A new route for the synthesis of 4-amino-5-fluoro-7-(2′-Deoxy- 2′-Fluoro-2′-C-methyl-β-d-ribofuranosyl)-1 H-pyrrolo[2,3-D] pyrimidine

Article abstract of DOI:10.1080/15257770.2013.797994

A new route for the synthesis of the anti-HCV nucleoside analogue, 4-amino-5-fluoro-7-(2′-deoxy-2′-fluoro-2′-C-methyl-β-d- ribofuranosyl)-1H-pyrrolo[2,3-d]pyrimidine 1, was developed.

Full text of DOI:10.1080/15257770.2013.797994

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A New Route for the Synthesis
of 4-Amino-5-Fluoro-7-(2′-
Deoxy-2′-Fluoro-2′-C-Methyl-β-
d- Ribofuranosyl)-1H-Pyrrolo[2,3-
D]Pyrimidine
Weidong Hu a b , Qinghua Yang a , Shuyang Wang a , Gang Huang a ,
Yueteng Zhang a , Jingjing Dong a , Jinfeng Kang a , Chuanjun Song a
& Junbiao Chang a
a College of Chemistry and Molecular Engineering, Zhengzhou
University , Zhengzhou , Henan Province , P. R. China
b Henan Key Laboratory of Fine Chemicals, Henan Academy of
Science , Zhengzhou , Henan Province , P. R. China
Published online: 07 Jun 2013.
To cite this article: Weidong Hu , Qinghua Yang , Shuyang Wang , Gang Huang , Yueteng Zhang ,
Jingjing Dong , Jinfeng Kang , Chuanjun Song & Junbiao Chang (2013) A New Route for the
Synthesis of 4-Amino-5-Fluoro-7-(2′-Deoxy-2′-Fluoro-2′-C-Methyl-β-d- Ribofuranosyl)-1H-
Pyrrolo[2,3-D]Pyrimidine, Nucleosides, Nucleotides and Nucleic Acids, 32:7, 389-395, DOI:
10.1080/15257770.2013.797994
To link to this article: http://dx.doi.org/10.1080/15257770.2013.797994
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Nucleosides, Nucleotides and Nucleic Acids, 32:389–395, 2013
Copyright ꢀC Taylor and Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770.2013.797994
A NEW ROUTE FOR THE SYNTHESIS OF 4-AMINO-5-
FLUORO-7-(2ꢀ-DEOXY-2ꢀ-FlUORO-2ꢀ-C-METHYL-β-D-
RIBOFURANOSYL)-1H-PYRROLO[2,3-D]PYRIMIDINE
Weidong Hu,1,2 Qinghua Yang,1 Shuyang Wang,1 Gang Huang,1
Yueteng Zhang,1 Jingjing Dong,1 Jinfeng Kang,1 Chuanjun Song,1
and Junbiao Chang1
1College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou,
Henan Province, P. R. China
2Henan Key Laboratory of Fine Chemicals, Henan Academy of Science, Zhengzhou, Henan
Province, P. R. China
A new route for the synthesis of the anti-HCV nucleoside analogue, 4-amino-5-fluoro-7-(2ꢁ-
2
deoxy-2ꢁ-fluoro-2ꢁ-C-methyl-β-d-ribofuranosyl)-1H-pyrrolo[2,3-d]pyrimidine 1, was developed.
Keywords 2ꢁ-Deoxy-2ꢁ-fluoro-2ꢁ-C-methyl nucleoside; Vorbru¨ggen procedure; anti-HCV
activity
INTRODUCTION
2ꢁ-Deoxy-2ꢁ-fluoro-2ꢁ-C-methyl nucleoside analogues are known for their
promising activity against HCV replication.[1] In an earlier article, we
reported the synthesis and anti-HCV activity study of 4-amino-5-fluoro-
7-(2ꢁ-deoxy-2ꢁ-fluoro-2ꢁ-C-methyl-β-d-ribofuranosyl)-1H -pyrrolo[2,3-d]pyri-
midine 1.[2] The key step of our synthesis was a Mitsunobu condensation
between 4-chloro-5-fluoro-pyrrolo[2,3-d]pyrimidine and the 3ꢁ, 5ꢁ-dibenzoyl-
protected 2-deoxy-2-fluoro-2-C-methylribofuranose.[2] While successful, a
disappointing 15% yield of the desired β-anomer was obtained. Recently,
Schinazi and coworkers found that the triphosphate of compound 1 demon-
strated inhibitory effects against both wild type and S282T mutant HCV
polymerases.[3] Therefore, a more efficient route for the synthesis of 1 was
desirable in order to evaluate its biological activities further. Herein, we
Received 13 March 2013; accepted 17 April 2013.
We are grateful to the National Natural Science Foundation of China (#21172202) for financial
support.
Address correspondence to Chuanjun Song; Junbiao Chang, College of Chemistry and Molec-
ular Engineering, Zhengzhou University, Zhengzhou, Henan Province 450001, P. R. China. E-mail:
chjsong@zzu.edu.cn; changjunbiao@zzu.edu.cn
389

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W. Hu et al.
report an alternative synthetic route to compound 1, featuring a modified
Vorbru¨ggen procedure[4] for sugar-base condensation (Scheme 1).
SCHEME 1 Reagent and conditions: (A) Ac2O, Et3N, DCM, r.t., 3 hours, 83%; (B) BSA, TMSOTf,
CH3CN, 80◦C, 2 hours, 45%; (C) Et3N/MeOH, r.t., 24 hours, 90%; (D) Dess–Martin periodinane, DCM,
0◦C – r.t.; (E) MeMgBr, Et2O, −78◦C, 8 hours, 65% over the two steps; (F) DAST, DCM, −20◦C, 2 hours,
41%; (G) BBr3, DCM, −78◦C, 3 hours, 85%; (H) NH4OH, 1,4-dioxane, 120◦C, 14 hours, 95%.
As shown in Scheme 1, acylation of the known 3,5-di-O-benzyl-β-D-
ribofuranose 2[5] gave the β-anomer 3, which was coupled with 4-chloro-
5-fluoro-pyrrolo[2,3-d]pyrimidine 4 under a modified Vorbru¨ggen proce-
dure[4] to give the β-anomer 5 in 45% isolated yield. The corresponding
α-anomer of 5 was not observed. Transesterification of 5 with basic methanol
afforded 6 in 90% yield. The oxidation reaction of the 2ꢁ-hydroxyl group of 6
with Dess–Martin periodinane in dichloromethane[6,7] proceeded smoothly
and gave 7 as a single spot on tlc upon completion. However, it was highly
sensitive to the air while neat. It was found that 7 rapidly decomposed in
contact with air after evaporation of the solvent on rotary evaporator and ap-
peared as a stripe at the bottom of tlc plate, thus was handled under nitrogen
and used directly for the next step without further purification. Stereospe-
cific installation of a methyl group on the α face of the ribofuranose was
accomplished by reaction of 7 with methylmagnesium bromide in diethyl
ether and resulted in the formation of compound 8 in 65% isolated yield
over the two steps. The structure of 8 was supported by nuclear Overhauser
1
effect (NOE) H NMR difference spectroscopy (Figure 1). Irradiation of
the 2ꢁ-C-CH3 resonance resulted in large enhancements of Hꢁ-4 (m, δ 3.85),
Hꢁ-1 (d, δ 6.40), and the diastereotopic benzyl methine protons (m, δ 4.63).

2ꢁ-Deoxy-2ꢁ-Fluoro-2ꢁ-C-Methyl-β-D-Ribofuranosyl
391
FIGURE 1 1H NMR NOE correlations of compounds 8 and 9.
Treatment of 8 with DAST in CH2Cl2 gave a complex reaction mixture, from
which compound 9 could be isolated in 41% yield. The stereochemistry of
9 was also determined by NOE 1H NMR difference spectroscopy (Figure 1).
Upon irradiation of the doublet at δ 1.02 (2ꢁ-CH3) in compound 9, NOEs
were observed with the doublet of doublets at δ 4.25 (H-3ꢁ), the anomeric
doublet of doublets at δ 6.60, and the doublet at δ 7.68 (H-6). Deprotec-
tion of the benzyl groups in 9 with boron tribromide in dichloromethane,
followed by displacement of the 4-chloro substituent with aqueous ammo-
nia furnished 1, the spectroscopic data of which were identical with those
previously reported by us.[2]
In summary, we have developed an alternative route for the synthesis of
nucleoside analogue 1. Although somewhat more linear, the overall yield of
this route is compatible with our previous route.
EXPERIMENTAL
1,2-Di-O-acetyl-3,5-di-O-benzyl-β-D-ribofuranose 3. Acetic anhydride (14.2
mL, 0.15 mol) was added dropwise to a mixture of dibenzylribofuranose
2 (10.0 g, 30.3 mmol), triethyl amine (25.0 mL, 0.18 mol), and DMAP
(0.8 g, 6.38 mmol) in dry DCM (400 mL). After addition, the mixture was
stirred at r.t. for 3 hours and then quenched with H2O (200 mL). The
separated organic phase was washed successively with H2O (200 mL), satu-
rated aqueous sodium bicarbonate (2 × 100 mL) and brine (100 mL)—then
dried (Na2SO4), filtered, and evaporated in vacuo. The residue was purified
by column chromatography by silica gel (10% ethyl acetate in petroleum
ether) to give the title compound 3 (10.4 g, 83%) as a sticky oil: δH
(300 MHz, CDCl3) 7.37–7.28 (10H, m, Ar-H), 6.13 (1H, s, H-1), 5.31

392
W. Hu et al.
(1H, d, J = 4.2 Hz, H-2), 4.65–4.44 (4H, m, PhCH2), 4.31 (1H, dd,
J = 7.8, 4.2 Hz, H-3), 4.23 (1H, m, H-4), 3.68 (1H, dd, J = 10.8, 3.0 Hz,
H-5α), 3.55 (1H, dd, J = 10.8, 3.9 Hz, H-5β), 2.14 (3H, s, CH3), and 1.93
(3H, s, CH3); m/z (ESI) 415 ([M + H]+, 100%).
4-Chloro-5-fluoro-7-(2ꢁ-O-acetyl-3ꢁ,5ꢁ-di-O-benzyl-β-D-ribofuranosyl)-1H-pyrrolo
[2,3-d]pyrimidine 5. BSA (3.4 mL, 13.28 mmol) was added to a solution of
pyrrolo[2,3-d]pyrimidine 4 (2.0 g, 11.66 mmol) in dry acetonitrile (50 mL)
under N2. The resulting mixture was stirred at room temperature (r.t.)
for 10 minutes. A solution of ribofuranose 3 (5.2 g, 12.56 mmol) in dry
acetonitrile (30 mL) was added, followed by dropwise addition of TMSOTf
(2.2 mL, 12.64 mmol). After addition, the mixture was stirred at r.t. for
0.5 hour, then heated to 80◦C for 2 hours. The cooled solution was diluted
with ethyl acetate (400 mL) and then washed successively with saturated
sodium bicarbonate (400 mL) and brine (400 mL). The separated organic
layer was dried (Na2SO4), filtered, and evaporated in vacuo. The residue
was purified by column chromatography by silica gel (20% ethyl acetate in
petroleum ether) to give the title compound 5 (2.7 g, 45%) as a sticky oil:
δH (300 MHz, CDCl3) 8.60 (1H, s, H-2), 7.41–7.26 (11H, m, Ar-H and H-6),
5.59 (1H, d, J = 3.3 Hz, H-1ꢁ), 5.46 (1H, t, J = 4.8 Hz, H-2ꢁ), 4.62–4.42 (5H,
m, PhCH2 and H-3ꢁ), 4.27 (1H, m, H-4ꢁ), 3.78 (1H, dd, J = 10.8, 2.7 Hz,
H-5ꢁα), 3.56 (1H, dd, J = 10.8, 2.7 Hz, H-5ꢁβ), and 2.10 (3H, s, CH3); m/z
(ESI) 548 ([M + Na]+, 100%) and 526 ([M + H]+, 80%).
4-Chloro-5-fluoro-7-(3ꢁ,5ꢁ-di-O-benzyl-β-D-ribofuranosyl)-1H-pyrrolo[2,3-d]
pyrimidine 6. A mixture of 5 (1.94 g, 3.69 mmol) and 5% triethyl amine in
methanol (20 mL) was stirred at r.t. for 12 hours, before being evaporated
in vacuo. The residue was purified by column chromatography by silica gel
(20% ethyl acetate in petroleum ether) to give the title compound 6 (1.60 g,
90%) as a sticky oil: δH (300 MHz, CDCl3) 8.59 (1H, s, H-2), 7.43–7.31 (11H,
m, Ar-H and H-6), 6.38 (1H, dd, J = 5.4, 1.8 Hz, H-1ꢁ), 4.79–4.51 (4H, m,
PhCH2), 4.45 (1H, m, H-4ꢁ), 4.32 (1H, dd, J = 5.7, 3.3 Hz, H-3ꢁ), 4.23 (1H,
dd, J = 5.4, 3.3 Hz, H-2ꢁ), 3.76 (1H, dd, J = 10.5, 3.0 Hz, H-5ꢁα), and 3.56
(1H, dd, J = 10.5, 2.7 Hz, H-5ꢁβ); m/z (ESI) 522 ([M + K]+, 50%), 506 ([M
+ Na]+, 100%), and 484 ([M + H]+, 70%).
4-Chloro-5-fluoro-7-(3ꢁ,5ꢁ-di-O-benzyl-2ꢁ-C-methyl-β-D-ribofuranosyl)-1H-
pyrrolo[2,3-d]pyrimidine 8. To an ice-cooled mixture of Dess–Martin pe-
riodinane (16.25 g, 38.33 mmol) in dry DCM (600 mL) under N2, was
added dropwise a solution of 6 (6.25 g, 12.93 mmol) in dry DCM (50 mL).
After addition, the mixture was stirred for 0.5 hour before the cooling
bath was removed. The mixture was stirred further for 2 days at r.t. and
then quenched with a solution of sodium thiosulfate (57.5 g) dissolved in
saturated aqueous sodium bicarbonate (630 mL). After no bubbling, the

2ꢁ-Deoxy-2ꢁ-Fluoro-2ꢁ-C-Methyl-β-D-Ribofuranosyl
393
organic layer was separated and washed successively with saturated aqueous
sodium bicarbonate (300 mL), H2O (300 mL), and brine (100 mL)—then
dried (Na2SO4), filtered, and evaporated in vacuo. The residue under N2
was dissolved in dry diethyl ether (300 mL). The resulting mixture was
cooled to −78◦C. A solution of methyl magnesium bromide in diethyl ether
(13.8 mL) was added. The mixture was stirred at −78◦C for 8 hours, before
being quenched with 1 M ammonium chloride solution (62 mL). The
separated organic layer was washed successively with H2O (200 mL) and
brine (200 mL)—then dried (Na2SO4), filtered, and evaporated in vacuo.
The residue was purified by column chromatography by silica gel (10%
ethyl acetate in petroleum ether) to give the title compound 8 (4.17 g, 65%
over the two steps) as a sticky oil: δH (300 M Hz, CDCl3) 8.59 (1H, s, H-2),
7.50 (1H, d, J = 2.4 Hz, H-6), 7.44–7.30 (10H, m, Ar-H), 6.40 (1H, d, J =
2.4 Hz, H-1ꢁ), 4.70–4.57 (4H, m, PhCH2), 4.23 (1H, d, J = 2.1 Hz, H-3ꢁ),
3.86–3.79 (2H, m, H-4ꢁ and H-5ꢁα), 3.55 (1H, dd, J = 10.5, 1.8 Hz, H-5ꢁβ),
and 1.30 (3H, s, CH3); δC (75 MHz, CDCl3) 151.2, 150.3, 147.5, 140.9 (d,
J FC = 249.8 Hz), 136.2, 132.0, 128.8, 128.6, 128.1, 128.0, 127.8, 112.0 (d, J FC
= 27.3 Hz), 107.3 (d, J FC = 14.2 Hz), 87.0, 85.1, 82.8, 81.7, 74.1, 72.6, 69.6
and 17.1; m/z (ESI) 520 ([M + Na]+, 100%) and 498 ([M + H]+, 75%).
4-Chloro-5-fluoro-7-(3ꢁ,5ꢁ-di-O-benzyl-2ꢁ-deoxy-2ꢁ-fluoro-2ꢁ-C-methyl-β-D-
ribofuranosyl)-1H-pyrrolo[2,3-d]pyrimidine 9. DAST (0.76 mL, 5.80 mmol)
was added dropwise to a stirred solution of 8 (1.91 g, 3.84 mmol) in dry
DCM (40 mL) at −20◦C under N2. After addition, the resulting mixture
was stirred at −20◦C for an additional 2 hours before being quenched with
saturated aqueous sodium bicarbonate (40 mL). The separated organic
layer was washed successively with saturated aqueous sodium bicarbonate
(20 mL), H2O (20 mL), and brine (20 mL)—then dried (Na2SO4),
filtered, and evaporated in vacuo. The residue was purified by column
chromatography by silica gel (6% ethyl acetate in petroleum ether) to give
the title compound 9 (0.78 g, 41%) as a sticky oil: δH (300 MHz, CDCl3) 8.60
(1H, s, H-2), 7.68 (1H, d, J = 2.4 Hz, H-6), 7.42–7.29 (10H, m, Ar-H), 6.60
(1H, dd, J = 16.5, 1.8 Hz, H-1ꢁ), 4.72–4.47 (4H, m, PhCH2), 4.30 (1H, m,
H-4ꢁ), 4.25 (1H, dd, J = 22.8, 9.3 Hz, H-3ꢁ), 3.98 (1H, dd, J = 11.4, 1.5 Hz,
H-5ꢁα), 3.68 (1H, dd, J = 11.4, 1.8 Hz, H-5ꢁβ), and 1.01 (1H, d, J = 22.0 Hz,
CH3); δC (75 MHz, CDCl3) 151.6, 150.5, 146.5, 141.5 (d, J FC = 252.1 Hz),
137.1, 128.6, 128.5, 128.4, 128.2, 128.1, 109.2 (d, J FC = 27.5 Hz), 107.2 (d,
J FC = 14.1 Hz), 100.5 (d, J FC = 182.8 Hz), 88.1 (d, J FC = 38.2 Hz), 79.9,
77.1 (d, J FC = 16.5 Hz), 74.1, 73.7, 67.3, and 16.7 (d, J FC = 25.1 Hz); m/z
(ESI) 522 ([M + Na]+, 100%) and 500 ([M + H]+, 50%).
4-Chloro-5-fluoro-7-(2ꢁ-deoxy-2ꢁ-fluoro-2ꢁ-C-methyl-β-D-ribofuranosyl)-1H-
pyrrolo[2,3-d]pyrimidine 10. A solution of 9 (1.07 g, 2.14 mmol) in dry DCM
(300 mL) under N2 was cooled to −78◦C. Boron tribromide (1M, 4.3 mL,

394
W. Hu et al.
4.3 mmol) was added dropwise. After addition, the mixture was stirred
at −78◦C for 3 hours. Triethylamine (4.3 mL) and methanol (4.2 mL)
were added and the mixture was stirred further for 0.5 hour before being
evaporated in vacuo. The residue was partitioned between H2O (50 mL)
and DCM (100 mL). The separated aqueous phase was extracted with DCM
(2 × 100 mL). The combined organic extracts were washed successively with
H2O (100 mL) and brine (100 mL)—then dried (Na2SO4), filtered, and
evaporated in vacuo. The residue was purified by column chromatography
by silica gel (5% methanol in DCM) to give the title compound 10 (0.58 g,
85%) as a colorless solid: δH (300 MHz, DMSO-d6) 8.75 (1H, s, H-2), 8.11
(1H, d, J = 1.8 Hz, H-6), 6.52 (1H, dd, J = 17.1, 1.5 Hz, H-1ꢁ), 5.73 (1H,
d, J = 7.5 Hz, 3ꢁ-OH), 5.39 (1H, t, J = 4.8 Hz, 5ꢁ-OH), 4.13 (1H, ddd, J =
24.9, 8.7, 6.9 Hz, H-3ꢁ), 3.96–3.68 (3H, m, H-4ꢁ and H-5ꢁ), and 0.99 (3H, d, J
= 22.5 Hz, CH3); m/z (ESI) 342 ([M + Na]+, 100%) and 320 ([M + H]+,
70%).
4-Amino-5-fluoro-7-(2ꢁ-deoxy-2ꢁ-fluoro-2ꢁ-C-methyl-β-D-ribofuranosyl)-1H-
pyrrolo[2,3-d]pyrimidine (1). A mixture of 10 (0.16 g, 0.5 mmol), 1,4-dioxane
(8 mL), and 25–28% aqueous ammonia (20 mL) in an autoclave was heated
to 120◦C for 14 hours before being evaporated in vacuo. The residue was
purified by column chromatography by silica gel (5% methanol in DCM) to
give the title compound 1 (0.15 g, 95%) as a colorless solid: δH (300 MHz,
DMSO-d6) 8.10 (1H, s, H-2), 7.44 (1H, d, J = 1.8 Hz, H-6), 7.09 (2H, br.
s, NH2), 6.37 (1H, d, J = 17.9 Hz, H-1ꢁ), 5.61 (1H, d, J = 6.9 Hz, 3ꢁ-OH),
5.25 (1H, t, J = 4.8 Hz, 5ꢁ-OH), 4.06 (1H, ddd, J = 26.0, 9.5, 7.7 Hz, H-3ꢁ),
3.88–3.38 (3H, m, H-4ꢁ and H-5ꢁ), and 0.94 (3H, d, J = 22.3 Hz, CH3); δC
(75 MHz, DMSO-d6) 155.9 (C-4), 153.1 (C-2), 145.8 (C-8), 142.8 (C-5, d, J FC
= 245.7 Hz), 103.4 (C-6, d, J FC = 26.3 Hz), 101.3 (C-2ꢁ, d, J FC = 179.9 Hz),
92.1 (C-9, d, J FC = 16.6 Hz), 87.2 (C-1ꢁ, d, J FC = 38.8 Hz), 81.7 (C-4ꢁ), 70.4
(C-3ꢁ, d, J FC = 17.3 Hz), 59.0 (C-5ꢁ), and 16.1 (CH3, d, J FC = 25.6 Hz); m/z
(ESI) 323 ([M + Na]+, 100%) and 301 ([M + H]+, 70%) [Found: M+ + H,
301.1150. C12H15F2N4O3 requires 301.1112].
REFERENCES
1. Clark, J.L.; Hollecker, L.; Mason, J.C.; Stuyver, L.J.; Tharnish, P.M.; Lostia, S.; McBrayer, T.R.; Schi-
nazi, R.F.; Watanabe, K.A.; Otto, M.J.; Furman, P.A.; Stec, W.J.; Patterson, S.E.; Pankiewicz, K.W.
Design, synthesis, and antiviral activity of 2ꢁ-deoxy-2ꢁ-fluoro-2ꢁ-C-methylcytidine, a potent inhibitor
of hepatitis C virus replication. J. Med. Chem. 2005, 48, 5504–5508.
2. Hu, W.; Wang, P.; Song, C.; Pan, Z.; Wang, Q.; Guo, X.; Yu, X.; Shen, Z.; Wang, S.; Chang, J. Synthesis
and anti-HCV activity of a new 2ꢁ-deoxy-2ꢁ-fluoro-2ꢁ-C-methyl nucleoside analogue. Bioorg. Med. Chem.
Lett. 2010, 20, 7297–7298.
3. Shi, J.; Zhou, L.; Zhang, H.; McBrayer, T.R.; Detorio, M.A.; Johns, M.; Bassit, L.; Powdrill,
M.H.; Whitaker, T.; Coats, S.J.; Go¨tte, M.; Schinazi, R.F. Synthesis and antiviral activity of 2ꢁ-
deoxy-2ꢁ-fluoro-2ꢁ-C-methyl-7-deazapurine nucleosides, their phosphoramidate prodrugs and 5ꢁ-
triphosphates. Bioorg. Med. Chem. Lett. 2011, 21, 7094–7098.

2ꢁ-Deoxy-2ꢁ-Fluoro-2ꢁ-C-Methyl-β-D-Ribofuranosyl
395
4. (a) Wang, X.; Seth, P.P.; Ranken, R.; Swayze, E.E.; Migawa, M.T. Synthesis and biological activ-
ity of 5-fluorotubercidin, Nucleosides, Nucleotides Nucleic Acids. 2004, 23, 161–170. (b) Seela, F.;
Ming, X. 7-Functionalized 7-deazapurine β-D and β-L-ribonucleosides related to tubercidin and
7-deazainosine: glycosylation of pyrrolo[2,3-d]pyrimidines with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D or
β-L-ribofuranose, Tetrahedron 2007, 63, 9850–9861. (c) Suydam, I.T.; Strobel, S.A. Fluorine substi-
tuted adenosines as probes of nucleobase protonation in functional RNAs. J. Am. Chem. Soc. 2008,
130, 13639–13648.
5. Lucas, S.D.; Rauter, A.P.; Schneider, J.; Wessel, H.P. Synthesis of 3-fluoro-oxetane δ-amino acids. J.
Carbohydr. Chem. 2009, 28, 431–446.
6. Li, N.-S.; Lu, J.; Piccirilli, J.A. Efficient synthesis of methyl 3,5-di-O-benzyl-α-D-ribofuranoside and
application to the synthesis of 2ꢁ-C-β-alkoxymethyluridines. Org. Lett. 2007, 9, 3009–3012.
7. Eldrup, A.B.; Prhavc, M.; Brooks, J.; Bhat, B.; Prakash, T.P.; Song, Q.; Bera, S.; Bhat, N.; Dande, P.;
Cook, P.D.; Bennett, C.F.; Carroll, S.S.; Ball, R.G.; Bosserman, M.; Burlein, C.; Colwell, L.F.; Fay,
J.F.; Flores, O.A.; Getty, K.; LaFemina, R.L.; Leone, J.; MacCoss, M.; McMasters, D.R.; Tomassini,
J.E.; Langen, D.V.; Wolanski, B.; Olsen, D.B. Structure-activity relationship of heterobase-modified
2ꢁ-C-methyl ribonucleosides as inhibitors of hepatitis C virus RNA replication. J. Med. Chem. 2004, 47,
5284–5297.