Synthesis of 2-deoxy-2-fluoro-2-C-methyl-D-ribofuranoses

Article abstract of DOI:10.1080/07328300600859783

The synthesis of methyl 3,5-di-O-benzoyl-2-deoxy-2-fluoro-2-C-methyl- β-D-ribofuranoside and the conversion to the corresponding 1-O-acetyl-3,5-di-O-benzoyl-2-deoxy-2-fluoro-2-C-methyl-D-ribofuranose and 1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-2-C-methyl-D-r

Full text of DOI:10.1080/07328300600859783

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Synthesis of
2‐Deoxy‐2‐Fluoro‐2‐C‐Methyl‐D‐Ribofuranoses
Jeremy L. Clark a b , J. Christian Mason a c , Ann J. Hobbs a d , Laurent
Hollecker a e & Raymond F. Schinazi f
a Pharmasset, Inc. , Tucker, GA, USA
b Southern Research Institute , Birmingham, AL, USA
c Washington University, School of Medicine , St. Louis, MO, USA
d Bio-Lab Inc. , Lawrenceville, GA, USA
e Monserrato, CA, Italy
f Center for AIDS Research, Emory University/Veterans Affairs Medical
Center , Decatur, GA, USA
Published online: 22 Sep 2006.
To cite this article: Jeremy L. Clark , J. Christian Mason , Ann J. Hobbs , Laurent Hollecker & Raymond
F. Schinazi (2006) Synthesis of 2‐Deoxy‐2‐Fluoro‐2‐C‐Methyl‐D‐Ribofuranoses, Journal of Carbohydrate
Chemistry, 25:6, 461-470, DOI: 10.1080/07328300600859783
To link to this article: http://dx.doi.org/10.1080/07328300600859783
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Journal of Carbohydrate Chemistry, 25:461–470, 2006
Copyright # Taylor & Francis Group, LLC
ISSN: 0732-8303 print 1532-2327 online
DOI: 10.1080/07328300600859783
Synthesis of 2-Deoxy-2-
Fluoro-2-C-Methyl-D-
Ribofuranoses
Jeremy L. Clark
Pharmasset, Inc., Tucker, GA, USA and Southern Research Institute, Birmingham,
AL, USA
J. Christian Masonꢀ
Pharmasset, Inc., Tucker, GA, USA and Washington University, School of Medicine,
St. Louis, MO, USA
Ann J. Hobbs
Pharmasset, Inc., Tucker, GA, USA and Bio-Lab Inc., Lawrenceville, GA, USA
Laurent Hollecker
Pharmasset, Inc., Tucker, GA, USA and Via San Fillippo, Monserrato (CA), Italy
Raymond F. Schinazi
Center for AIDS Research, Emory University/Veterans Affairs Medical Center,
Decatur, GA, USA
The synthesis of methyl 3,5-di-O-benzoyl-2-deoxy-2-fluoro-2-C-methyl-b-D-ribofurano-
side and the conversion to the corresponding 1-O-acetyl-3,5-di-O-benzoyl-2-deoxy-2-
fluoro-2-C-methyl-D-ribofuranose and 1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-2-C-methyl-
D-ribofuranose is reported. The key synthetic step is the fluorination of the tertiary
center of methyl 3,5-di-O-benzyl-2-C-methyl-b-D-arabinofuranoside to provide methyl
Received December 28, 2005; accepted May 30, 2006.
*
Deceased April 2005.
Address correspondence to Jeremy L. Clark, Pharmasset, Inc., Tucker, GA, USA.
E-mail: j.clark@sri.org
461

J. L. Clark et al.
462
3,5-di-O-benzyl-2-deoxy-2-fluoro-2-C-methyl-b-D-ribofuranoside.
Keywords Synthesis, Ribofuranoses, Fluorination, Oligonucleotides
Nucleoside analogs containing 20-modifications are important not only as
chemotherapeutic agents, but also as tools for studying the structure and
function of oligonucleotides (Fig. 1). The synthesis of 20,20-difluorocytidine (1)
was first reported in 1988 and, in 1996, this compound received FDA
approval for the treatment of metastatic pancreas cancer.[1] 20-Deoxy-20-fluoro-
cytidine (2) has shown in vitro activity against both DNA[2] and RNA
viruses.[3,4] (20S)-20-Deoxy-20-C-methylcytidine (SMDC) (3) demonstrated
very potent in vitro cytotoxicity against several leukemia cancer cell lines[5]
and has been used for studying the mechanism of the group II intron
ribozyme due to its conformational similarity to RNA.[6] Several 20-C-methyl-
nucleosides, such as 20-C-methylcytidine (4), have proven effective at inhibiting
HCV RNA replication in vitro and the 30-O-L-valinyl ester of 4 (NM283, valopi-
citabine) is currently in phase 2b clinical trials.[7] Additionally, 20-C-methylri-
bonucleosides have been utilized to varying degrees as biological probes for
studying RNA and ribozyme function.[8]
Recently, the synthesis of 20-deoxy-20-fluoro-20-C-methylcytidine was
described starting from N4-benzoyl-(2-C-methyl-3,5-di-O-benzoyl-b-D-arabino-
furanosyl)cytosine.[9] While such a linear synthetic approach has the
Figure 1: Structures of several 20-modified nucleosides.

Synthesis of 2-Deoxy-2-Fluoro-2-C-Methyl-D-Ribofuranoses
463
advantage of avoiding the glycosylation reaction to a nucleobase, it does not
provide the opportunity to prepare a wide variety of base-modified nucleoside
analogs. In this regard, a more convenient approach to the preparation of
these compounds is a convergent approach in which a protected 2-deoxy-2-
fluoro-2-C-methyl-D-ribofuranose is prepared first and then used to glycosylate
a variety of nucleobases. The synthesis of methyl 3,5-di-O-benzoyl-2-deoxy-2-
fluoro-2-C-methyl-b-D-ribofuranoside (9) and its conversion to 1-O-acetyl-3,
5-di-O-benzoyl-2-deoxy-2-fluoro-2-C-methyl-D-ribofuranose (11) and 1,3,5-tri-
O-benzoyl-2-deoxy-2-fluoro-2-C-methyl-D-ribofuranose (12) is reported herein.
The major synthetic challenge for the synthesis of the 2-deoxy-2-fluoro-2-C-
methyl-D-ribofuranoses (8–12) is the stereoselective introduction of the
fluorine atom at the 2-position. In the initial synthetic planning, the number
of literature examples describing the nucleophilic fluorination of tertiary
alcohols, particularly those desiring stereospecificity, were scarce. Of the few
literature examples that describe the nucleophilic fluorination of tertiary
alcohols, both inversion[10] and retention of configuration[11] were reported.
For the synthesis of methyl 3,5-di-O-benzyl-2-deoxy-2-fluoro-2-C-methyl-b-D-
ribofuranoside (8), it was reasoned that the carbohydrate starting material,
methyl 3,5-di-O-benzyl-2-C-methyl-b-D-arabinofuranoside (7), would not only
serve to introduce the fluorine in the ribose configuration, but also minimize
the number of stereocenters requiring assembly.
Methyl 3,5-di-O-benzyl-2-C-methyl-b-D-arabinofuranoside (7) was prepared
in nine steps starting from D-xylose (Sch. 1). The intermediate methyl 3,5-di-O-
benzyl-D-ribofuranoside (5) was obtained as an inseparable 1:4 a-b mixture by
essentially the same procedure described by Ritzmann et al.[12] A few minor
changes from the procedure of Ritzmann allowed for the preparation of
Scheme 1: Reagents and conditions: (a) TEMPO, NaOCl, 08C; (b) MeLi, Et2O, 2788C; (c) DAST,
CH2Cl2, rt; (d) (i) Pd/C, cyclohexene, reflux, (ii) BzCl, pyridine; (e) ꢀ80% HCO2H, 60–708C; (f)
Ac2O or BzCl, TEA, CH2Cl2.

J. L. Clark et al.
464
compound 5 using no column chromatography. For example, a 4-chlorobenzoyl
protecting group was used to protect the 5-hydroxyl group rather than the
methoxycarbonyl group used by Ritzmann and a catalytic TEMPO oxidation
was found more effective than a ruthenium tetraoxide oxidation.[13] Addition-
ally, the same catalytic TEMPO oxidiation was successful for the conversion
of 5 to 6; however, a slightly larger excess of TEMPO and sodium hypochlorite
was required.
The majority of the synthetic efforts for introducing 2-C alkyl groups on
carbohydrates have focused on the addition of the alkyl group from the b-face
of the furanose ring.[14–17] However, since the anomeric mixture of ketone 6
consisted of ꢀ80% of the desired b-anomer, it was anticipated that methyl
lithium addition should proceed from the a face of the furanose ring to
provide 7 as the major product. Accordingly, treating the anomeric mixture of
2-ketone (6) with methyl lithium at 2788C provided a reaction mixture from
which the desired methyl 3,5-di-O-benzyl-2-C-methyl-b-D-arabinofuranoside
(7) was isolated in 78.3%. The identification and isolation of the minor diaster-
eomers from the crude reaction mixture was difficult due to the presence of the
a-anomer. Therefore, the stereoselectivity for the b-anomer was not deter-
mined. The structure of 7 was supported by nuclear Overhauser enhancement
(NOE) 1H NMR difference spectroscopy (Fig. 2). Irradiation of the 2-C-CH3 res-
onance (s, d 1.40) resulted in large enhancements of H-4 (m, d 4.03), H-1 (s, d
4.48), and the diastereotopic benzyl methine protons (d, d 4.83).
Treating 7 with DAST in CH2Cl2 provided a complex reaction mixture from
which methyl 3,5-di-O-benzyl-2-deoxy-2-fluoro-2-C-methyl-b-D-ribofuranoside
(8) was isolated in 20% yield. The regiochemistry and the stereochemistry of
the fluorination was determined by 1H and 13C NMR. Since several rearrange-
ments have been reported in the DAST fluorination of pentofuranoses, it was
necessary to ensure that the fluorination had proceeded regioselectively.[18,19]
Analysis of the 1H and 13C NMR spectra revealed the anticipated 19F couplings
1
arising from a C-2 fluorinated product. The three 19F, H couplings that were
evident in the 1H NMR spectrum of compound 8 were a doublet at d 1.43
(2-CH3), a doublet of doublets at d 3.87 (H-3), and a doublet at d 4.72 (H-1).
The four observed 13C multiplicties arising from 19F coupling were a doublet
at d 17.0 (2-CH3), a doublet at d 81.1 (C-3), a doublet at d 99.7 (C-2), and a
Figure 2: 1H NMR NOE correlations of compounds 7 and 8.

Synthesis of 2-Deoxy-2-Fluoro-2-C-Methyl-D-Ribofuranoses
465
doublet at d 106.7 (C-1). Additionally, the presence of the C-2 fluorine was
further supported by the significant low-field shift in the C-2 13C resonance
due to an a effect (d 99.7 for 8 vs. d 79.5 for 7).[20] The stereochemistry of the
1
DAST fluorination was determined by NOE H NMR difference spectroscopy
(Fig. 2). For compound 8, relatively large NOEs were observed between the
2-CH3 and H-3 and, to a lesser extent, between the 2-CH3 and H-1.
The benzyl protecting groups of 8 were removed using transfer hydrogenolysis
(Pd/C, cyclohexene) and replaced with benzoyl protecting groups to provide
methyl 3,5-di-O-benzoyl-2-deoxy-2-fluoro-2-C-methyl-b-D-ribofuranoside (9).
Formic acid cleavage of furanoside 9 at 60 to 708C provided 10 that was acylated
to provide anomeric mixtures of 1-O-acetyl-3,5-di-O-benzoyl-2-deoxy-2-fluoro-2-
C-methyl-D-ribofuranose (11) and 1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-2-C-
methyl-D-ribofuranose (12) in 85.6% and 88.7% yield, respectively (Sch. 2).
Vorbru¨ggen condensation of 12 with silylated N4-benzoylcytosine was
achieved as described by Harry-O’kuru et al.[15,17] Condensation of 12 with
the preformed bis(trimethylsilyl)N4-benzoylcytosine in acetonitrile/SnCl4 at
50 to 558C provided 13 in 70% yield as an ꢀ1:1 a-b mixture. The pure
b-anomer was isolated in 37% yield from the crude anomeric mixture by
silica gel chromatography. The structure of the b-anomer obtained from the
glycosylation was identical to the N4-benzoyl-1-(30,50-di-O-benzoyl-20-fluoro-20-
C-methyl)cytidine (13) prepared by the linear approach.[9]
In summary, the synthesis of the novel carbohydrate building blocks
needed for making a variety of base modified 20-fluoronucleosides is described.
This approach should provide numerous diverse 2-deoxy-2-fluoro-2-C-methyl-
D-ribofuranose nucleosides for HCV structure-activity relationship studies in
addition to mechanistic studies related to RNA.
EXPERIMENTAL
All reagents and anhydrous solvents were purchased from Aldrich or Acros and
1
were used as received. H, 19F, and 13C NMR spectra were obtained with a
Varian Unity Plus 400 spectrometer at 400, 376, and 100 MHz, respectively.
Scheme 2: Reagents and conditions: (a) bis(trimethylsilyl)N4-benzoylcytosine, SnCl4, MeCN,
50–558C, 4 h.

J. L. Clark et al.
466
1H and 13C NMR chemical shifts are reported as d (ppm) downfield with respect
to an internal standard of tetramethylsilane, while 19F chemical shifts are
reported downfield from an external standard of hexafluorobenzene. Atlantic
Microlab, Inc. of Norcross, GA provided the elemental analysis.
Methyl 3,5-di-O-benzyl-2-C-methyl-b-D-arabinofuranoside (7). Compound
6 (7.70 g, 22.5 mmol) was dissolved in anhydrous diethyl ether and cooled to
2788C. To this solution was added MeLi (30 mL, 1.6 M in diethyl ether)
dropwise over 5 min. After the reaction was complete, the mixture was
treated cautiously with ammonium chloride (1M, 65 mL) and the mixture
was warmed to rt and stirred for 1 h. The organic phase was separated, dried
(Na2SO4), filtered, and concentrated to dryness. Silica gel chromatography
eluting with 1:4 EtOAc-hexanes followed by crystallization from diethyl
ether-hexanes afforded pure 7 (6.31 g, 78.3%). mp 48.0–50.58C. 1H NMR
(CDCl3): d 1.39 (s, 3H, 2-CH3), 2.93 (s, 1H, OH), 3.40 (s, 3H, OCH3), 3.49 (dd,
1H, J ¼ 6.9, 10.3 Hz, H-5), 3.57 (dd, 1H, J ¼ 3.9, 10.3 Hz, H-5a), 3.83 (d, 1H,
J ¼ 7.3 Hz, H-3), 4.03 (m, 1H, H-4), 4.48 (s, 1H, H-1), 4.58 (m, 3H, OCH2Ph),
4.83 (d, 1H, J ¼ 11.6 Hz, OCH2Ph), 7.30–7.35 (m, 10H, Ph). 13C NMR
(CDCl3): d 18.4, 55.4, 72.2, 73.4, 79.5, 80.2, 84.7, 107.4, 127.7, 127.8, 127.83,
128.5, 138.2, 138.3. Anal. Calcd. for C21H26O5: C, 70.37; H, 7.31. Found: C,
70.25; H, 7.18.
Methyl
3,5-di-O-benzyl-2-deoxy-2-fluoro-2-C-methyl-b-D-ribofurano-
side (8). Compound 7 (3.50 g, 9.76 mmol) was dissolved in CH2Cl2 (40.0 mL)
and treated with DAST (4.0 mL, 30.3 mmol) at rt under argon. The solution
was stirred at rt overnight. The so-obtained mixture was poured into sat
NaHCO3 (100 mL) and washed with sat NaHCO3 (1 ꢁ 15 mL) until gas evol-
ution ceased. The organic layer was then washed with water (1 ꢁ 25 mL).
Silica gel chromatography (1:5 EtOAc-hexanes) gave 8 (0.671 g, 19.3%) that
was sufficiently pure for the next step. An analytical sample was obtained by
further silica gel chromatography. 1H NMR (CDCl3): d 1.43 (d, 3H,
J ¼ 22.8 Hz, 2-CH3), 3.35 (s, 3H, OCH3), 3.49 (dd, 1H, J ¼ 5.4, 10.5 Hz, H-5),
3.55 (dd, 1H, J ¼ 4.1, 10.5 Hz, H-5a), 3.87 (dd, 1H, J ¼ 7.5, 23.5 Hz, H-3),
4.26 (m, 1H, H-4), 4.56 (d, 2H, J ¼ 6.9 Hz, OCH2Ph), 4.66 (d, 2H, J ¼ 8.2 Hz,
OCH2Ph), 4.72 (d, 1H, J ¼ 10.8 Hz, H-1), 7.29–7.36 (m, 10H, Ph). 13C NMR
(CDCl3):
d
17.0 (d, J ¼ 24.4 Hz), 55.1, 71.0, 73.3, 73.7, 80.2, 81.1
(d, J ¼ 15.5 Hz), 99.7 (d, J ¼ 179.3 Hz), 106.7 (d, J ¼ 32.5 Hz), 127.7, 128.0,
128.2, 128.3, 128.5, 128.6, 137.7, 138.2. 19F NMR (CDCl3): d 23.3 (m, 1F).
Anal. Calcd. for C21H25FO4: C, 69.98; H, 6.99. Found: C, 70.03; H, 7.04.
Methyl 3,5-di-O-benzoyl-2-deoxy-2-fluoro-2-C-methyl-b-D-ribofurano-
side (9). Compound 8 (0.39 g, 1.1 mmol) was dissolved in 1:2 EtOH-EtOAc
and treated with Pd/C (ꢀ0.1 g) and cyclohexene (ꢀ1 mL). The mixture was

Synthesis of 2-Deoxy-2-Fluoro-2-C-Methyl-D-Ribofuranoses
467
heated under reflux overnight and then filtered through celite. The solvent was
removed in vacuo and the residue was dissolved in pyridine (5.0 mL). To this
solution was added benzoyl chloride (0.22 mL, 1.83 mmol) and the mixture
was stirred at rt overnight. The pyridine was removed in vacuo and the
residue was partitioned between CH2Cl2 and satd NaHCO3 (10.0 mL). The
organic phase was dried (Na2SO4) and filtered, and the solution was concen-
trated to dryness. Column chromatography eluting with 1:5 EtOAc-hexanes
1
provided pure 9 (0.350 g, 83.3% for 2 steps). H NMR (CDCl3): d 1.53 (d, 3H,
J ¼ 22.4 Hz, 2-CH3), 3.39 (s, 3H, OCH3), 4.46 (dd, 1H, J ¼ 4.7, 11.6 Hz, H-5),
4.58 (m, 1H, H-4), 4.65 (dd, 1H, J ¼ 3.9, 11.6 Hz, H-5a), 4.87 (d, 1H,
J ¼ 9.8 Hz, H-1), 5.64 (dd, 2H, J ¼ 7.8, 24.1 Hz, H-3), 7.37 (app t, 2H,
J ¼ 9.8 Hz, Ph), 7.47 (app t, 2H, Ph), 7.53 (app t, 1H, J ¼ 7.3 Hz, Ph), 7.61
(app t, 1H, Ph), 8.02 (d, 2H, J ¼ 8.3 Hz, Ph), 8.10 (d, 2H, Ph). 13C NMR
(CDCl3): d 16.6 (d, J ¼ 23.5 Hz), 55.3, 64.7, 75.0 (d, J ¼ 14.3 Hz), 78.0, 99.7
(d, J ¼ 180.1 Hz), 106.8 (d, J ¼ 31.8 Hz), 128.3, 128.5, 128.9, 129.0, 129.7,
129.8, 130.0, 130.6, 133.0, 133.7, 134.6, 165.8, 166.1. 19F NMR (CDCl3): d
22.65 (m, 1F). Anal. Calcd. for C21H21FO6: C, 64.94; H, 5.45. Found: C,
64.87; H, 5.32.
3,5-Di-O-benzoyl-2-deoxy-2-fluoro-2-C-methyl-D-ribofuranose (10). Compound
9 (0.540 g, 1.39 mmol) was dissolved in formic acid (25.0 mL, 95–98%) and
diluted with water (5.0 mL). The resulting solution was heated at 60–708C
for 2 days whereby TLC (1:3 EtOAc-hexanes) showed starting material (Rf
0.6) in addition to single, more polar component (Rf 0.4). The solvent was
removed in vacuo, coevaporated with toluene (4ꢁ 5 mL), and chromatographed
on silica gel using a gradient of 1:8 to 1:4 EtOAc-hexanes to provide an
1
anomeric mixture of 10 as a syrup (0.271 g, 52.1%). H NMR (CDCl3): d 1.58
(d, 3H, J ¼ 22.6 Hz, 2-CH3), 1.59 (d, 1H, J ¼ 22.8 Hz, 2-CH3), 3.45 (s, 1.3H,
OH), 4.42–4.69 (m, 4H, H-5, H-4, H-1), 5.28 (m, 0.3H, H-4), 5.34 (dd, 1H,
J ¼ 2.8, 9.6 Hz, H-5a), 5.41 (dd, 0.3H, J ¼ 8.2, 19.0 Hz, H-3), 5.65 (dd, 1H,
J ¼ 7.4, 23.4 Hz, H-3), 7.34–7.39 (m, 3H, Ph), 7.44–7.54 (m, 4H, Ph), 7.60–
7.63 (m, 1H, Ph), 7.97–8.02 (m, 3H, Ph), 8.08–8.11 (m, 3H, Ph). Anal. Calcd.
.
for C20H19FO6 0.1H2O: C, 63.86; H, 5.14. Found: C, 63.89; H, 5.30.
1-O-Acetyl-3,5-di-O-benzoyl-2-deoxy-2-fluoro-2-C-methyl-D-ribofuranose
(11). A solution of 10 (0.042 g, 0.112 mmol) in anhydrous CH2Cl2 (5.0 mL) was
treated sequentially with TEA (0.02 mL, 0.157 mmol) and Ac2O (0.014 mL,
0.146 mmol). After stirring overnight at rt, the solvent was removed in vacuo
and the residue was purified by column chromatography eluting with a
gradient of 1:20 to 1:10 EtOAc-hexanes. Compound 11 was isolated as a
colorless syrup (0.040 g, 85.6%) containing a 4:1 a-b mixture. 1H NMR
(CDCl3): d 1.53 (d, 3H, J ¼ 22.3 Hz, 2-CH3), 1.72 (d, J ¼ 22.4 Hz, 12H,
2-CH3), 1.98 (s, 3H, COCH3), 2.19 (s, 12H, COCH3), 4.44 (dd, 1H, J ¼ 4.4,

J. L. Clark et al.
468
12.0 Hz, H-5), 4.56 (dd, 4H, J ¼ 4.8, 12.3 Hz, H-5a), 4.63–4.72 (m, 5H, H-5,
H-4), 4.73–4.79 (m, 4H, H-5a, H-4), 5.27 (app t, 4H, J ¼ 5.9, 11.7 Hz, H-3),
5.69 (dd, 1H, J ¼ 8.2, 23.7 Hz, H-3), 6.19 (d, 4H, J ¼ 2.0 Hz, H-1), 6.23
(d, 1H, J ¼ 9.7 Hz, H-1), 7.35–7.50 (m, 20H, Ph), 7.52–7.63 (m, 10H, Ph),
8.02 (d, 10H, J ¼ 7.5 Hz, Ph), 8.09 (d, 10H, J ¼ 7.5 Hz, Ph). 13C (CDCl3): d
16.58 (d, J ¼ 23.8 Hz), 21.0, 21.1, 22.05 (d, J ¼ 25.4 Hz), 22.8, 73.8
(d, J ¼ 14.8 Hz), 74.2 (d, J ¼ 15.7 Hz), 78.8, 80.5, 94.4 (d, J ¼ 206.7 Hz), 98.5,
(d, J ¼ 35.1 Hz), 98.3 (d, 1H, J ¼ 18.4 Hz), 98.2, 98.3, 98.4, 98.7, 128.4, 128.6,
128.65, 128.7, 129.0, 129.5, 129.8, 130.0, 130.2, 133.3, 133.4, 133.8, 134.0,
165.8, 166.2, 169.7. 19F NMR (CDCl3): d 24.89 (m, a anomer), 22.90 (m, b
anomer). Anal. Calcd. for C22H21FO7: C, 63.46; H, 5.08. Found: C, 63.56; H,
5.04.
1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-2-C-methyl-D-ribofuranose (12). This
compound was prepared and purified by the same method described for 11
except that benzoyl chloride was used as the acylating agent. Starting with
compound 10 (0.202 g, 0.540 mmol) provided 12 as a syrup (0.229 g, 88.7%).
1H NMR (CDCl3): d 1.79 (d, 3H, J ¼ 22.4 Hz, 2-CH3), 4.62 (dd, 1H, J ¼ 4.8,
12.4 Hz, H-5), 4.73 (dd, 1H, J ¼ 3.6, 12.4 Hz, H-5a), 4.85 (m, 1H, H-4), 5.34
(dd, 1H, J ¼ 4.0, 5.2 Hz, H-3), 6.42 (s, 1H, H-1), 7.41–7.48 (m, 6H, Ph), 7.55–
7.63 (m, 3H, Ph), 8.02–8.05 (m, 2H, Ph), 8.11–8.14 (m, 4H, Ph). Anal. Calcd.
for C27H23FO7: C, 67.78; H, 4.85. Found: C, 67.59; H, 4.81.
N4-Benzoyl-1-(30,50-di-O-benzoyl-20-fluoro-20-C-methyl)cytidine
(13).
Compounds 13-b and 13-a were prepared following known literature
methods.[15,17] N4 benzoylcytosine (0.150 g, 0.69 mmol) was silylated as pre-
viously described and treated with a solution of 12 (0.22 g, 0.46 mmol) in anhy-
drous MeCN (5 mL) with stirring under argon.[8] Stannic chloride (0.12 mL,
0.85 mmol) was added slowly and the resulting solution was placed in an oil
bath maintained at 50–558C for 4 h. The crude reaction was diluted with
EtOAc (10 mL) and quenched with saturated NaHCO3 (25.0 mL). The
organic layer was separated, washed with brine (10.0 mL), dried (Na2SO4),
1
and concentrated to dryness. Analysis of the crude reaction mixture by H
NMR indicated a 1:1 a-b mixture that was purified by silica gel chromato-
graphy eluting with 1:1 EtOAc-hexanes to afford compound 13-b (0.097 g,
37.0%) as a white solid. Further elution gave compound 13-a (0.088 g, 33.0%)
as a clear glass. Analytical samples were obtained by crystallization from the
indicated solvents. The 1H NMR of compound 13-b was identical to that
obtained by the linear approach starting from cytidine.
N4-Benzoyl-1-(30,50-di-O-benzoyl-20-fluoro-20-C-methyl)cytidine (13-a)
(a anomer). mp 174–1758C (CH2Cl2-hexanes), 1H NMR (CDCl3): d 1.67
(d, 3H, J ¼ 24.4 Hz, 20-CH3), 4.54 (dd, 1H, J ¼ 4.2, 12.2 Hz, H-50), 4.75 (dd,

Synthesis of 2-Deoxy-2-Fluoro-2-C-Methyl-D-Ribofuranoses
469
1H, J ¼ 3.4, 12.2 Hz, H-5a0), 4.83–4.86 (m, 1H, H-40), 5.75 (dd, 1H, J ¼ 9.2,
22.4 Hz, H-30), 6.62 (d, 1H, J ¼ 19.2 Hz, H-10), 7.39–7.63 (m, 9H, Ph), 7.90
(m, 3H, Ph), 8.00 (d, 2H, J ¼ 8.4 Hz, Ph), 8.08 (d, 2H, J ¼ 8.8 Hz, Ph), 8.71
(bs, 1H, NHPh). Anal. Calcd. for C31H26FN3O7: C, 65.14; H, 4.59; N, 7.35.
Found: C, 65.10; H, 4.55; N, 7.25.
N4-Benzoyl-1-(30,50-di-O-benzoyl-20-fluoro-20-C-methyl)cytidine (13-b)
(b anomer). mp 239–2418C (CH2Cl2-hexanes), lit mp 2418C (CH2Cl2-
hexanes).[9] Anal. Calcd. for C31H26FN3O7: C, 65.14; H, 4.59; N, 7.35. Found:
C, 65.20; H, 4.63; N, 7.34.
ACKNOWLEDGEMENT
Dr. R. F. Schinazi is the principal founder and former consultant of Pharmasset
Inc. His laboratory received no funding for this work. This paper is dedicated to
the loving memory of our friend and colleague Dr. J. Christian Mason.
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