hours, saturated NH4Cl solution (8 mL) was
added, and the reaction mixture was warmed slowly to room temperature.
The mixture was extracted with EtOAc (2 × 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 a triene 7 (2.12 g, 79%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ
5.85–5.37 (m, 3H), 5.37–5.30 (m, 2H), 5.14–4.93 (m, 3H), 4.65 (d, J = 2.4
Hz, 1H), 3.88 (d, J = 9.9 Hz, 1H), 3.75 (d, J = 9.9 Hz, 1H), 0.86 (m, 18H),
0.01 (m, 12H); 13C NMR (CDCl3) δ 151.35, 140.35, 139.30, 116.56, 115.21,
113.93, 113.31, 70.98, 65.91, 64.18, 52.59, 25.88, 18.29, −5.43; Anal. calcd.
for C22H44O3Si2 · 0.5 EtOAc: C, 63.10; H, 10.59. Found: C, 63.19; H, 10.44.

Exomethylene Carbocyclic Nucleosides
1243
( )-4,4-Bis-(tert-butyldimethylsilanyloxymethyl)-5-methylene-cyclopent-
2-enol (8): A second generation Grubbs’ catalyst (80 mg, 0.11 mmol) was
added to a solution of compound 7 (3.92 g, 9.5 mmol) in dry CH2Cl2 (40
mL). The reaction mixture was refluxed overnight and concentrated. The
residue was purified by silica gel column chromatography (EtOAc/hexane,
1
1:20) to give compound 8 (2.7 g, 74%) as a colorless oil: H NMR (CDCl3,
300 MHz) δ 5.98 (dd, J = 6.0, 2.4 Hz, 1H), 5.68 (d, J = 6.0 Hz, 1H), 5.32
(s, 1H), 5.11 (s, 1H), 4.79 (dd, J = 10.8, 1.5 Hz, 1H), 3.74 (d, J = 9.3 Hz,
1H), 3.60 (d, J = 9.6 Hz, 1H), 3.50 (d, J = 9.3 Hz, 1H), 3.43 (d, J = 9.6
Hz, 1H), 0.87 (s, 18H), 0.01 (s, 12H); 13C NMR (CDCl3) δ 154.77, 137.14,
134.04, 110.04, 77.96, 67.01, 66.76, 57.72, 25.55, 18.39, −5.54; MS (FAB+)
m/z 385 (M+H)+, 407 (M+Na)+; Anal. Calcd. for C20H40O3Si2: C, 62.44;
H, 10.48. Found: C, 62.53; H, 10.54.
( )-9-[4,4-Bis-(tert-butyldimethylsilanyloxymethyl)-5-methylene-
cyclopent-2-enyl]-6-chloropurine (9): To a solution containing compound
8 (173 mg, 0.45 mmol), triphenylphosphine (0.705 g, 1.35 mmol) and
6-chloropurine (173 mg, 1.12 mmol) in anhydrous 1,4-dioxane (4 mL)
and DMF (2 mL), diisopropyl azodicarboxylate (0.25 mL) was added
dropwise at –20◦C for 30 minutes under nitrogen. The reaction mixture was
stirred for 2 hours at –20◦C under nitrogen. The solvent was concentrated
under reduced pressure and the residue was purified by silica gel column
chromatography (EtOAc/hexane, 1:3) to give compound 9 (75 mg, 32%)
1
as a white solid: m.p. 158–160◦C; H NMR (CDCl3, 300 MHz) δ 8.71 (s,
1H), 8.17 (s, 1H), 6.22 (m, 2H), 5.90 (dd, J = 5.7, 2.1 Hz, 1H), 5.26 (d,
J = 2.4 Hz, 1H), 5.08 (d, J = 1.5 Hz, 1H), 3.85 (d, J = 9.3 Hz, 1H), 3.72
(d, J = 9.3 Hz, 1H), 3.60 (d, J = 9.6 Hz, 1H), 3.54 (d, J = 9.6 Hz, 1H),
0.84 (m, 18H), 0.01 (m, 12H); 13C NMR (CDCl3) δ 155.34, 154.47, 152.45,
148.28, 147.20, 137.71, 134.51, 130.04, 111.77, 68.00, 63.35, 57.28, 25.51,
18.32, −5.60; MS (FAB+) m/z 521 (M+H)+, 543 (M+Na)+; Anal. Calcd.
for C25H41ClN4O2Si2: C, 57.61; H, 7.93; N, 10.75. Found: C, 57.67; H, 8.05;
N, 10.82.
( )-9-[4,4-Bis-(hydroxymethyl)-5-methylene-cyclopent-2-enyl]-6-
chloropurine (10): TBAF (0.76 mL, 1.0 M solution in THF) at 0◦C
was added to a solution of compound 9 (100 mg, 0.191 mmol) in
THF/CH3CN(2/2 mL). The mixture was stirred overnight at room
temperature and concentrated. The residue was purified by silica gel
column chromatography (MeOH/CH2Cl2, 1:8) to give compound 10
(79.25 mg, 72%) as a white solid: m.p. 163–165◦C; 1H NMR (DMSO-d6, 300
MHz) δ 8.78 (s, 1H), 8.22 (s, 1H), 6.18 (d, J = 5.9 Hz, 1H), 6.02 (s, 1H),
5.93 (d, J = 6.0 Hz, 1H), 5.27 (br s, 1H), 5.13 (s, 1H), 4.94 (t, J = 5.0 Hz,
1H), 4,77 (t, J = 5.2 Hz, 1H), 3.88 (d, J = 9.9 Hz, 1H), 3.74 (d, J = 9.9 Hz,
1H), 3.64 (d, J = 9.6 Hz, 1H), 3.58 (d, J = 9.6 Hz, 1H); 13C NMR (CDCl3)
δ 155.88, 154.54, 151.57, 148.66, 146.37, 138.98, 133.99, 130.02, 111.21,
78.09, 66.49, 56.32; MS (FAB+) m/z 293 (M+H)+, 315 (M+Na)+; Anal.

1244
H. Li et al.
Calcd. for C13H13ClN4O2: C, 53.34; H, 4.48; N, 19.14. Found: C, 53.28; H,
4.52; N, 19.06.
( )-9-[4,4-Bis-(hydroxymethyl)-5-methylene-cyclopent-2-enyl] adenine
(11): Compound 10 (79 mg, 0.27 mmol) was dissolved in saturated
methanolic ammonia (5 mL) and the resulting solution was stirred
overnight at 90–95◦C in a steel bomb. After removing the reaction
solvent, the residue was purified by silica gel column chromatography
(CH2Cl2/MeOH, 4:1) to give compound 11 (72.8 mg, 70%) as a white
solid: m.p. 177–179◦C; UV (H2O) λmax 261.5.0 nm; 1H NMR (DMSO-d6, 300
MHz) δ 8.10 (s, 1H), 8.01 (s, 1H), 6.12 (dd, J = 6.0, 1.5 Hz, 1H), 6.00 (t, J
= 2.4 Hz, 1H), 5.94 (dd, J = 6.0, 2.1 Hz, 1H), 5.19 (d, J = 2.4 Hz, 1H), 4.96
(br s, 1H), 4.93 (t, J = 5.2 Hz, 1H), 4,76 (t, J = 5.2 Hz, 1H), 3.75 (d, J =
9.8 Hz, 1H), 3.65 (d, J = 9.8 Hz, 1H), 3.60 (d, J = 9.6 Hz, 1H), 3.55 (d, J =
9.6 Hz, 1H); 13C NMR (DMSO-d6) δ 155, 69, 154.77, 152.76, 150.34, 141.72,
137.14, 134.04, 119.64, 110.24, 67.01, 66.44, 62.43, 58.72; MS (FAB+) m/z
274 (M+H)+, 296 (M+Na)+; Anal. Calcd. for C13H15N5O2 · 1.0 H2O: C,
53.59; H, 5.88; N, 24.04. Found: C, 53.48; H, 5.80; N, 23.86.
( )-1-[4,4-Bis-(tert-butyldimethylsilanyloxymethyl)-5-methylene-
cyclopent-2-enyl]-N3-benzoylthymine (12): The benzoylthymine analogue
was synthesized using a similar reaction procedure as that described for
compound 9 as a white solid: m.p. 160–163◦C; yield 43%; 1H NMR (CDCl3,
300 MHz) δ 7.89–7.85 (m, 2H), 7.61–7.55 (m, 1H), 7.45–7.40 (m, 2H), 7.15
(s, 1H), 6.31 (dd, J = 5.4, 1.8 Hz, 1H), 6.24 (dd, J = 5.4, 1.5 Hz, 1H), 5.98
(t, J = 1.8 Hz, 1H), 4.70 (d, J = 2.0 Hz, 2H), 3.67–3.57 (m, 4H), 1.88 (s,
3H), 0.86 (m, 18H), 0.02 (m, 12H); 13C NMR (CDCl3) δ 169.05, 163.30,
149.70, 142.05, 140.58, 134.56, 131,70, 130.39, 129.03, 123.35, 110.64, 66.02,
64.59, 57.51, 25.89, 18.28, 12.38, -5.45; MS (FAB+) m/z 619 (M+Na)+;
Anal. Calcd. for C32H48N2O5Si2: C, 64.39; H, 8.11; N, 4.69. Found: C, 64.51;
H, 7.98; N, 4.58.
( )-1-[4,4-Bis-(tert-butyldimethylsilanyloxymethyl)-5-methylene-
cyclopent-2-enyl]-N3-benzoyluracil (13): The benzoyluracil derivative
was synthesized by a procedure similar to that used to prepare 9 as a white
1
solid: m.p. 157–159◦C; yield 39%; H NMR (CDCl3, 300 MHz) δ 7.92–7.88
(m, 2H), 7.63–7.56 (m, 1H), 7.48–7.42 (m, 2H), 7.27 (d, J = 8.1 Hz, 1H),
6.32 (dd, J = 5.4, 1.8 Hz, 1H), 6.27 (dd, J = 5.1, 1.5 Hz, 1H), 6.03 (t, J =
1.8 Hz, 1H), 5.76 (d, J = 8.1 Hz, 1H), 4.64 (d, J = 1.5 Hz, 2H), 3.68 (d,
J = 9.0 Hz, 2H), 3.60 (d, J = 9.0 Hz, 2H), 0.85 (m, 18H), 0.01 (m, 12H);
13C NMR (CDCl3) δ 168.56, 162.57, 149.65, 147.46, 144.65, 140.76, 134.52,
132.65, 130.21, 129.14, 129.07, 128.54, 102.21, 70.08, 64.68, 62.43, 57.64,
25.76, 18.32, −5.49; MS (FAB+) m/z 583 (M+H)+, 605 (M+Na)+; Anal.
Calcd. for C31H46N2O5Si2: C, 63.88; H, 7.95; N, 4.81. Found: C, 63.95; H,
8.06; N, 4.75.
( )-1-[4,4-Bis-(tert-butyldimethylsilanyloxymethyl)-5-methylene-
cyclopent-2-enyl]-N4-benzoylcytosine (18): The benzoylcytosine derivative

Exomethylene Carbocyclic Nucleosides
1245
was synthesized by a procedure similar to that used to prepare 9 as a white
1
solid: m.p. 167–169◦C; yield 38%; H NMR (CDCl3, 300 MHz) δ 7.90–7.83
(m, 2H), 7.78–7.73 (m, 2H), 7.48–7.41 (m, 2H), 7.29(d,J = 7.8 Hz, 1H),
6.35 (dd, J = 5.4, 1.8 Hz, 1H), 6.28 (dd, J = 5.1, 1.6 Hz, 1H), 6.00 (d, J =
1.9 Hz, 1H), 5.54 (d, J = 7.8 Hz, 1H), 4.71 (d, J = 1.6 Hz, 2H), 3.67–59
(m, 4H), 0.87 (s, 18H), 0.01 (s, 12H); 13C NMR (CDCl3) δ 165.92, 165.88,
164.48, 160.66, 159.28, 154.75, 140.45, 139.28, 137.14, 132.88, 131,84,
129.02, 127.26, 110.23, 93.80, 67.02, 65.83, 64.87, 59.32, 25.90, 18.27, −5.59;
MS (FAB+) m/z 583 (M+H)+; Anal. Calcd. for C31H47N3O4Si2: C, 63.99;
H, 8.14; N, 7.22. Found: C, 64.16; H, 8.23; N, 7.32.
( )-1-[4,4-Bis-(hydroxymethyl)-5-methylene-cyclopent-2-enyl]-N3-
benzoylthymine (14): For the desilylation of benzoylthymine analogue
12, the reaction procedure was similar to that described for compound
1
10 as a white solid: m.p. 155–157◦C; Yield 73%; H NMR (DMSO-d6, 300
MHz) δ 7.88–7.84 (m, 2H), 7.60 (m, 1H), 7.46–7.41 (m, 2H), 7.09 (s, 1H),
6.30–6.25 (m, 2H), 5.99 (m, 1H), 4.89 (t, J = 5.4 Hz, 1H), 4.80 (t, J =
5.4 Hz, 1H), 4.65 (d, J = 1.8 Hz, 2H), 3.69–3.60 (m, 4H), 1.87 (s, 3H);
13C NMR (CDCl3) δ 168.78, 163.03, 149.43, 147.80, 142.2, 139.90, 134,54,
131.43, 130.40, 129.32, 128.32, 120.35, 109.64, 66.32, 64.43, 58.32,12.22; MS
(FAB+) m/z 369 (M+H)+, 391 (M+Na)+; Anal. Calcd. for C20H20N2O5: C,
65.21; H, 5.47; N, 7.60. Found: C, 65.35; H, 5.30; N, 7.53.
( )-1-[4,4-Bis-(hydroxymethyl)-5-methylene-cyclopent-2-enyl]-N3-
benzoyluracil (15): For the desilylation of benzoyluracil derivative 13,
the reaction procedure was similar to that used in the preparation of 10 as
1
a white solid: m.p. 169–171◦C; yield 80%; H NMR (DMSO-d6, 300 MHz)
δ 7.88 (m, 2H), 7.59 (d, J = 6.2 Hz, 1H), 7.48–7.42 (m, 2H), 7.31 (d, J =
8.0 Hz, 1H), 6.33–6.28 (m, 2H), 6.04 (d, J = 1.9 Hz, 1H), 5.73 (d, J = 8.0
Hz, 1H), 4.90 (t, J = 5.4 Hz, 1H), 4.80 (t, J = 5.4 Hz, 1H), 4.67 (d, J =
1.6 Hz, 2H), 3.67 (d, J = 9.1 Hz, 2H), 3.58 (d, J = 9.1 Hz, 2H); 13C NMR
(CDCl3) δ 168.20, 163.11, 148.32, 146.67, 143.71, 141.77, 137.30, 133.81,
131.99, 130.71, 129.54, 129.02, 127.34, 101.76, 68.65, 63.21, 63.03, 58.65; MS
(FAB+) m/z 355 (M+H)+, 377 (M+Na)+; Anal. Calcd. for C19H18N2O5: C,
64.40; H, 5.12; N, 7.91. Found: C, 64.57; H, 5.05; N, 7.89.
( )-1-[4,4-Bis-(hydroxymethyl)-5-methylene-cyclopent-2-enyl]-N4-
benzoylcytosine (19): For the desilylation of benzoylcytosine derivative
18, the reaction procedure was similar to that used to prepare 10 as a
1
white solid: m.p. 167–169◦C; yield 71%; H NMR (DMSO-d6, 300 MHz) δ
7.89–7.84 (dd, J = 5.4, 1.8 Hz, 2H), 7.75–7.71 (m, 2H), 7.45 (m, 2H), 7.25
(d, J = 7.9 Hz, 1H), 6.32 (dd, J = 5.4, 1.9 Hz, 1H), 6.26 (dd, J = 5.2, 1.7 Hz,
1H), 6.01 (t, J = 2.0 Hz, 1H), 5.57 (d, J = 7.8 Hz, 1H), 4.86 (t, J = 5.3 Hz,
1H), 4.76 (br s, 1H), 4.68 (d, J = 1.7 Hz, 2H), 3.69 (d, J = 9.6 Hz, 2H), 3.56
(d, J = 9.6 Hz, 2H); 13C NMR (CDCl3) δ 166.43, 165.32, 163.67, 161.70,
158.21, 153.40, 142.21, 140.23, 136.90, 133.16, 131.22, 130.54, 128.52,
109.32, 94.01, 68.27, 64.67, 64.02, 57.30; MS (FAB+) m/z 254 (M+H)+,

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H. Li et al.
FIGURE 1 Examples of antiviral olefinic carbonucleosides.
SCHEME 3 Synthesis of thymine & uracil nucleoside analogues.
376 (M+Na)+; Anal. Calcd. for C19H19N3O4: C, 64.58; H, 5.42; N, 11.89.
Found: C, 64.65; H, 5.38; N, 11.82. Figure 1, Scheme 3, Scheme 4
( )-1-[4,4-Bis-(hydroxymethyl)-5-methylene-cyclopent-2-enyl]thymine
(16): To the solution of benzoylthymine derivative 14 (79 mg, 0.214 mmol)
in MeOH (5 mL), NaOMe (0.5 mL, 1.0 M solution in MeOH) was added
and the mixture was stirred overnight at room temperature. Glacial acetic
acid (0.1 mL) was added to the mixture for neutralization. The mixture was
concentrated under reduced pressure and the residue was purified by silica
gel column chromatography (CH2Cl2/MeOH, 4:1) to give compound 16
(39 mg, 70%) as a white solid: yield 79%; m.p. 169–171◦C; UV (H2O) λmax
268.5.0 nm; 1H NMR (DMSO-d6, 300 MHz) δ 11.21 (br s, 1H), 7.11 (s, 1H),
6.29–6.24 (m, 2H), 6.01 (t, J = 1.9 Hz, 1H), 4.87 (t, J = 5.3 Hz, 1H), 4.79
(t, J = 5.4 Hz, 1H), 4.68 (s, 2H), 3.66 (d, J = 10.0 Hz, 2H), 3.53 (d, J =

Exomethylene Carbocyclic Nucleosides
1247
SCHEME 4 Synthesis of cytosine nucleoside analogue.
9.9 Hz, 2H), 1.89 (s, 3H); 13C NMR (DMSO-d6) δ 164.58, 154.43, 151.39,
142.50, 137.29, 133.98, 109.28, 110.79, 66.99, 66.32, 61.47, 59.32, 12.43; MS
(FAB+) m/z 265 (M+H)+, 287 (M+Na)+; Anal. Calcd. for C13H16N2O4 ·
0.5 MeOH: C, 57.84; H, 6.47; N, 9.99. Found: C, 57.74; H, 6.56; N, 10.09.
( )-1-[4,4-Bis-(hydroxymethyl)-5-methylene-cyclopent-2-enyl]uracil (17):
The uracil derivative was synthesized from 15 using a procedure similar to
that described for the preparation of 16: yield 72%; m.p. 163–165◦C; UV
(H2O) λmax 262.5.0 nm; 1H NMR (DMSO-d6, 300 MHz) δ 11.23 (br s, 1H),
7.35 (d, J = 8.0 Hz, 1H), 6.02 (m, 2H), 6.01 (s, 1H), 5.69 (d, J = 8.0 Hz,
1H), 4.91 (t, J = 5.2 Hz, 1H), 4.82 (t, J = 5.3 Hz, 1H), 4.69 (s, 2H), 3.68
(d, J = 10.1 Hz, 2H), 3.55 (d, J = 10.0 Hz, 2H); 13C NMR (DMSO-d6) δ
163, 87, 154.21, 151.98, 145.87, 136.93, 134.21, 101.22, 111.01, 67.31, 66.94,
62.44, 58.99; MS (FAB+) m/z 251 (M+H)+, 273 (M+Na)+; Anal. Calcd. for
C12H14N2O4 · 1.0 H2O: C, 53.66; H, 6.01; N, 10.44. Found: C, 53.70; H, 5.94;
N, 10.34.
( )-1-[4,4-Bis-(hydroxymethyl)-5-methylene-cyclopent-2-enyl]cytosine
(20): The cytosine derivative 20 was synthesized from 19 by a procedure
similar to that used in the preparation of 16: yield 70%; m.p. 166–168◦C;
1
UV (H2O) λmax 272.5.0 nm; H NMR (DMSO-d6, 300 MHz) δ 7.30 (d,
J = 7.8 Hz, 1H), 7.07 (br d, 2H), 6.36 (dd, J = 5.4, 1.8 Hz, 1H), 6.27 (dd,
J = 5.3, 1.6 Hz, 1H), 6.02 (br s, 1H), 5.56 (d, J = 7.8 Hz, 1H), 4.89
(t, J = 5.2 Hz, 1H), 4.79 (t, J = 5.3 Hz, 1H), 4.65 (d, J = 1.9 Hz, 2H),
3.65 (d, J = 9.9 Hz, 2H), 3.54 (d, J = 9.8 Hz, 2H); 13C NMR (DMSO-d6) δ
165, 21, 156.44, 153.97, 145.36, 134.51, 133.86, 93.58, 110.75, 67.76, 66.54,
63.02, 58.31; MS (FAB+) m/z 250 (M+H)+, 272 (M+Na)+; Anal. Calcd.

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H. Li et al.
for C12H15N3O3 · 1.0 H2O: C, 53.92; H, 6.41; N, 15.72. Found: C, 54.12; H,
6.29; N, 15.70
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