Synthesis of 2'-fluoro and 2',4'-dimethyl pyrimidine C-nucleoside analogues as potential anti-HCV agents

Article abstract of DOI:10.1080/15257771003705617

Stereoselective synthesis of novel 2'-fluoro and 2',4'-dimethyl carbocyclic pyrimidine C-nucleoside analogues using selective fluorination of an epoxide opening reaction is described. The key fluorinated intermediate 7 was prepared from the epoxide intermediate 5 via selective ring opening of the epoxide. Synthesis of isonucleosidic bases through the mesylate 7 and final deprotection provided the target carbocyclic pyrimidine C-nucleoside analogues. The synthesized compounds 15 and 18 were evaluated as inhibitors of the hepatitis C virus (HCV) in the Huh-7 cell line in vitro.

Full text of DOI:10.1080/15257771003705617

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Synthesis of 2′-Fluoro and 2′,4′-
Dimethyl Pyrimidine C-Nucleoside
Analogues as Potential Anti-HCV Agents
Lian Jin Liu a & Joon Hee Hong a
a BK21- Project Team, College of Pharmacy , Chosun University ,
Kwangju, Republic of Korea
Published online: 19 Apr 2010.
To cite this article: Lian Jin Liu & Joon Hee Hong (2010) Synthesis of 2′-Fluoro and 2′,4′-Dimethyl
Pyrimidine C-Nucleoside Analogues as Potential Anti-HCV Agents, Nucleosides, Nucleotides and
Nucleic Acids, 29:3, 216-227, DOI: 10.1080/15257771003705617
To link to this article: http://dx.doi.org/10.1080/15257771003705617
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Nucleosides, Nucleotides and Nucleic Acids, 29:216–227, 2010
Copyright ꢀC Taylor and Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257771003705617
SYNTHESIS OF 2ꢀ-FLUORO AND 2ꢀ,4ꢀ-DIMETHYL PYRIMIDINE
C-NUCLEOSIDE ANALOGUES AS POTENTIAL ANTI-HCV AGENTS
Lian Jin Liu and Joon Hee Hong
BK21- Project Team, College of Pharmacy, Chosun University, Kwangju, Republic of Korea
Stereoselective synthesis of novel 2ꢁ-fluoro and 2ꢁ,4ꢁ-dimethyl carbocyclic pyrimidine C-nucleoside
2
analogues using selective fluorination of an epoxide opening reaction is described. The key fluori-
nated intermediate 7 was prepared from the epoxide intermediate 5 via selective ring opening of the
epoxide. Synthesis of isonucleosidic bases through the mesylate 7 and final deprotection provided the
target carbocyclic pyrimidine C-nucleoside analogues. The synthesized compounds 15 and 18 were
evaluated as inhibitors of the hepatitis C virus (HCV) in the Huh-7 cell line in vitro.
Keywords Carbocyclic C-nucleoside; cis-fluorohydrin; anti-HCV agent; Krapcho’s pro-
cedure
INTRODUCTION
Carbocyclic C-nucleoside[1] is a unique class of nucleosides in which the
heterocycle is connected to a sugar moiety by a C-C bond instead of the C-N
bond of the carbocyclic nucleosides. C-Nucleosides have received consider-
able attention due to their chemical stability and interesting biological activ-
ities of naturally occurring compounds such as isocytidine,[2] thiazofurin,[3]
and 9-deazaadenosine.[4] Few examples of carbocyclic C-nucleosides[5] have
been synthesized, probably due to difficulties in synthesis.
Hepatitis C virus (HCV) infection[6] accounts for many hepatitis cases
worldwide and is also strongly associated with the development of cirrhosis
and hepatocellular carcinoma. The current standard therapy for chronic
HCV infection is interferon-α in combination with ribavirin, which is inade-
quate because of the low response rates as well as its side effects.[7]
The molecular virology of HCV has led to the identification of a num-
ber of antiviral molecular targets, including the NS5B RNA-dependent RNA
polymerase. Inhibition of this enzyme prevents HCV replication, making
Received 1 December 2009; accepted 16 February 2010.
Address correspondence to Joon Hee Hong, College of Pharmacy, Chosun University, Kwangju
501-759, Republic of Korea. E-mail: hongjh@chosun.ac.kr
216

2 ꢁ-C-Fluorinated Pyrimidine C-Nucleosides
217
NH2
NH2
N
N
O
N
O
N
HO
N3
H3C
O
HO
H3C
O
HO
OH
HO
OH
2'-C-Methyl-4'-azidocytidine (2)
2'-C-Methylcytidine (1)
NH2
N
O
N
HO
H3C
O
HO
F
2'-C-Methyl-2'-C-fluorocytidine (3)
FIGURE 1 Structure of potent anti-HCV agents.
this enzyme a crucial target for new anti-HCV agents. Many nucleoside ana-
logues have been evaluated as anti-HCV agents.[8] These nucleosides are
incorporated into viral RNA like a substrate after being converted to their
corresponding triphosphates, and act as chain terminators. Modification in
the vicinity of the 2ꢁ-hydroxy of the ribose in natural ribonucleosides can pro-
duce effective RNA chain terminators.[9] For example, replacement of the 2ꢁ-
hydrogen of natural ribonucleosides with a methyl group yields compounds
with excellent chain-terminating properties. 2ꢁ-C-Methylcytidine[10] 1 and 2ꢁ-
C-methyl-4’-azidocytidine[11] 2 are potent anti-HCV agents (Figure 1). More
recently, 2ꢁ-C-fluoro-2ꢁ-C-methylcytidine[12] 3 was designed as a hepatitis C
virus RNA-dependant RNA polymerase (HCV RdRp) inhibitor and showed
better inhibitory activity in the HCV replicon assay than 2ꢁ-C-methylcytidine,
with low cellular toxicity.
Based on these branched pyrimidine nucleoside analogues, we designed
fluorinated analogues of carbocyclic C-nucleosides as anti-HCV agents, fo-
cusing on the modifications of the 2ꢁ and 4ꢁ-positions of the potent 2ꢁ(β)-C
methyl carbodine nucleosides. Substitution at the 2ꢁ-position and further
modification of the 4ꢁ-position might impose favorable steric as well as elec-
tronic effects on the interaction with HCV polymerase.
As depicted in Scheme 1, we used the benzyloxymethylated cyclopen-
tenone intermediate 6 as starting material, which could be readily syn-
thesized via commercially available methylcyclopentenone 4 as described
in a previous report.[13] An attempt was made to methylate the enone
derivative 5 using a typical enolate alkylation procedure (LiHMDS/CH3I) to

218
L. J. Liu and J. H. Hong
BnO
H3C
BnO
i
ref. 13
O
CH3
O
CH3
O
CH3
6
4
5
ii
BnO
H3C
BnO
BnO
iii
iv
CH3
CH3
H3C
HO
H3C
BnO
X Y CH3
O
O
8
9
7a: X = OH, Y = H (40%)
7b: X = H, Y = OH (41%)
SCHEME 1 Synthesis of fluorinated epoxide intermediate 9. Reagents: i) LiHMDS, CH3I, THF, −78◦C;
ii) NaBH4, CeCI3·7H2O, MeOH, 0◦C; iii) m-CPBA, CH2CI2; iv) BnBr, NaH, DMF.
produce 6, which was subjected to Luche’s reduction conditions[14] (NaBH4,
CeCl3·7H2O), to provide enol derivatives 7a and 7b without stereoselectivity.
The correct configuration for these compounds could readily be assigned
through the NOE comparisons between proximal protons in the cyclopen-
tenol structures. On irradiation of C5(CH3)-H, relatively weak NOE was
observed at C1-H (0.6%) of 7a, compared to that of 7b (1.2%; Figure 2).
The allylic alcohol 7a was subjected to stereoselective epoxidation con-
ditions (m-CPBA, NaHCO3, CH2Cl2) to give epoxide derivative 8 as the only
product. The hydroxy functional group of 8 was protected with another
benzyl group under normal benzylation conditions (BnBr, NaH, DMF) to
provide a fully protected intermediate 9, which underwent a ring-opening
fluorination reaction with hydrofluoric acid in the presence of silicon flu-
orides and additives to provide cis-fluorohydrin in good yield using the
reported procedure.[15] For the synthesis of target fluorinated carbocyclic
pyrimidine C-nucleosides, we utilized the key intermediate 11 prepared from
methanesulfonylation of 10 with MsCl and TEA in anhydrous CH2Cl2. The
mesylate intermediate 11 was alkylated with diethyl malonate by nucleophilic
SN2 substitution conditions to give 12 with chiral inversion. Decarboethoxy-
lation of 12 using Krapcho’s condition (LiCl, DMSO, H2O) gave fluoroester
derivative 13. The isocytosine base was built by sequential treatment of 13
BnO
H3C
BnO
H3C
OH
H
H
0.6%
HO
7b
1.2%
7a
FIGURE 2 NOE differences of isomers 7a & 7b.

2 ꢁ-C-Fluorinated Pyrimidine C-Nucleosides
219
with lithium diisopropylamide (LDA), ethyl formate, and guanidine carbon-
ate in the presence of sodium ethoxide in ethanol to provide carbocyclic
isocytidine analogue 14. Debenzylation of 14 with palladium black[16] in 5%
formic acid afforded 15 in good yield (Scheme 2).
EtO2C
BnO
CO2Et
CH3
BnO
BnO
CH3
OH
CH3
ii
iii
i
H3C
BnO
H3C
BnO
9
H3C
BnO
OMs
F
F
F
12
10
11
iv
NH2
N
NH2
N
HN
CO2Et
CH3
HN
BnO
O
v
O
vi
BnO
H3C
BnO
HO
CH3
CH3
F
H3C
BnO
H3C
HO
F
13
F
14
15
SCHEME 2 Synthesis of target 2ꢁ-fluorinated isocytosine nucleoside analogue. Reagents: i) 47% HF,
(NH4)2SiF6, CsF; ii) MsCI, TEA, CH2CI2; iii) NaH, CH2(CO2Et)2, THF; iv) LiCI, DMSO; v) (a)
LDA/THF, HCOEt; (b) H2NC(=NH)NH2.carbonate, NaOEt/EtOH; vi) Pd black, 5% HCO2H in MeOH,
reflux overnight.
Under similar conditions, synthesis of the carbocyclic isouridine ana-
logue 18 was prepared from the same intermediate 13 as describe for isocy-
tidine.[17] Generation of enolate with lithium diisopropylamide in THF and
formylation with ethyl formate gave the corresponding anion, which was
methylated with iodomethane in DMF to give the methyl enol ether deriva-
tive 16. Treatment of 16 with urea in the presence of potassium tert-butoxide
in THF provided isouridine analogue 17. Debenzylation was performed by
a similar procedure as described for 15 to provide the target isouridine
derivative 18 (Scheme 3).
The synthesized compounds were tested for anti-HCV activity using an in
vitro assay composed of a human hepatocarcinoma cell line (Huh-7) sup-
porting multiplication of an HCV replicon named NK-R2AN.[18] But unlike
2ꢁ-fluoro-2ꢁ-C-methylcytidine, tested compounds 15 and 18 demonstrated no
activity or cytotoxicity in the HCV assay.
In summary, the present ring-opening fluorination of epoxide using
hydrofluoric acid offers a convenient procedure for the synthesis of cis-
fluorhydrins. On the basis of potent anti-HCV activity of 2ꢁ-modified nucleo-
sides, we have designed and synthesized 2ꢁ-fluoro-2ꢁ,4ꢁ-dimethyl pyrimidine
C-nucleoside derivatives. Also, the synthesis of other analogues (A,G,T) is in
progress and will be reported elsewhere.

220
L. J. Liu and J. H. Hong
OCH3
H
CO2Et
CH3
CO2Et
i
BnO
BnO
CH3
H3C
BnO
H3C
BnO
F
F
ii
13
16
O
O
HN
NH
HN
NH
O
iii
BnO
O
HO
CH3
CH3
H3C
BnO
H3C
HO
F
F
17
18
SCHEME 3 Synthesis of target 2ꢁ-flourinated isouracil nucleoside analogue. Reagents: i) (a) LDA/THF,
HCOEt; (b) Mel, DMF; ii) NH2CONH2, t-BuOK, THF; iii) Pd black, 5% HCO2H in MeOH, reflux
overnight.
EXPERIMENTAL
Melting points were determined on a Mel-temp II laboratory device
and are uncorrected. NMR spectra were recorded on a JEOL JNM-AL300
Fourier transform; 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). Ultraviolet (UV) spectra
were obtained on a Beckman DU-7 spectrophotometer. The elemental
analyses were performed using a Perkin-Elmer 2400 analyzer (Perkin-Elmer,
Norwalk, CT, USA). Thin layer chromatography (TLC) was performed on
Uniplates (silica gel) purchased from Analtech Co. (7558, Newark, DE,
USA). All reactions were performed under an atmosphere of nitrogen un-
less specified. Dry dichloromethane, benzene, and pyridine were obtained
by distillation from CaH2. Dry tetrahydrofuran (THF) was obtained by
distillation from Na and benzophenone immediately prior to use.
( )-5-Benzyloxymethyl-2,5-dimethyl-cyclopent-2-enone (6): To a stirred
solution of lithium hexamethyldisilazane (LiHMDS, 10.32 mL, 1.0 M solu-
tion in THF) in tetrahydrofuran (25 mL), a solution of compound 5 (1.116
g, 5.16 mmol) in tetrahydrofuran (8 mL) was added at –78◦C. After stir-
ring for 1.5 hours at the same temperature, the reaction temperature was
elevated to –20◦C and stirred for an additional 1 hour at the same temper-
ature. Iodomethane (1.1 g, 7.74 mmol) was then added to this mixture at
–78◦C and stirred for 3 hours. The mixture was warmed to –20◦C and the
mixture was stirred for an additional 2 hours. The reaction was quenched

2 ꢁ-C-Fluorinated Pyrimidine C-Nucleosides
221
with addition of a saturated ammonium chloride solution (8.0 mL). The
resulting mixture was warmed to room temperature, poured into water (100
mL) and extracted with ethyl acetate (100 mL). The organic layer was dried
over anhydrous magnesium sulfate, filtered, concentrated in vacuo, and pu-
rified by column chromatography (EtOAc/hexane, 1:25) to give compound
6 (927 mg, 78%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 7.35–7.30
(m, 5H), 6.98 (m, 1H), 4.54 (s, 2H), 4.53 (s, 2H), 3.51 (d, J = 6.2 Hz, 1H),
3.42 (d, J = 6.2 Hz, 1H), 1.98–1.94 (m, 2H), 1.77 (s, 3H), 1.32 (s, 3H); 13C
NMR (CDCl3) δ 207.3, 152.3, 140.1, 137.9, 128.3, 127.9, 127.1, 126.4, 74.4,
72.2, 58.8, 30.2, 12.3, 10.4; Anal. Calcd. for C15H18O2: C, 78.23; H, 7.88.
Found: C, 78.32; H, 7.96.
(rel)-(1S,5S)-5-Benzyloxymethyl-2,5-dimethyl-cyclopent-2-enol (7a) and
(rel)-(1R,5S)-5-benzyloxymethyl-2,5-dimethyl-cyclopent-2-enol (7b): CeCl3·
7H2O (6.26 g, 16.8 mmol) was added to a solution of 6 (2.54 g, 11.04 mmol)
in MeOH (65 mL) at 0◦C and stirred for 30 minutes. Then, NaBH4 (832
mg, 22.0 mmol) was carefully added to the mixture and stirred for 3 hours
at room temperature. The reaction mixture was quenched by addition of
acetic acid (3.6 mL) and concentrated under reduced pressure. The result-
ing residue was dissolved in H2O (120 mL) and extracted with EtOAc (120
mL) two times. The organic layer was sequentially washed with sat. NaHCO3
(100 mL) and brine (100 mL). The organic phase was dried over anhydrous
magnesium sulfate, filtered, concentrated in vacuo, and purified by column
chromatography (EtOAc/hexane, 1:15) to give compounds 7a (1.02 g, 40%)
1
and 7b (1.05 g, 41%) as syrups, respectively: data for 7a; H NMR (CDCl3,
300 MHz) δ 7.36 (m, 5H), 5.47 (m, 1H), 4.59 (s, 2H), 4.01 (s, 1H), 3.43 (d, J
= 6.6 Hz, 1H), 3.39 (d, J = 6.6 Hz, 1H), 2.39–2.24 (m, 2H), 1.69 (s, 3H), 1.19
(s, 3H); 13C NMR (CDCl3) δ 140.6, 137.9, 127.6, 127.1, 126.9, 125.4, 85.3,
76.2, 73.1, 51.8, 34.2, 13.4, 10.7; Anal. Calcd. for C15H20O2: C, 77.55; H, 8.68.
Found: C, 77.47; H, 8.53; data for 7b; 1H NMR (CDCl3, 300 MHz) δ 7.36–7.34
(m, 5H), 5.50 (m, 1H), 4.58 (s, 2H), 4.12 (s, 1H), 3.42 (dd, J = 10.2, 4.8 Hz,
2H), 2.38–2.26 (m, 2H), 1.59 (s, 3H), 1.21 (s, 3H); 13C NMR (CDCl3) δ 140.9,
138.0, 127.5, 127.0, 126.4, 125.2, 86.1, 77.0, 72.2, 52.2, 35.8, 14.7, 11.1; Anal.
Calcd. for C15H20O2: C, 77.55; H, 8.68. Found: C, 77.66; H, 8.70.
(rel)-(1S,2R,3R,5S)-3-Benzyloxymethyl-1,3-dimethyl-6-oxa-bicyclo[3.1.0]
hexan-2-ol (8): m-Chloroperbenzoic acid (3.64 g, 15.6 mmol, 77% purity)
was added to a solution of 7a (2.78 g, 11.96 mmol) in anhydrous CH2Cl2
(58 mL) at 0◦C. The solution was stirred at 0◦C for 1 hours and stirred for
additional 2 hours at room temperature. A saturated NaHCO3 solution (120
mL) was added to the reaction mixture and extracted with EtOAc (120 mL)
two times. The combined organic layer was washed with brine, dried over
anhydrous magnesium sulfate, filtered, concentrated in vacuo, and purified
by column chromatography (EtOAc/hexane, 1:10) to give compound 8
1
(2.46 g, 83%) as an oil: H NMR (CDCl3, 300 MHz) δ 7.37–7.35 (m, 5H),
4.57 (s, 2H), 3.99 (s, 1H), 3.47 (d, J = 7.2 Hz, 1H), 3.34 (d, J = 7.3 Hz, 1H),
3.12 (m, 1H), 1.78 (m, 1H), 1.62 (m, 1H), 1.52 (s, 3H), 1.18 (s, 3H); 13C

222
L. J. Liu and J. H. Hong
NMR (CDCl3) δ 137.8, 127.6, 127.2, 126.7, 83.3, 76.7, 75.3, 66.2, 60.1, 28.7,
24.2, 17.2, 14.2; Anal. Calcd. for C15H20O3: C, 72.55; H, 8.12. Found: C,
72.42; H, 8.05.
(rel)-(1S,2R,3S,5S)-2-Benzyloxy-3-benzyloxymethyl-1,3-dimethyl-6-oxa-
bicyclo[3.1.0]hexane (9): NaH (312 mg, 13.0 mmol) was slowly added
to a solution of epoxide derivative 8 (2.49 g, 10.75 mmol) in dry DMF
(30 mL) at 0◦C. After 30 minutes, benzyl bromide (2.02 g, 11.82 mmol)
was added, and the reaction mixture was stirred for 4 hours at room
temperature. The mixture was quenched by adding saturated ammonium
chloride (2.5 mL) and concentrated under reduced pressure. The residue
was dissolved in water (100 mL) and extracted with ethyl acetate (100 mL)
two times. The combined organic layer was washed with brine, dried over
anhydrous MgSO4, filtered, and evaporated. The filtrate was concentrated
under reduced pressure and the residue was purified by silica gel column
chromatography (EtOAc/hexane, 1:30) to give 9 (2.73 g, 75%) as a syrup.
1H NMR (CDCl3, 300 MHz) δ 7.36–7.34 (m, 10H), 4.63 (s, 2H), 4.60 (s,
2H), 3.41 (d, J = 7.0 Hz, 1H), 3.32 (d, J = 7.1 Hz, 1H), 3.21 (s, 1H), 2.61
(m, 1H), 1.66–1.54 (m, 2H), 1.38 (s, 3H), 1.19 (s, 3H); 13C NMR (CDCl3)
δ 137.8, 137.6, 127.9, 127.5, 127.1, 126.8, 126.6, 89.8, 78.2, 76.5, 74.2, 65.9,
59.4, 28.7, 23.6, 18.0, 13.6; Anal. Calcd. for C22H26O3: C, 78.07; H, 7.74.
Found: C, 77.94; H, 7.68.
(rel)-(1S,2S,3R,4S)-3-Benzyloxy-4-benzyloxymethyl-2-fluoro-2,4-dimethyl-
cyclopentanol (10): 47% Hydrofluoric acid (0.154 mL, 3.6 mmol) was added
to a mixture of (NH4)2SiF6 (1.06 g, 6.0 mmol), CsF (182 mg, 1.2 mmol),
and epoxide 9 (406 mg, 1.2 mmol) in 1,2-dichloroethane (15 mL) at 0◦C,
and the mixture was stirred for 5 hours at the same temperature. A saturated
NaHCO3 solution (40 mL) was slowly added and the whole mixture was
extracted with diethyl ether (70 mL) two times. The combined organic
layer was washed with brine, dried over anhydrous MgSO4, filtered, and
evaporated. The filtrate was concentrated under vacuum and the residue
was purified by silica gel column chromatography (EtOAc/hexane, 1:10)
1
to give alcohol 10 (193 mg, 45%) as a colorless oil: H NMR (CDCl3, 300
MHz) δ 7.37–7.31 (m, 10H), 4.67 (s, 2H), 4.61 (s, 2H), 3.69 (ddd, J = 3.2,
6.4, 18.6 Hz, 1H), 3.48 (d, J = 20.2 Hz, 1H), 3.21 (dd, J = 8.6, 12.4 Hz, 2H),
1.71 (dd, J = 6.4, 12.0 Hz, 1H), 1.61 (dd, J = 8.6, 12.0 Hz, 1H), 1.38 (d, J =
20.6 Hz, 3H), 1.15 (s, 3H); 13C NMR (CDCl3) δ 138.1, 137.8, 128.7, 127.9,
127.5, 127.1, 126.7, 126.2, 103.2 (d, J = 184.4 Hz), 86.4 (d, J = 21.2 Hz),
77.1, 74.8, 74.1, 72.4 (d, J = 20.2 Hz), 28.8, 26.4, 15.4 (d, J = 22.8 Hz), 13.4;
Anal. Calcd. for C22H27FO3: C, 73.72; H, 7.59. Found: C, 73.62; H, 7.63.
(rel)-(1S,2S,3R,4S)-Methanesulfonic acid-3-benzyloxy-4-benzyloxymethyl-
2-fluoro-2,4-dimethyl-cyclopentanyl ester (11): MsCl (0.59 g, 5.15 mmol) was
added to a solution of the alcohol 10 (1.68 g, 4.68 mmol) and triethylamine
(1.5 mL) in anhydrous CH2Cl2 (40 mL) at 0◦C. The mixture was stirred
for 5 hours at room temperature, and quenched by a saturated NaHCO3

2 ꢁ-C-Fluorinated Pyrimidine C-Nucleosides
223
solution (1.0 mL). The mixture was poured into excess cold water (100 mL)
and extracted with EtOAc (100 mL) two times. The combined organic layer
was washed with brine, dried over anhydrous magnesium sulfate and filtered.
The filtrate was concentrated in vacuo, and the residue was purified by silica
gel column chromatography (EtOAc/hexane, 1:5) to give mesylate 11 (1.59
g, 78%) as a syrup: 1H NMR (CDCl3, 300 MHz) δ 7.36–7.32 (m, 10H), 5.12
(ddd, J = 3.3, 6.8, 19.2 Hz, 1H), 4.70 (s, 2H), 4.63 (s, 2H), 3.54 (d, J = 19.8
Hz, 1H), 3.33 (dd, J = 8.2, 12.2 Hz, 2H), 3.01 (s, 3H), 1.73 (dd, J = 6.2, 12.2
Hz, 1H), 1.63 (dd, J = 8.4, 12.1 Hz, 1H), 1.34 (d, J = 20.2 Hz, 3H), 1.14
(s, 3H); 13C NMR (CDCl3) δ 138.0, 137.7, 128.5, 128.0, 127.8, 127.4, 126.9,
126.4, 98.1 (d, J = 182.8 Hz), 85.2 (d, J = 21.8 Hz), 78.1, 76.8, 75.1, 68.8 (d,
J = 19.4 Hz), 37.4, 29.4, 25.6, 15.7 (d, J = 21.4 Hz), 12.1.
(rel)-(1S,2S,3R,4S)-2-[3-Benzyloxy-4-benzyloxymethyl-2-fluoro-2,4-dimet
hyl-cyclopentanyl] malonic acid diethyl ester (12): Diethyl malonate (4.5 g,
28.12 mmol) in THF (60 mL) was added to a solution of NaH (0.45 g, 18.75
mmol) in THF (50 mL) under a nitrogen atmosphere at 0◦C and stirred
for 1.5 hours at room temperature. Mesylate 11 (3.32 g, 7.6 mmol) in THF
(50 mL) was slowly added to the reaction mixture and stirred overnight
at room temperature. The mixture was quenched by the addition of water
(150 mL) and extracted with ethyl acetate (150 mL) twice. The combined
organic layer was washed with brine, dried over anhydrous magnesium
sulfate and filtered. The filtrate was concentrated in vacuo, and the residue
was purified by silica gel column chromatography (EtOAc/hexane, 1:15)
1
to give 12 (2.62 g, 69%) as a colorless oil: H NMR (CDCl3, 300 MHz) δ
7.36–7.31 (m, 10H), 4.73 (s, 2H), 4.69 (s, 2H), 4.14 (m, 4H), 3.35 (dd, J =
8.0, 12.4 Hz, 2H), 3.19 (d, J = 5.8 Hz, 1H), 3.12–3.08 (m, 2H), 1.49 (d, J =
20.2 Hz, 3H), 1.39–1.30 (m, 8H), 1.16 (s, 3H); 13C NMR (CDCl3) δ 170.4,
170.1, 138.1, 137.9, 128.9, 128.6, 128.1, 127.8, 127.4, 126.9, 96.2 (d, J =
185.2 Hz), 89.4 (d, J = 20.4 Hz), 77.4, 76.6, 75.1, 68.8 (d, J = 21.4 Hz), 60.3,
43.2, 30.2, 28.8 (d, J = 23.2 Hz, 1H), 21.3, 17.3 (d, J = 20.4 Hz), 15.3, 13.2;
Anal. Calcd. for C29H37FO6: C, 69.58; H, 7.45. Found: C, 69.50; H, 7.39.
(rel)-(1S,2S,3R,4S)-[3-Benzyloxy-4-benzyloxymethyl-2-fluoro-2,4-dimethyl-
cyclopentanyl] acetic acid ethyl ester (13): LiCl (470 mg, 11.1 mmol) and
H2O (2 drops) were added to a solution of 12 (1.85 g, 3.7 mmol) in DMSO
(10 mL). The mixture was stirred overnight at 170◦C. After cooling to
room temperature, the reaction mixture was poured into H2O (80 mL)
and extracted with diethyl ether (80 mL) two times. The combined organic
layer was washed with brine, dried over anhydrous magnesium sulfate, and
filtered. The filtrate was concentrated in vacuo, and the residue was purified
by silica gel column chromatography (EtOAc/hexane, 1:15) to give 13 (1.2
1
g, 76%) as a colorless syrup: H NMR (CDCl3, 300 MHz) δ 7.36–7.33 (m,
10H), 4.70 (s, 2H), 4.67 (s, 2H), 4.12 (q, J = 7.2 Hz, 2H), 3.18–3.09 (m,
3H), 2.44–2.36 (m, 1H), 2.17 (dd, J = 7.4, 12.6 Hz, 2H), 1.46 (d, J = 19.2
Hz, 3H), 1.37–1.29 (m, 2H), 1.24 (t, J = 7.2 Hz, 3H), 1.14 (s, 3H); 13C NMR

224
L. J. Liu and J. H. Hong
(CDCl3) δ 171.1, 137.9, 127.5, 128.8, 128.4, 128.1, 127.7, 127.3, 126.5, 98.6
(d, J = 187.6 Hz), 90.8 (d, J = 20.0 Hz), 76.8, 75.2, 73.4, 60.1 32.6 (J =
19.8 Hz), 29.3, 28.1, 24.5, 17.5 (J = 23.6 Hz), 15.2, 12.5; Anal. Calcd. for
C26H33FO4: C, 72.87; H, 7.76. Found: C, 72.93; H, 7.82.
(rel)-(1S,2S,3R,4S)-1-(3-Benzyloxy-4-benzyloxymethyl-2-fluoro-2,4-dimeth
yl-cyclopentan-1-yl) isocytosine (14): A solution of 13 (1.36 g, 3.18 mmol
in THF 20 mL) was slowly added to a solution of lithium diisopropylamide
(4.8 mL, 1 M in hexane) in THF (12 mL) at –78◦C under a nitrogen atmo-
sphere. The mixture was stirred at the same temperature for 1.5 hours and
ethyl formate (0.933 mg, 12.6 mmol) was added to the mixture and stirred
overnight at room temperature. The mixture was poured into saturated
NH4Cl solution (100 mL) and extracted with EtOAc (2 × 100 mL). The
combined organic layer was washed with brine, dried over MgSO4, and
evaporated to dryness to obtain a crude residue. The residue was dissolved
in absolute ethanol (10 mL). To a solution of guanidine carbonate (1.62 g,
9.0 mmol) in EtOH (20 mL), EtONa/EtOH (21% solution, 3.88 mL, 12.0
mmol) was added and stirred for 2 hours. To this mixture, the above-
obtained residue in ethanol (10 mL) was added and refluxed overnight. The
mixture was filtered, concentrated in vacuo, and the residue was purified by
silica gel column chromatography (EtOAc/hexane/MeOH, 4:1:0.1) to give
14 (847 mg, 59%) as a white solid: m.p. 143–145◦C; 1H NMR (DMSO-d6, 300
MHz) δ 10.88 (br s, 1H), 7.37–7.33 (m, 10H), 7.21 (s, 1H), 6.49 (br s, 2H),
4.75 (s, 2H), 4.69 (s, 2H), 3.35 (d, J = 8.2 Hz, 1H), 3.21 (d, J = 8.2 Hz, 1H),
3.11 (d, J = 19.0 Hz, 1H), 2.57 (ddd, J = 3.4, 8.2, 18.8 Hz, 1H), 1.51–1.40
(m, 5H), 1.16 (s, 1H); 13C NMR (DMSO-d6) δ 163.5, 155.2, 138.7, 138.3,
134.7, 127.9, 127.6, 115.3, 95,4 (J = 184.4 Hz), 89.6 (J = 19.8 Hz), 77.3,
75.7, 36.7 (J = 20.6 Hz), 29.4, 22.1, 18.1 (J = 21.8 Hz), 14.2; Anal. Calcd.
for C26H30FN3O3: C, 69.16; H, 6.70; N, 9.31. Found: C, 69.20; H, 6.61; N,
9.25.
(rel)-(1S,2S,3R,4S)-1-(3-Hydroxy-4-hydroxymethyl-2-fluoro-2,4-dimethyl-
cyclopentan-1-yl) isocytosine (15): Pd black (98% Pd, 10 mg, catalytic
amount) was added to a stirred solution of 14 (115 mg, 0.254 mmol) in
5% formic acid in MeOH (20 mL), and the reaction mixture was refluxed
overnight. The mixture was filtered through a Celite pad and washed with
MeOH several times. After solvent evaporation, the residue was purified
by silica gel column chromatography (CH2Cl2/MeOH, 5:1) to give 15 (56
mg, 82%) as a white solid: m.p. 198–200◦C; UV (H2O) λmax 289.5 nm; 1H
NMR (DMSO-d6, 300 MHz) δ 12.43 (s, 1H), 8.29 (br s, 2H), 7.33 (s, 1H),
5.07 (d, J = 4.6 Hz, 1H), 4.90 (t, J = 5.0 Hz, 1H), 3.53–3.41 (m, 3H), 2.52
(ddd, J = 3.6, 8.4, 19.2 Hz, 1H), 1.49–1.39 (m, 5H), 1.13 (s, 1H); 13C NMR
(DMSO-d6) δ 161.3, 153.1, 146.2, 134.7, 116.5, 96.7 (J = 179.8 Hz), 85.2
(J = 21.2 Hz), 35.6 (J = 21.2 Hz), 33.3, 22.6, 17.2 (J = 24.2 Hz), 13.2; Anal.
Calcd. for C12H18FN3O3(+1.0 MeOH): C, 51.47; H, 7.31; N, 13.85. Found:
C, 51.53; H, 7.33; N, 13.79.

2 ꢁ-C-Fluorinated Pyrimidine C-Nucleosides
225
(rel)-(1S,2S,3R,4S)-1-(3-Benzyloxy-4-benzyloxymethyl-2-fluoro-2,4-dimeth
yl-cyclopentan-1-yl) 3-methoxy-acrylic acid ethyl ester (16): A solution of 13
(1.35 g, 3.156 mmol) in THF (25 mL) was added to a solution of lithium
diisopropylamide (LDA, 2M in hexane, 2.352 mL) in THF (13 mL) at
–78◦C under nitrogen atmosphere. The mixture was stirred at the same
temperature for 1 hour and then ethyl formate (933 mg, 12.6 mmol)
was added. After being stirred at −78◦C for an additional 1.5 hours, the
mixture was warmed up to room temperature and stirred overnight. The
resulting mixture was evaporated to dryness and the residue was dissolved
in dry DMF (10.0 mL) and iodomethane (1.34 g, 9.48 mmol) was added
slowly to the mixture under a nitrogen atmosphere. After being stirred for
5 hours at room temperature, the mixture was concentrated under reduced
pressure. The residue was dissolved in water (100 mL) and extracted with
ethyl acetate (100 mL) twice. The combined organic layers were washed
with brine, dried over MgSO4 and concentrated in vacuo, and the residue
was purified by silica gel column chromatography (EtOAc/hexane, 1:15)
1
to give 16 (920 mg, 62%) as a colorless syrup: H NMR (CDCl3, 300 MHz)
δ 7.36–7.33 (m, 11H), 4.69 (s, 2H), 4.63 (s, 2H), 4.13 (q, J = 7.2 Hz, 2H),
3.35–3.27 (m, 5H), 3.12 (d, J = 19.0 Hz, 1H), 1H), 2.49 (dd, J = 6.2, 18.8
Hz, 1H), 1.51–1.45 (m, 4H), 1.34 (d, J = 8.0 Hz, 1H), 1.24 (t, J = 7.2 Hz,
3H), 1.13 (s, 3H); 13C NMR (CDCl3) δ 166.8, 154.2, 138.2, 137.6, 127.9,
127.2, 126.3, 110.2, 95.4 (J = 181.8 Hz), 90.4 (J = 22.1 Hz), 77.8, 73.6, 54.6,
61.7, 34.2 (J = 20.2 Hz), 29.2, 18.3 (J = 24.2 Hz), 14.1, 12.7; Anal. Calcd.
for C28H35FO5: C, 71.47; H, 7.50. Found: C, 71.53; H, 7.47.
(rel)-(1S,2S,3R,4S)-1-(3-Benzyloxy-4-benzyloxymethyl-2-fluoro-2,4-dimeth
yl-cyclopentan-1-yl) isouracil (17): A mixture of urea (240 mg, 3.996 mmol)
and KOtBu (443 mg, 3.996 mmol) in THF (15 mL) was stirred for 1.5 hours
at room temperature and then 16 (937 mg, 1.992 mmol) in THF (15 mL)
was added to the mixture under anhydrous conditions. The mixture was
refluxed overnight and evaporated under reduced pressure. The residue
was purified by silica gel column chromatography (EtOAc/hexane, 1:3) to
give 17 (297 mg, 33%) as a white solid: m.p. 165–167◦C; 1H NMR (DMSO-d6,
300 MHz) δ 11.16 (br s, 1H), 10.75 (br s, 1H), 7.35–7.32 (m, 10H), 6.96 (s,
1H), 4.70 (s, 2H), 4.64 (s, 2H), 3.40 (d, J = 8.8 Hz, 1H), 3.31 (d, J = 8.9 Hz,
1H), 3.14 (d, J = 19.4 Hz, 1H), 2.51 (dd, J = 6.8, 19.8 Hz, 1H), 1.53–1.42
(m, 5H), 1.17 (d, J = 19.2 Hz, 1H); 13C NMR (DMSO-d6) δ 164.5, 151.4,
143.9, 137.5, 128.9, 127.5, 126.3, 110.2, 95.2 (J = 182.8 Hz), 90.2, 89.9 (J =
19.8 Hz), 77.3, 75.2, 73.8, 35.3 (J = 20.0 Hz), 29.3, 21.2, 17.3 (J = 21.8 Hz),
14.3; Anal. Calcd. for C26H29FN2O4: C, 69.01; H, 6.46; N, 6.19. Found: C,
69.09; H, 6.40; N, 6.23.
(rel)-(1S,2S,3R,4S)-1-(3-Hydroxy-4-hydroxymethyl-2-fluoro-2,4-dimethyl-
cyclopentan-1-yl) isouracil (18): Isouridine derivative 18 was prepared from
17 using a similar procedure described for 15: yield 88%; m.p. 208–210◦C:
1
UV (H2O) λmax 262.0 nm; H NMR (DMSO-d6, 300 MHz) δ 11.13 (br s,

226
L. J. Liu and J. H. Hong
1H), 10.73 (br s, 1H), 7.03 (s, 1H), 5.19 (d, J = 4.6 Hz, 1H), 4.86 (t, J = 4.4
Hz, 1H), 3.60–3.53 (m, 2H), 3.43 (d, J = 9.5 Hz, 1H), 2.51 (ddd, J = 3.2,
8.9, 19.6 Hz, 1H), 1.51–1.42 (m, 3H), 1.15 (d, J = 19.2 Hz, 1H); 13C NMR
(DMSO-d6) δ 165.0, 151.2, 147.3, 114.8, 97.2 (J = 184.4 Hz), 85.6 (J = 21.0
Hz), 68.2, 35.2 (J = 18.8 Hz), 32.7, 21.3, 17.1 (J = 23.1 Hz), 13.8; Anal.
Calcd. for C12H17FN2O4 (+ 1.0 H2O): C, 49.65; H, 6.59; N, 9.65. Found: C,
49.73; H, 6.63; N, 9.70.
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