Synthesis of 3'-fluoro-2',3'-dideoxy-2',3'-didehydro-4'-ethynyl-D- and -L-furanosyl nucleosides.

Article abstract of DOI:10.1021/jo049597h

An efficient procedure has been developed for the synthesis of 3'-fluoro-2',3'-dideoxy-2',3'-didehydro-4'-ethynyl D- and L-furanosyl nucleosides (1 and 2) starting from 2,3-O-isopropylidene-d-glyceraldehyde. The key intermediate 1-O-benzoyl-3E-fluoro-3,4-

Full text of DOI:10.1021/jo049597h

Syn th esis of 3′-F lu or o-2′,3′-d id eoxy-2′,3′-d id eh yd r o-4′-eth yn yl-D-
a n d -L-fu r a n osyl Nu cleosid es
Xin Chen,† Wen Zhou,† Raymond F. Schinazi,‡ and Chung K. Chu*,†
College of Pharmacy, The University of Georgia, Athens, Georgia 30602, and Emory University School of
Medicine/ Veterans Affairs Medical Center, Decatur, Georgia 30033
dchu@rx.uga.edu
Received March 11, 2004
An efficient procedure has been developed for the synthesis of 3′-fluoro-2′,3′-dideoxy-2′,3′-didehydro-
4′-ethynyl D- and L-furanosyl nucleosides (1 and 2) starting from 2,3-O-isopropylidene-D-glycer-
aldehyde. The key intermediate 1-O-benzoyl-3E-fluoro-3,4-unsaturated-5,6-di(tert-butyldimethyl-
silyloxy)-2-hexanone 8 was obtained in nine steps with the overall yield of 22%. The R,â-unsaturated
ketone 8 was then treated with ethynylmagnesium bromide in a typical Grignard reaction procedure
to afford the two intermediates 9 and 10, which after deprotection, oxidation, and acetylation gave
the corresponding 4-ethynyl-substituted D- and L-sugar moieties 15 and 16, respectively. A series
of D- and L-pyrimidine and purine nucleosides were prepared by the coupling of the sugar moieties
with various silylprotected bases. The anomeric mixtures were obtained after condensation. After
separation, the â-isomers were further deprotected to yield the target nucleosides. All the newly
synthesized 4′-substituted nucleosides were tested for their activities against HIV, among which
the D-adenine derivative showed moderate anti-HIV activity (EC50 ) 25.1 µM) without significant
cytotoxicity.
In tr od u ction
series, 2′3′-didehydro-3′-deoxythymidine (D4T)8 and the
carbocyclic 2-amino-6-cyclopropylaminopurine analogue,
abacavir,9 have been approved by the FDA for the
treatment of HIV infection. There has been considerable
interest in the modification of nucleosides with a fluorine
atom as potential antiviral agents.10 It has been shown
that the introduction of fluorine atoms enhances the drug
activity,11 and to discover novel drugs, varieties of
nucleosides with a fluorinated sugar have been synthe-
sized.10,12,13 Besides the modification of the nucleosides
focused on 2′- and 3′-positions, certain 4′-substituted
nucleosides have been described in the literature as
potential antiviral agents.14 For example, 4′-azidothymi-
In the treatment of acquired immunodeficiency syn-
drome (AIDS), a number of anti-HIV chemotherapeutic
agents have been developed, among which nucleoside
analogues remain in the forefront of anti-HIV chemo-
therapeutic regimens. However, side effects and the
emergence of drug-resistant mutants continue to be a
problem with these antiviral agents.1-5 It is now clear
that judicious combination chemotherapy is the optimum
way to improve the quality of life and survival of patients
infected with HIV-1.6 Therefore, the development of
structurally new nucleoside derivatives, which have
potent antiviral activities and low toxicity, as well as
novel resistant profiles, are urgently needed to provide
better choices for the combination chemotherapy.
(8) Lin, T.-S.; Schinazi, R. F.; Prusoff, W. H. Biochem. Pharmocol.
1987, 36, 2713.
(9) Coates, J . A. V.; Inggall, H. J .; Pearson, B. A.; et al. Antiviral
Res. 1991, 15, 161.
(10) (a) Owen, G. R.; Verheyden, J . P. H.; Moffatt, J . G. J . Org.
Chem. 1976, 41, 3010. (b) Marquez, V. E.; Tseng, C. K.-H.; Mitsuya,
H.; Aoki, S.; Kelley, J . A.; Ford, H., J r.; Roth, J . S.; Broder, S.; J ohns,
D. G.; Driscoll, J . S. J . Med. Chem. 1990, 33, 978. (c) Pai, S. B.; Liu,
S.-H.; Zhu, Y.-L.; Chu, C. K.; Cheng, Y.-C. Antimicrob. Agents.
Chemother. 1996, 40, 380. (d) Lee, K.; Choi, Y.; Gullen, E.; Schlueter-
Wirtz, S.; Schinazi, R. F.; Cheng, Y. C.; Chu, C. K. Carbohydr. Res.
2000, 328, 49.
Nucleosides with 2′,3′-dideoxy-2′,3′-didehydro sugars
often exhibit potent antiviral activities.7 Among the
* To whom correspondence should be addressed. Tel: (706) 542-
5379. Fax: (706) 542-5381.
† The University of Georgia.
‡ Emory University School of Medicine/Veterans Affairs Medical
Center.
(1) Richman, D. D. Antimicrob. Agents Chemother. 1993, 37, 1207.
(2) Schinazi, R. F. Persp. Drug Des. 1993, 1, 151.
(3) De Clercq, E. Bioche. Pharmacol. 1994, 47, 155.
(4) Tisdale, M.; Alnadaf, T.; Coursens, D. Antimicrob. Agents
Chemother. 1997, 41, 1094.
(5) Tantillo, C.; Ding J .; J acobo-Molina, A.; Nanni, R. G.; Boyer, P.
L.; Hughs, S. H. J . Mol. Biol. 1994, 243, 369.
(6) (a) Fischl, M. A. AIDS 13 (Suppl.) 1999, S49-S59. (b) Mitsuya,
H.; Erickson, J . In Textbook of AIDS medicine; Merigan, J . G., Bartlet,
D., Bolognesi, Eds.; Williams & Wilkins: Baltimore, MD, 1999; pp
751-780.
(7) Shi, J .; McAtee, J . J .; Wirtz, S. S.; Tharnish, P.; J uodawlkis, A.;
Liotta, D. C.; Schinazi, R. F. J . Med. Chem. 1999, 42, 859.
(11) Resnati, G. Tetrahedron 1993, 49, 9385.
(12) Bergstorm, D. E.; Swartling, D. J . In Fluorine-containing
molecules: structure, reactivity, synthesis, and applications; Liebman,
J . F., Greeberg, A., Dolbier, W. R., J r., Eds.; VCH Publishers: New
York, 1988; pp 259-308.
(13) (a) Choi, Y.; Choo, H.; Chong, Y.; Lee, S.; Olgen, S.; Schinazi,
R. F.; Chu, C. K. Org. Lett. 2002, 4, 305. (b) Gumina, G.; Schinazi, R.
F.; Chu, C. K. Org. Lett. 2001, 3, 4177. (c) Lee, K.; Choi, Y.; Gumina,
G.; Zhou, W.; Schinazi, R. F.; Chu, C. K. J . Med. Chem. 2002, 45, 1313.
(d) Lee, K.; Choi, Y.; Gullen, E.; Schlueter-Wirtz, S.; Schinazi, R. F.;
Cheng, Y.-C.; Chu, C. K. J . Med. Chem. 1999, 42, 1320. (e) Chong, Y.;
Gumina, G.; Mathew, J . S.; Schinazi, R. F.; Chu, C. K. J . Med. Chem.
2003, 46, 3245.
10.1021/jo049597h CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/10/2004
6034
J . Org. Chem. 2004, 69, 6034-6041

3′-Fluoro-4′-ethynyl-2′,3′-unsaturated Nucleosides
dine (4′-AZT),15 which has the hydrogen atom at the 4′
position substituted with an azido group, exerted potent
activity against HIV-1 in vitro. Other 4′-substitutions,
such as fluoro,16 cyano,17 methyl,18 ethynyl,19 and even
an unusual oxetane,17 have also exhibited interesting
antiviral activity. Therefore, it was of interest to synthe-
size additional 4′-substituted nucleosides as potential
antiviral agents. In our previous studies, we found that
the fluorinated 2′,3′-dideoxy-2′,3′-didehydro nucleosides
showed antiviral activities without significant cytotox-
ity.13 Here, we report the synthesis of 3′-fluoro-2′,3′-
dideoxy-2′,3′-didehydro-4′-ethynyl nucleosides.
nucleoside in a multistep sequence.22 Although it allows
for the introduction of both purine and pyrimidine bases
as well as modified bases, the synthetic steps become
even longer and may not be applicable to the 2′,3′-
dideoxy-2′,3′-didehydro nucleosides. To find a more ef-
ficient way to produce the fluorinated 2′,3′-dideoxy-
2′,3′-didehydro-4′-C-subsituted nucleosides, we recently
developed a novel synthetic route for both D- and L-3′-
fluoro-2′,3′-dideoxy-2′,3′-didehydro-4′-ethynyl nucleosides
starting from 2,3-O-isopropylidene-D-glyceraldehyde.
The lactone 3, prepared from 2,3-O-isopropylidene-D-
glyceraldehyde by a previously published method,13c,23,24
was treated with methyltriphenylphosphonium bromide
to give the diene 4 as an inseparable E and Z mixture in
91% yield (Scheme 1). (E/Z ) 5:2 detected by NMR. The
ratio of E and Z isomers was determined on the basis of
1
the signals of 2-H in H NMR. The E isomer had the 2-H
signal (δ 6.57 ppm) at lower field than that of the Z
isomer (δ 6.22 ppm) according to the NMR data of
compounds 5 and 5a ). During the Wittig process, the
allylic hydrogen atom, 4-H, was removed by the strong
base to form a double bond between C-4 and C-3, and
the original double bond between the position of C-2 and
C-3 was migrated to the position between C-2 and C-1,
which resulted in an E/Z mixture. At the same time, the
configuration at C-4 position in compound 3a , which was
equivalent to the C-5 position in compounds 4, remained
R by an unknown mechanism. Probably the interaction
between the oxygen atom in the hydroxyl group and the
silicon atom in the TBDMS protecting group of the
hydroxyl group at C-5 position had some effect on the
retention of the hydroxyl stereochemistry at the C-4
position. However, it should be stressed that the stereo-
chemistry of C-4 in compound 3a is not important
because these two adjacent hydroxyl groups would be
oxidized and cleaved by sodium periodate to form the
aldehyde 13 or 14 (Scheme 2). The E/Z mixture was
further reacted with tert-butyldimethylsilyl chloride to
afford the fully protected compounds, and the desired E
isomer 5 could be readily separated from the Z isomer
5a by silica gel column chromatography. The structures
of compounds 5 and 5a were determined by NMR on the
basis of the coupling constants (J ) of 4-H with the fluorine
atom at C-3 position. The J value was bigger when 4-H
and the fluorine atom were in E positions to each other
(J ) 35.87 Hz) than when they were in Z positions (J )
20.74 Hz). Extensive NOE studies of these two com-
pounds also supported the structural assignment. NOE
(1.40%) was observed between 2-H and 4-H in compound
5a when 4-H was irradiated, while no NOE was observed
between the same hydrogen atoms in compound 5. Also,
NOEs were observed between 5-H and 4-H in both
compound 5 (4.12%) and compound 5a (5.43%) when 5-H
was irradiated, which confirmed that the configurations
at the C-5 position in both compounds were R. Compound
5 was converted to an anomeric diol 6 through the typical
oxidation procedure using OsO4 and 4-methylmorpholine
N-oxide. Selective benzoylation of the primary hydroxyl
Resu lts a n d Discu ssion
Several synthetic approaches have been reported for
the synthesis of 4′-carbon-branched nucleosides, among
which reactions of various 5′-oxo nucleoside derivatives
such as 4′-formyl and 4′-acyl nucleosides have been
utilized.17a,20 The 4′-hydroxymethyl group is synthesized
by the Cannizzaro reaction, which is then converted to
the alkyl groups to afford various complex derivatives.21
This lengthy sequence was not readily applicable to the
purine nucleosides due to instability toward the neces-
sary oxidation step. Another interesting route employs
dimethyl L-tartrate and builds up the 4′-substituted
(14) For a review, see: Prisbe, E. J .; Magg, H.; Verheyden, J . P. H.;
Rydzewski, R. M. In Nucleosides and Nucleotides as Antitumor and
Antiviral Agents; Chu, C. K., Baker, D. C., Eds.; Pergamon: New York,
1993; pp 101-113.
(15) Maag, H.; Rydzewski, R. M.; McRoberts, M. J .; Crawford-Ruth,
D.; Verheyden, J . P.; Prisbe, E. J . J . Med. Chem. 1992, 37, 431.
(16) (a) Maguire, A. R.; Meng, W.-d.; Roberts, S. M.; Willetts, A. J .
J . Chem. Soc., Perkin Trans.
1 1993, 1795. (b) J enkins, I. D.;
Verheyden, J . P. H.; Moffatt, J . G. J . Am. Chem. Soc. 1976, 98, 3346.
(c) Guillerm, D.; Muzard, M.; Allart, B.; Guillerm, G. Bioorg. Med.
Chem. Lett. 1995, 5, 1455.
(17) (a) O-Yang, C.; Wu, H. Y.; Fraser-Smith, E.; Walker, K. A. M.
Tetrahedron Lett. 1992, 33, 37. (b) O-Yang, C.; Kurz, W.; Eugui, E.
M.; McRoberts, M. J .; Verheyden, J . P. H.; Kurz, L. J .; Walker, K. A.
M. Tetrahedron Lett. 1992, 33, 41.
(18) (a) Waga, T.; Ohrui, H.; Meguro, H. Nucleosides Nucleotides
1996, 15, 287. (b) Waga, T.; Nishizaki, T.; Ohrui, H.; Meguro, H. Biosci.,
Biotechnol., Biochem. 1993, 57, 1433.
(19) (a) Sugimoto, I.; Shuto, S.; Mori, S.; Shigeta, S.; Matsuda, A.
Bioorg. Med. Chem. Lett. 1999, 9, 385. (b) Nomura, M.; Shuto, S.;
Tanaka, M.; Mori, S.; Shigeta, S.; Matsuda, A. J . Med. Chem. 1999,
42, 2901. (c) Ohrui, H.; Kohgo, S.; Kitano, K.; Sakata, S.; Kodama, E.;
Yoshimura, K.; Matsuoka, M.; Shigeta, S.; Mitsuya, H. J . Med. Chem.
2000, 43, 4516.
(20) (a) Youssefyeh, R. D.; Verheyden, J . P. H.; Moffatt, J . G. J . Org.
Chem. 1979, 44, 1301. (b) J ones, G. H.; Taniguchi, M.; Tegg, D.; Moffatt,
J . G. J . Org. Chem. 1979, 44, 1309. (c) Maag, H.; Schimidt, B.; Rose,
S. J . Tetrahedron Lett. 1994, 35, 6449.
(21) (a) Marx, A.; Erdmann, P.; Senn, M.; Korner, S.; J ungo, T.;
Petretta, M.; Imwinkelried, P.; Dussy, A.; Kulicke, K, J .; Macko, L.;
Zehnder, M.; Giese, B. Helv. Chim. Acta 1996, 79, 1980. (b)Thrane,
H.; Fesnholt, J .; Regner, M.; Wengel, J . Tetrahedron 1995, 51, 10389.
(22) (a) Crich, D.; Hao, X. J . Org. Chem. 1998, 63, 3796. (b) Crich,
D.; Hao, X. J . Org. Chem. 1999, 64, 4016.
(23) Hafele, B.; J ager, V. A. Liebigs Ann. Chem. 1987, 85.
(24) (a) Morikawa, T.; Sasaki, H.; Mori, K.; Shiro, M.; Taguchi, T.;
Simmons-Smith Chem. Pharm. Bull. 1992, 40, 3189. (b) Choi, Y.; Lee,
K.; Hong, J . H.; Schinazi, R. F.; Chu, C. K. Tetrahedron Lett. 1998,
39, 4437.
J . Org. Chem, Vol. 69, No. 18, 2004 6035

Chen et al.
SCHEME 1a
a
Reagents: (a) CH3P(Ph)3Br, NaH, DMSO, THF; (b) TBDMSCl, imidazole, CH2Cl2; (c) OsO4, NMO, acetone, H2O; (d) BzCl, Py, 0 °C;
(e) PCC, 4 Å molecular sieves, CH2Cl2.
group of 6 by treatment with benzoyl chloride in the
solution of dry pyridine at 0 °C gave the corresponding
monobenzoate 7. The monobenzoylated compound was
then oxidized by pyridinium chlorochromate (PCC) in
CH2Cl2 to furnish the R,â-unsaturated ketone 8, the key
intermediate in the whole synthetic route, which was
subjected to a standard Grignard reaction procedure to
give a separable mixture of 9 and 10 in a ratio of 3:2 with
a total yield of 72%. The stereochemistry of these dia-
completed. In all of the cases for thymine, cytosine, and
adenine, the R/â anomers were readily separated by silica
gel column chromatography. The thymine nucleosides 17
and 26 were obtained together with their R isomers 19
and 28 in 73% and 71% yield, respectively, with a ratio
of R/â ) 1:3 within 1 h. Likewise, condensation of
compound 15 or 16 with silylated N4-benzoylcytosine in
anhydrous acetonitrile gave the protected cytosine de-
rivatives 18 or 27, respectively, as well as the R isomers
(R/â ) 1:3). After separation of the desired â anomers
from their R analogues on silica gel column chromatog-
raphy, ammonolysis using saturated methanolic am-
monia at room temperature was employed to deprotect
the individual anomers to afford the free nucleosides 23,
24, 32, and 33.
Condensation of compound 15 or 16 with silylated N6-
isobutyryladenine in dry acetonitrile at room tempera-
ture for 12 h gave a separable R and â mixture of the
protected adenine nucleosides 21/22 or 30/31 in a yield
of 63% and 62%, respectively, with a ratio of R/â ) 1:1
(Table 1). The â anomers (21 and 30) were separated and
deprotected by saturated methanolic ammonia at room
temperature for 12 h to give the target nucleosides 25
and 34, respectively.
1
stereomers 9 and 10 at C-2 was determined by H NMR
as well as the NOE studies for 18 and 20 (vide infra).
The signal of the proton of 2R-OH (or â-OH, δ 5.87 ppm)
in compound 9 was significantly downfield (∆δ ) 0.78
ppm) from that of the proton of 2S-OH (R-OH, δ 5.09
ppm, overlapped with the signal of 5-H) in compound 10,
due to the interaction of the â-OH with the bulky
5-TBDMS group. The tert-butyldimethylsilyl groups in
compound 9 were removed by tetrabutylammonium
fluoride to afford the trihydroxy compound 11. Oxidation
of compound 11 with sodium periodate gave the aldehyde
compound 13, which was reacted with acetic anhydride
in the solution of pyridine to produce the 3-fluoro-2,3-
unsaturated-4-ethynyl-D-furanose 15. The same series of
reactions including the deprotection, oxidation, and
acetylation was applied to compound 10 and furnished
the modified L-sugar moiety 16.
Compounds 15 and 16 proved to be suitable intermedi-
ates for coupling with various heterocyclic bases. Thus,
treatment of acetonitrile solution of 15 or 16 with suitably
protected forms of bases in the presence of trimethylsilyl
trifluoromethane sulfonate (TMSOTf) provided D- or
L-nucleosides in moderate to good yields as R/â mixtures
(Scheme 3). For trimethylsilylated pyrimidines, comple-
tion of the condensation reaction took less than 1 h, while
a prolonged reaction time increased the formation of the
R isomers. However, for purines, specifically for adenine,
it took about 12 h or more for the coupling reaction to be
The stereochemical assignments of these R and â
anomers were determined on the basis of NOE experi-
ments of the cytosine derivatives (18/20). NOE (3%) was
observed between the 6-H and the proton in the 4′-
ethynyl group in the R-cytosine derivative 20 when the
6-H was irradiated, whereas no NOE was observed
between the same positions in the â-isomer 18. This
assignment was also supported by lower-field chemical
shifts on the proton of the 4′-ethynyl group in compound
20 (R-form), compared to that of the 4′-ethynyl proton in
compound 18 (â-form), due to the deshielding effects by
the heterocyclic base. This assignment based on the NOE
6036 J . Org. Chem., Vol. 69, No. 18, 2004

3′-Fluoro-4′-ethynyl-2′,3′-unsaturated Nucleosides
SCHEME 2a
SCHEME 3a
a
Reagents: (a) silylated base, TMSOTf, CH3CN; (b) NH3/
a
CH3OH.
Reagents: (a) HCCMgBr, THF, 50 °C; (b) TBAF, HOAc, THF;
(c) NaIO4, EtOH, H2O; (d) Ac2O, Py.
TABLE 1. r/â Ra tio Obta in ed fr om th e Con d en sa tion
Rea ction
experiments was one of the major determinants for the
assignment of the intermediates 9 and 10.
15
16
All the synthesized 3′-fluoro-2′,3′-dideoxy-2′,3′-didehy-
dro-4′-ethynyl-D- and -L-furanosyl nucleosides (23-25,
32-34) were evaluated against HIV-1 in human periph-
eral blood mononuclear (PBM) cells in vitro.25 Among the
tested nucleosides, only the D-adenine analogue shows
moderate anti-HIV activity with an EC50 value of 25.1
µM (EC50 ) 0.004 µM for AZT) without cytotoxicity up
to 100 µM.
In conclusion, we described a new and efficient route
for the synthesis of 3′-fluoro-2′,3′-dideoxy-2′,3′-didehydro-
4′-ethynyl-D- and -L-furanosyl nucleosides. Our scheme
features a convergent approach in which D- and L-
nucleosides can be synthesized from the same starting
material to produce a series of 4′-ethynyl nucleosides.
This general method can be applied to the synthesis of
both 3′- and 4′-substituted 2′,3′-dideoxy-2′,3′-didehydro
nucleosides of biological interest.
thymine
19 (R)/17 (â) ) 1:3 28 (R)/26 (â) ) 1:3
20 (R)/18 (â) ) 1:3 29 (R)/27 (â) ) 1:3
N4-benzoylcytosine
N6-isobutyryladenine 22 (R)/21 (â) ) 1:1 31 (R)/30 (â) ) 1:1
with DMSO. After being stirred at room temperature for 30
min, the mixture was cooled to 0 °C again and then methyl-
triphenylphosphonium bromide (112 g, 0.314 mol) was added.
After being stirred at room temperature for 1 h, the resulting
slightly green mixture was cooled to 5 °C and treated with a
solution of compound 3 (33.01 g, 0.133 mol) in 200 mL of THF.
The reaction mixture was stirred at room temperature for
another 2 h, and then 200 mL of Et2O was added, the yellowish
solid was filtered off, and the filtrate was concentrated to
dryness. Purification on silica gel (hexanes/EtOAc, 25:1) gave
compound 4 (E/Z mixture, E-4/Z-4, 5:2) as a pale yellow oil
(29.8 g, 91.0%): MS (ESI) m/z 269 (M + Na)+. Anal. Calcd for
C
12H23O2FSi: C, 58.50; H, 9.41. Found: C, 58.48; H, 9.49.
(5R)-5,6-Di[(ter t-bu tyld im eth ylsilyloxy)m eth yl]-3E-flu -
or o-1,3-d ih exen e (5). Compound 4 (29.8 g, 0.121 mol) was
dissolved in 200 mL of CH2Cl2, and then tert-butyldimethylsily
chloride (27.44 g, 0.182 mol) was added together with imidazole
Exp er im en ta l Section
(5R)-5-Hydr oxy-6-[(ter t-bu tyldim eth ylsilyloxy)m eth yl]-
3-flu or o-1,3-d ih exen e (4). A suspension of NaH (11.8 g, 0.492
mol) in THF (960 mL) was cooled to 5 °C and then treated
(25) Chu, C. K.; Schinazi, R. F.; Ahn, M. K.; Ullas, G. V.; Gu, Z. P.
J . Med. Chem. 1989, 32, 612.
J . Org. Chem, Vol. 69, No. 18, 2004 6037

Chen et al.
(12.36 g, 0.182 mmol). The resulting mixture was stirred at
room temperature for 2 h until it was treated with ice and
diluted with CH2Cl2. The organic layers were combined, dried
over Na2SO4, and concentrated to dryness. The residue ob-
tained was purified on column chromatography (100% hex-
anes) to afford compound 5 as a yellowish oil (27.42 g, 62.9%).
The Z-form isomer 5a was also obtained as a yellowish oil (10.5
g, 24.1%).
67.5 (d, J ) 2.88 Hz), 65.8 (d, J ) 27.81 Hz), 64.3 (d, J ) 3.84
Hz), 26.0, 25.7, 18.7, 18.1, -4.8 (d, J ) 25.89 Hz), -5.4; MS
(ESI) m/z 499 (MH)+, 512 (M + Na)+. Anal. Calcd for C25H43O5-
FSi2: C, 60.20; H, 8.69. Found: C, 60.48; H, 8.83.
(5R)-1-O-Ben zoyl-5,6-d i[(ter t-b u t yld im et h ylsilyloxy)-
m eth yl]-3,4-d ih yd r o-3-flu or o-2-h exa n on e (8). To a solution
of compound 7 (14 g, 28.11 mmol) in CH2Cl2 (300 mL) were
added pyridium chlorochromate (14 g, 64.95 mmol) and 4 Å
molecular sieves (14 g). The resulting mixture was stirred at
room temperature for 4 h. The reaction mixture was then
filtered through a pad of silica gel, and the filtrate was
condensed. The residue was purified on the column chromato-
graph (hexanes/EtOAc, 50:1) to give compound 8 (10.04 g,
Compound 5: [R]27 -4.85 (c 0.75, acetone); 1H NMR
D
(CDCl3) δ 6.43 (m, 1H), 5.60 (d, J ) 17.08 Hz), 5.28 (dd, 1H, J
) 1.46, 11.23 Hz), 5.12 (dd, 1H, J ) 8.79, 20.74 Hz), 4.37 (m,
1H), 3.61 (ddd, 1H, J ) 0.98, 6.10, 10.01 Hz), 3.47 (dd, 1H, J
) 6.35, 10.01 Hz), 0.87 (s, 9H), 0.86 (s, 9H), 0.05 (d, 6H, J )
8.05 Hz), 0.04 (d, 6H, J ) 4.64 Hz); 13C NMR (CDCl3) δ 156.7
(d, J ) 247.40 Hz), 125.1 (d, J ) 25.89 Hz), 116.5 (d, J ) 5.75
Hz), 110.9 (d, J ) 21.10 Hz), 63.7 (d, J ) 12.47 Hz), 67.8, 31.3,
25.9, 18.3, 18.1, -4.5 (d, J ) 21.10 Hz), -5.4; MS (ESI) m/z
383 (M + Na)+. Anal. Calcd for C18H37O2FSi2: C, 59.95; H,
10.34. Found: C, 60.18; H, 10.39.
72.0% yield) as a yellowish oil: [R]25 -2.12 (c 0.35, acetone);
D
1H NMR (CDCl3) δ 8.12 (m, 2H), 7.60 (m, 1H), 7.48 (m, 2H),
5.82 (dd, 1H, J ) 22.29, 8.81 Hz), 5.19 (m, 3H), 3.62 (m, 1H),
3.54 (m, 1H), 0.92 (d, 9H, J ) 3.03 Hz), 0.88 (d, 9H, J ) 1.41
Hz), 0.06 (d, 6H, J ) 2.69 Hz), 0.04 (d, 6H, J ) 6.39 Hz); 13C
NMR (CDCl3) δ 188.3 (d, J ) 38.6 Hz), 165.6, 151.1 (d, J )
256.9 Hz), 133.4, 130.1, 128.6, 128.5, 124.6 (d, J ) 13.4 Hz),
67.7 (d, J ) 8 Hz), 67.3 (d, J ) 3.13 Hz), 67.0, 25.9, 18.3, 18.1,
-4.8, -5.4; MS (ESI) m/z 497 (MH)+, 519 (M + Na)+. Anal.
Calcd for C25H41O5FSi2‚0.1hexane: C, 60.84; H, 8.46. Found:
C, 60.95; H, 8.49.
Compound 5a : [R]24 +4.57 (c 1.25, acetone); 1H NMR
D
(CDCl3) δ 6.05 (m, 1H), 5.59 (d, J ) 17.08 Hz), 5.15 (dd, 1H, J
) 1.49, 10.98 Hz), 4.75 (dd, 1H, J ) 8.79, 35.87 Hz), 4.63 (dd,
J ) 6.35, 15.13 Hz, 1H), 3.55 (dd, 1H, J ) 6.35, 10.01 Hz),
3.44 (dd, 1H, J ) 5.37, 10.01 Hz), 0.84 (s, 9H), 0.83 (s, 9H),
0.03 (d, 6H, J ) 5.98 Hz), 0.02 (d, 6H, J ) 4.64 Hz); 13C NMR
(CDCl3) δ 156.1 (d, J ) 212. 20 Hz), 128.6 (d, J ) 25.89 Hz),
115.4 (d, J ) 4.79 Hz), 111.9 (d, J ) 13.43 Hz), 67.6, 67.5,
25.9, 25.8, 18.3, 18.2, -4.8 (d, J ) 2.88 Hz), -5.3 (J ) 10.55
Hz); MS (ESI) m/z 383 (M + Na)+. Anal. Calcd for C18H37O2-
FSi2: C, 59.95; H, 10.34. Found: C, 60.21; H, 10.43.
(2R,5R)-1-O-Ben zoyl-5,6-di[(ter t-bu tyldim eth ylsilyloxy)-
m eth yl]-3E-flu or o-2-h yd r oxyl-2-eth yn yl-3-h exen e (9) a n d
(2S,5R)-1-O-Ben zoyl-5,6-d i[(ter t-bu tyld im eth ylsilyloxy)-
m eth yl]-3E-flu or o-2-h yd r oxyl-2-eth yn yl-3-h exen e (10). To
a stirred solution of compound 8 (5.56 g, 11.21 mmol) in dry
THF (200 mL) was added ethynylmagnesium bromide (0.5 M
in THF, 34 mL, 17 mmol) under N2 atmosphere. The resulting
mixture was then stirred at 50 °C for 2 h until 50 mL of EtOAc
was added to terminate the reaction. After removal of the
solvent, saturated NH4Cl solution was added, and the mixture
was extracted several times with EtOAc. The organic layers
were combined, dried over anhydrous Na2SO4, and evaporated.
The residue was separated on column chromatography over
silica gel (hexanes/EtOAc, 50:1) to give the compound 9 (2.53
g, 43.2% yield) and compound 10 (1.69 g, 28.9% yield) as
yellowish oils.
(5R)-1,2-Dih yd oxy-5,6-d i[(ter t-bu tyld im eth ylsilyloxy)-
m eth yl]-3E-flu or o-3-h exen e (6). To a solution of compound
5 (36.4 g, 0.101 mol) in 500 mL of acetone at room temperature
was added 500 mL of a stock osmylation solution (prepared
by dissolving 85.58 g of 4-methylmorpholine N-oxide and 2 g
of osmium tetraoxide in 597 mL of water). The reaction
mixture was stirred at room temperature for 4 h. After the
reaction mixture was concentrated to half of the original
volume, the resulting solution was dissolved in EtOAc and
washed with saturated sodium bisulfite solution and brine.
The organic layers were combined, dried (Na2SO4), and
concentrated to give the crude diol 6 (anomeric mixture), which
was purified on column chromatography (CH2Cl2/MeOH, 50:
1) to give the pure compound 6 (33.03 g, 82.9% yield) as a
yellowish oil: 1H NMR (CDCl3) δ 5.19 (dd, 1H, J ) 8.54, 23.43
Hz), 4.73 (m, 1H), 4.41 (m, 1H), 3.95 (s, 1H), 3.79 (m, 1H),
3.72 (m, 1H), 3.65 (m, 1H), 3.33 (t, 1H, J ) 9.03 Hz), 2.22 (bs,
1H), 0.91 (s, 9H), 0.88 (s, 9H), 0.10 (d, 6H, J ) 0.98 Hz), 0.08
(s, 6H); 13C NMR (CDCl3) δ 158.2 (d, J ) 254.11 Hz), 111.6 (d,
J ) 18.18 Hz), 70.1 (d, J ) 33.56 Hz), 67.2, 66.9 (d, J ) 12.47
Hz), 64.0, 25.9, 25.7, 18.5, 18.1, -4.6, -4.9; MS (ESI) m/z 395
(MH)+, 417 (M + Na)+. Anal. Calcd for C18H39O4FSi2: C, 54.78;
H, 9.96. Found: C, 54.97; H, 10.12.
Compound 9: [R]24 +5.06 (c 5.40, acetone); 1H NMR
D
(CDCl3) δ 8.09 (m, 2H), 7.56 (m, 1H), 7.44 (m, 2H), 5.87 (s,
1H), 5.37 (dd, 1H, J ) 7.43, 25.04 Hz), 4.92 (dd, 1H, J ) 7.43,
12.91 Hz), 4.63 (d, 1H, J ) 11.35 Hz), 4.54 (d, 1H, J ) 11.35
Hz), 3.69 (m, 1H), 3.39 (t, 1H, J ) 8.3 Hz), 2.53 (s, 1H), 0.92
(s, 9H), 0.87 (s, 9H), 0.12 (d, 3H, J ) 3.13 Hz), 0.04 (d, 3H, J
) 3.91 Hz); 13C NMR (CDCl3) δ 166.0, 156.1 (d, J ) 258.9 Hz),
133.1, 129.9, 129.8, 128.3, 112.3, 81.6, 73.9, 69.5 (d, J ) 32.3
Hz), 67.9, 66.9 (d, J ) 10.1 Hz), 26.2, 25.7, 18.6, 18.0, -4.8 (d,
J ) 17.14 Hz), -5.4 (d, J ) 17.14 Hz); MS (ESI) m/z 523 (MH)+,
545 (M + Na)+. Anal. Calcd for C27H43O5FSi2‚0.1hexane: C,
62.38; H, 8.42. Found: C, 62.51; H, 8.26.
Compound 10: [R]24 +11.71 (c 1.15, acetone); 1H NMR
D
(CDCl3) δ 8.03 (m, 2H), 7.53 (m, 1H), 7.39 (m, 2H), 5.28 (ddd,
J ) 2.44, 8.54, 24.16 Hz, 1H), 5.09 (m, 2H), 4.58 (dd, 1H, J )
11.10 Hz), 4.51 (d, 1H, J ) 11.10 Hz), 3.67 (m, 1H), 3.39 (td,
1H, J ) 2.20, 9.03 Hz), 2.55 (s, 1H), 0.86 (d, 9H, J ) 2.67 Hz),
0.83 (d, 9H, J ) 2.44 Hz), 0.08 (d, 3H, J ) 1.46 Hz), 0.01 (dd,
3H, J ) 2.44, 8.30 Hz); 13C NMR (CDCl3) δ 166.1, 157.2 (d, J
) 262.74 Hz), 133.2, 129.9, 129.7, 128.3, 112.9, 80. 9, 73.8,
68.9 (d, J ) 3.84 Hz), 67.4, 66.7 (d, J ) 10.55 Hz), 26.0, 25.8,
18.6, 18.1, -5.4, -5.5 (d, J ) 17.14 Hz); MS (ESI) m/z 523
(MH)+, 545 (M + Na)+. Anal. Calcd for C27H43O5FSi2: C, 62.03;
H, 8.29. Found: C, 62.07; H, 8.28.
(2R,5R)-1-O-Ben zoyl-5,6-dih ydr oxy-3E-flu or o-2-h ydr oxy-
2-eth yn yl-3-h exen e (11). To a solution of compound 9 (1.57
g, 3.0 mmol) in 100 mL of THF were added tetrabutylammo-
nium fluoride (1.0 M in THF, 9 mL, 9.0 mmol) and HOAc (0.18
g, 3.0 mmol). The resulting mixture was then stirred at room
temperature for 2 h. After removal of the solvent, the residue
was subjected to column chromatography (CH2Cl2/MeOH, 20:
1) to give the compound 11 as a yellowish oil (0.86 g, 97.5%
(5R)-1-O-Ben zoyl-2-h yd r oxy-5,6-d i[(ter t-bu tyld im eth -
ylsilyloxy)m eth yl]-3E-flu or o-3-h exen e (7). To a solution of
compound 6 (21.2 g, 53.8 mmol) in dry pyridine (300 mL) was
added benzoyl chloride (6.81 g, 48.43 mmol) at 0 °C. The
reaction mixture was stirred at 0 °C for 2 h with the exclusion
of water. Then 20 mL of CH3OH was added to quench the
reaction. After removal of the solvents, the residue was
dissolved in CH2Cl2 and washed successively with saturated
NaHCO3 and CuSO4 solutions, dried (Na2SO4), and evapo-
rated. The pure compound 7 (20.27 g, 84.0% yield) was
obtained by purification on a flash column (hexanes/EtOAc,
50:1) as a yellowish oil. Some starting material remained and
was recovered: 1H NMR (CDCl3) δ 8.05 (m, 2H), 7.56 (m, 1H),
7.45 (m, 2H), 5.22 (dd, 1H, J ) 20.99, 8.55 Hz), 4.75 (m, 1H),
4.49 (d, 2H, J ) 5.13 Hz), 4.42 (m, 1H), 3.63 (m, 1H), 3.38 (m,
1H), 3.30 (s, 1H), 0.87 (d, 9H, J ) 0.82 Hz), 0.82 (d, 9H, J )
0.82 Hz), 0.04 (d, 6H, J ) 1.1 Hz), -0.02 (d, 6H, J ) 1.1 Hz);
13C NMR (CDCl3) δ 166.3, 159.1 (d, J ) 261.79 Hz), 133.1,
129.7, 128.3, 112.7 (d, J ) 18.22 Hz), 68.6 (d, J ) 11.51 Hz),
6038 J . Org. Chem., Vol. 69, No. 18, 2004

3′-Fluoro-4′-ethynyl-2′,3′-unsaturated Nucleosides
1
yield): [R]24 +5.96 (c 0.30, acetone); H NMR (CDCl3) δ 8.03
sphere until the acetate was consumed (detected by TLC). The
reaction was subsequently quenched with saturated aqueous
NaHCO3 solution and stirred until the evolution of CO2 ceased.
The resulting mixture was diluted with ethyl acetate, washed
with brine, dried over Na2SO4, filtered, and concentrated. The
residue was subjected to silica gel column chromatography
(CH2Cl2/MeOH, 100:1) to give the D- or L- R and â anomers of
the protected nucleosides.
D
(m, 2H), 7.55 (m, 1H), 7.42 (m, 2H), 5.88 (bs, 1H), 5.39 (dd,
1H, J ) 8.05, 24.40 Hz), 4.97 (m, 1H), 4.61 (dd, 1H, J ) 1.46,
11.23 Hz), 4.57 (dd, 1H, J ) 1.71, 11.23 Hz), 3.62 (dd, 1H, J )
2.63, 11.20 Hz), 3.52 (dd, 1H, J ) 7.57, 11.20 Hz), 2.66 (s, 1H);
13C NMR (CDCl3) δ 166.7, 158.7 (d, J ) 260.83 Hz), 133.8,
130.1, 129.5, 128.8, 109.9 (d, J ) 21.10 Hz), 80.6, 75.3, 69.8
(d, J ) 34.52 Hz), 68.4, 66.4 (d, J ) 10.55 Hz), 66.0; MS (ESI)
m/z 317 (M + Na)+. Anal. Calcd for C15H15O5F: C, 61.22; H,
5.14. Found: C, 60.96; H, 5.36.
1-(5-O-Ben zoyl-2,3-d id eoxy-2,3-d id eh yd r o-3-flu or o-4-
eth yn yl-â-D-fu r a n osyl)th ym in e (17) a n d Its r-Isom er (19).
A mixture of silylated thymine [prepared from 0.13 g (1.03
mmol) of thymine and 0.7 mL of N,O-bis(trimethylsilyl)-
acetamide (2.84 mmol)], 15 (0.24 g, 0.79 mmol), and TMSOTf
(0.16 mL, 0.86 mmol) in 10 mL of acetonitrile was stirred
under an argon atmosphere at room temperature for 1 h. After
extractive workup, purification by silica gel column chroma-
tography (CH2Cl2/MeOH, 100:1) gave â anomer 17 (0.16 g,
54.7% yield) as white needles and R-anomer 19 (0.053 g, 18.1%)
as a white solid.
(2S,5R)-1-O-Ben zoyl-5,6-dih ydr oxyl-3E-flu or o-2-h ydr ox-
yl-2-eth yn yl-3-h exen e (12). Using the same procedure de-
scribed for compound 11, compound 10 (1.44 g, 2.76 mmol)
was deprotected by TBAF (1.0 M in THF, 8.28 mL, 8.28 mmol)
and HOAc (0.17 g, 2.8 mmol) to give compound 12 (0.79 g,
97.3% yield) as a yellowish oil: [R]23 +8.43 (c 0.27, acetone);
D
1H NMR (CDCl3) δ 8.05 (m, 2H), 7.58 (m, 1H), 7.44 (m, 2H),
5.66 (s, 1H), 5.45 (dd, 1H, J ) 8.05, 24.41 Hz), 4.92 (s, 1H),
4.61 (m, 2H), 3.88 (d, 1H, J ) 11.35 Hz), 3.60 (m, 1H), 3.52
(m, 1H), 2.66 (d, 1H, J ) 1.71 Hz); 13C NMR (CDCl3) δ 166.5,
157.4 (d, J ) 259.87 Hz), 133.6, 129.9, 129.3, 128.6, 109.6 (d,
J ) 21.10 Hz), 80.3, 75.1, 70.0 (d, J ) 34.52 Hz), 68.3, 66.1 (d,
J ) 10.55 Hz), 66.0; MS (ESI) m/z 295 (MH)+, 317 (M + Na)+.
Anal. Calcd for C15H15O5F: C, 61.22; H, 5.14. Found: C, 61.11;
H, 5.36.
Compound 17: mp 189.5-191.0 °C; [R]23 +37.36 (c 0.4,
D
1
acetone); H NMR (CDCl3) δ 8.05 (bs, 1H), 8.02 (m, 2H), 7.63
(m, 1H), 7.49 (m, 2H), 7.09 (m, 2H), 5.47 (s, 1H), 4.84 (d, 1H,
J ) 12.69 Hz), 4.54 (d, 1H, J ) 12.69 Hz), 2.76 (s, 1H), 1.57 (s,
3H); 13C NMR (CDCl3) δ 165.3, 162.8, 159.5 (d, J ) 293.20
Hz), 150.1, 134.4, 133.9, 129.7, 129.1, 128.9, 112.0, 101.3 (d, J
) 9.67 Hz), 84.7 (d, J ) 13.69 Hz), 65.0, 11.5; MS (ESI) m/z
371 (MH)+, 393 (M + Na)+. Anal. Calcd for C19H15N2O5F: C,
61.62; H, 4.08; N, 7.56. Found: C, 61.32; H, 4.20; N, 7.27.
2,3-Did eoxy-2,3-d id eh yd r o-3-flu or o-4-eth yn yl-5-O-ben -
zoyl-1-O-a cetyl-D-fu r a n ose (15). To a solution of compound
11 (1.44 g, 4.90 mmol) in 24 mL of EtOH was added dropwise
a suspension of sodium periodate (2.52 g, 11.77 mmol) in 20
mL of water . The suspension mixture was stirred at room
temperature for 30 min, and then EtOAc and water were
added. The organic layer was separated and dried over Na2-
SO4. After removal of the solvent, the residue was purified by
a short silica gel column (hexanes/EtOAc, 6:1) to give com-
pound 13 (1.18 g, 91.9% yield) as a yellowish oil, which was
not stable enough.
Compound 13 (1.18 g, 4.50 mmol) was stirred with acetic
anhydride (11.8 mL) and dry pyridine (30 mL) at room
temperature for 3 h. Then ice-water (20 mL) was added, and
the mixture was extracted with CH2Cl2 several times. The
organic layers were combined, washed sequentially with
saturated NaHCO3 solution, saturated CuSO4 solution, and
brine, dried over Na2SO4, and concentrated. Chromatography
of the crude product in 10% hexanes/EtOAc gave the inter-
mediate 15 (1.16 g, 84.8%) as a yellowish oil: 1H NMR (CDCl3)
δ 8.14-7.27 (m, 5H), 6.86-6.79 (m, 1H), 5.50, 5.47 (2 × s, 1H),
4.82-4.44 (m, 2H), 2.80, 2.72 (2 × s, 1H), 2.13, 1.73 (2 × s,
3H); MS (ESI) m/z 327 (M + Na)+. Anal. Calcd for C16H13O5F:
C, 63.16; H, 4.31. Found: C, 63.24; H, 4.35.
Compound 19: mp 72.0-72.9 °C; [R]23 +138.23 (c 0.31,
D
acetone); 1H NMR (CDCl3) δ 9.53 (m, 1H), 8.03 (d, 2H, J )
7.81 Hz), 7.60 (m, 2H), 7.46 (m, 2H), 7.05 (d, 1H, J ) 2.91
Hz), 5.48 (s, 1H), 4.62 (m, 2H), 2.94 (s, 1H), 1.95 (s, 3H,); 13C
NMR (CDCl3) δ 165.4, 163.9, 158.9 (d, J ) 292.47 Hz), 150.6,
134.9, 133.7, 129.8, 129.0, 128.7, 112.2, 101.5 (d, J ) 9.59 Hz),
85.8 (d, J ) 13.43 Hz), 78.8, 78.3 (d, J ) 24.93 Hz), 77.0, 65.0,
12.7; MS (ESI) m/z 371 (MH)+, 393 (M + Na)+. Anal. Calcd
for C19H15N2O5F: C, 61.62; H, 4.08; N, 7.56. Found: C, 61.65;
H, 4.13; N, 7.32.
1-(5-O-Ben zoyl-2,3-d id eoxy-2,3-d id eh yd r o-3-flu or o-4-
eth yn yl-â-D-fu r a n osyl)-N4-ben zoylcytosin e (18) a n d Its
r-Isom er (20). Silylated N4-benzoylcytosine [prepared from
0.24 g (1.04 mmol) of N4-benzoylcytosine and 0.72 mL of N,O-
bis(trimethylsilyl)acetamide (2.92 mmol)], 15 (0.24 g, 0.79
mmol), and TMSOTf (0.16 mL, 0.86 mmol) in 10 mL of
acetonitrile were reacted at room temperature under an argon
atmosphere for 1 h. After extractive workup, isolation by silica
gel column chromatography (CH2Cl2/MeOH, 100:1) afforded
â anomer 18 (0.19 g, 52.4% yield) and R-anomer 20 (0.065 g,
17.9%) as white solids.
Compound 18: mp 90.5-91.7 °C; [R]24 +25.85 (c 0.3,
2,3-Did eoxy-2,3-d id eh yd r o-3-flu or o-4-eth yn yl-5-O-ben -
zoyl-1-O-a cetyl-L-fu r a n ose (16). Using the same procedure
described for compound 15, a solution of compound 12 (1.17
g, 3.98 mmol) in 21 mL of EtOH was oxidized by sodium
periodate (2.07 g, 9.67 mmol) in water (16 mL) to give
compound 14 (0.95 g, 3.63 mmol, 91.1% yield) as a yellowish
oil, which was then stirred with acetic anhydride (9.5 mL) and
dry pyridine (20 mL) at room temperature for 3 h to give
compound 16 (0.94 g, 85.2% yield) as yellowish syrup: 1H NMR
(CDCl3) δ 8.12-7.26 (m, 5H), 6.85-6.78 (m, 1H), 5.49, 5.46 (2
× s, 1H), 4.81-4.43 (m, 2H), 2.80, 2.72 (2 × s, 1H), 2.11, 1.72
(2 × s, 3H); MS (ESI) m/z 327 (M + Na)+. Anal. Calcd for
D
1
acetone); H NMR (CDCl3) δ 8.59 (bs, 1H), 7.97 (d, 2H), 7.91
(bs, 1H), 7.86 (m, 2H), 7.63 (m, 2H), 7.51 (m, 4H,), 7.10 (d,
1H, J ) 4.88 Hz), 5.70 (s, 1H), 4.74 (m, 2H), 2.79 (d, 1H, J )
1.95 Hz); 13C NMR (CDCl3) δ 167.6, 165.3, 159.1 (d, J ) 291.37
Hz), 144.2, 134.2, 133.6, 129.8, 129.2, 129.0, 127.8, 102.3 (d,
J ) 10.49 Hz), 87.6 (d, J ) 15.29 Hz), 79.3, 79.0 (d, J ) 24.93
Hz), 69.9, 65.1; MS (ESI) m/z 460 (MH)+, 482 (M + Na)+. Anal.
Calcd for C25H18N3O5F: C, 65.36; H, 3.95; N, 9.15. Found: C,
65.45; H, 3.89; N, 9.02.
Compound 20: mp 170.1-170.9 °C; [R]23 +149.80 (c 0.37,
D
acetone); 1H NMR (CDCl3) δ 8.74 (bs, 1H), 8.10 (bs, 1H), 8.07
(m, 2H), 7.91 (m, 2H), 7.63 (m, 2H), 7.52 (m, 4H), 7.02 (t, 1H,
J ) 1.95 Hz), 5.75 (s, 1H), 4.77 (dd, 1H, J ) 1.46, 12.20 Hz),
4.65 (dd, 1H, J ) 1.46, 12.20 Hz), 2.99 (d, 1H, J ) 1.95 Hz);
13C NMR (CDCl3) δ 168.2, 165.4, 158.4 (d, J ) 290.55 Hz),
144.3, 134.8, 133.4, 129.8, 129.2, 128.9, 127.6, 102.6 (d, J )
10.49 Hz), 88.6 (d, J ) 15.29 Hz), 79.3, 79.0 (d, J ) 24.93 Hz),
67.9, 64.7; MS (ESI) m/z 460 (MH)+, 482 (M + Na)+. Anal.
Calcd for C25H18N3O5F: C, 65.36; H, 3.95; N, 9.15. Found: C,
65.38; H, 3.96; N, 8.99.
C
16H13O5F: C, 63.16; H, 4.31. Found: C, 63.09; H, 4.41.
Gen er a l P r oced u r e for Con d en sa tion of Aceta te 15 or
16 w it h H et er ocyclic Ba ses. N,O-Bis(trimethylsilyl)acet-
amide was added at room temperature to a solution of the
heterocyclic base in anhydrous acetonitrile under argon at-
mosphere. The resulting mixture was then stirred at 50-60
°C for 2 h under argon atmosphere to form a clear solution.
After being cooled to room temperature, a solution of the
acetate 15 or 16 in dry acetonitrile was added followed by
trimethylsilyl trifluoromethanesulfonate (TMSOTf), and the
mixture was stirred at room temperature under argon atmo-
9-(5-O-Ben zoyl-2,3-d id eoxy-2,3-d id eh yd r o-3-flu or o-4-
et h yn yl-â-D-fu r a n osyl)-N6-isob u t ylr yla d en in e (21) a n d
J . Org. Chem, Vol. 69, No. 18, 2004 6039

Chen et al.
Its r-Isom er (22). Silylated N6-isobutylryladenine [prepared
from 0.36 g (1.18 mmol) of N6-isobutylryladenine and 1.08 mL
of N,O-bis(trimethylsilyl)acetamide (4.38 mmol)], 15 (0.36 g,
1.18 mmol), and TMSOTf (0.24 mL, 1.29 mmol) in 12 mL of
acetonitrile were reacted at room temperature under an argon
atmosphere for 12 h. After extractive workup, purification by
silica gel column chromatography (CH2Cl2/MeOH, 100:1) af-
forded â anomer 21 (0.17 g, 32.1% yield) and R-anomer 22 (0.18
g, 34.0%) as white solids.
â anomer 27 (0.19 g, 52.4% yield) and R-anomer 29 (0.063 g,
17.4%) as white solids.
Compound 27: mp 90.9-91.6 °C; [R]23 -26.47 (c 0.2,
D
1
acetone); H NMR (CDCl3) δ 8.59 (bs, 1H), 7.97 (d, 2H), 7.91
(bs, 1H), 7.86 (m, 2H), 7.63 (m, 2H), 7.51 (m, 4H), 7.10 (d, 1H,
J ) 4.88 Hz), 5.70 (s, 1H), 4.74 (m, 2H), 2.79 (d, 1H, J ) 1.95
Hz); 13C NMR (CDCl3) δ 167.7, 165.3, 159.1 (d, J ) 291.30 Hz),
144.2, 134.2, 133.7, 129.9, 129.2, 129.0, 128.7, 127.8, 102.6 (d,
J ) 10.49 Hz), 87.6 (d, J ) 15.29 Hz), 79.3, 79.0 (d, J ) 24.93
Hz), 69.8, 66.1; MS (ESI) m/z 460 (MH)+, 482 (M + Na)+. Anal.
Calcd for C25H18N3O5F: C, 65.36; H, 3.95; N, 9.15. Found: C,
65.19; H, 3.93; N, 9.05.
Compound 21: mp 98.5-99.3 °C; [R]25 +13.30 (c 0.23,
D
acetone); 1H NMR (CDCl3) δ 8.70 (s, 1H), 8.60 (s, 1H), 8.03 (s,
1H), 7.86 (m, 2H), 7.56 (m, 1H), 7.42 (m 2H), 7.16 (d, 1H, J )
3.42 Hz), 5.87 (s, 1H), 4.74 (d, 1H, J ) 12.45 Hz), 4.67 (d, 1H,
J ) 12.45 Hz), 3.21 (m, 1H), 2.81 (s, 1H), 1.30 (d, 6H, J ) 6.83
Hz); 13C NMR (CDCl3) δ 176.4, 165.6, 159.7 (d, J ) 293.43 Hz),
153.2, 151.2, 149.6, 140.5, 133.9, 129.8, 128.8, 122.1, 101.0 (d,
J ) 10.55 Hz), 84.5 (d, J ) 13.43 Hz), 79.1 (d, J ) 23.97 Hz),
77.7, 68.4, 65.2, 36.3, 19.4; MS (ESI) m/z 450 (MH)+, 472 (M
+ Na)+. Anal. Calcd for C23H20N5O4F‚1.1H2O: C, 58.87; H,
4.77; N, 14.92. Found: C, 58.84; H, 4.30; N, 14.80.
Compound 29: mp 170.5-172.6 °C; [R]25 -148.65 (c 1.31,
D
acetone); 1H NMR (CDCl3) δ 8.74 (bs, 1H), 8.10 (bs, 1H), 8.07
(m, 2H), 7.91 (m, 2H), 7.63 (m, 2H), 7.52 (m, 4H), 7.02 (t, 1H,
J ) 1.95 Hz), 5.75 (s, 1H), 4.77 (dd, 1H, J ) 1.46, 12.20 Hz),
4.65 (dd, 1H, J ) 1.46, 12.20 Hz), 2.99 (d, 1H, J ) 1.95 Hz);
13C NMR (CDCl3) δ 168.1, 165.4, 158.4 (d, J ) 290.55 Hz),
144.3, 134.8, 133.4, 129.8, 129.2, 128.9, 128.8, 127.6, 102.7 (d,
J ) 10.49 Hz), 88.6 (d, J ) 15.29 Hz), 79.3, 79.0 (d, J ) 24.93
Hz), 67.9, 64.7; MS (ESI) m/z 460 (MH)+, 482 (M + Na)+. Anal.
Calcd for C25H18N3O5F: C, 65.36; H, 3.95; N, 9.15. Found: C,
65.14; H, 3.83; N, 9.17.
Compound 22: mp 81.1-82.6 °C; [R]24 +162.15 (c 0.25,
D
acetone); 1H NMR (CDCl3) δ 8.73 (s, 1H), 8.58 (s, 1H), 8.29 (s,
1H), 8.06 (m, 2H), 7.63 (m, 1H), 7.50 (m 2H), 7.15 (dd, 1H, J
) 3.91, 1.46 Hz), 5.74 (s, 1H), 4.73 (d, 1H, J ) 12.20 Hz), 4.66
(d, 1H, J ) 12.20 Hz), 3.17 (m, 1H), 2.89 (s, 1H), 1.32 (d, 6H,
J ) 6.83 Hz); 13C NMR (CDCl3) δ 176.0, 165.4, 159.8 (d, J )
292.47 Hz), 153.1, 151.1, 149.5, 140.6, 133.7, 129.8, 128.7,
122.2, 101.0 (d, J ) 10.55 Hz), 83.9 (d, J ) 13.43 Hz), 78.9,
78.4 (d, J ) 24.93 Hz), 68.2, 64.6, 36.3, 19.2; MS (ESI) m/z
450 (MH)+, 472 (M + Na)+. Anal. Calcd for C23H20N5O4F‚
0.6H2O: C, 60.02; H, 4.64; N, 15.22. Found: C, 60.18; H, 4.59;
N, 14.96.
9-(5-O-Ben zoyl-2,3-d id eoxy-2,3-d id eh yd r o-3-flu or o-4-
eth yn yl-â-L-fu r a n osyl)-N6-isobu tylr yla d en in e (30) a n d Its
r-Isom er (31). Silylated N6-isobutylryladenine [prepared from
0.36 g (1.18 mmol) of N6-isobutylryladenine and 1.08 mL of
N,O-bis(trimethylsilyl)acetamide (4.38 mmol)], 16 (0.36 g, 1.18
mmol), and TMSOTf (0.24 mL, 1.29 mmol) in 12 mL of
acetonitrile were reacted at room temperature under an argon
atmosphere for 12 h. After extractive workup, purification by
silica gel column chromatography (CH2Cl2/MeOH, 100:1) af-
forded â anomer 30 (0.17 g, 32.1% yield) and R-anomer 31 (0.16
g, 30.2% yield) as white solids.
1-(5-O-Ben zoyl-2,3-d id eoxy-2,3-d id eh yd r o-3-flu or o-4-
eth yn yl-â-L-fu r a n osyl)th ym in e (26) a n d Its r-Isom er (28).
A mixture of silylated thymine [prepared from 0.13 g (1.03
mmol) of thymine and 0.7 mL of N,O-bis(trimethylsilyl)-
acetamide (2.84 mmol)], 16 (0.24 g, 0.79 mmol), and TMSOTf
(0.16 mL, 0.86 mmol) in 10 mL of acetonitrile was stirred
under an argon atmosphere at room temperature for 1 h. After
extractive workup, purification by silica gel column chroma-
tography (CH2Cl2/MeOH, 100:1) gave â anomer 26 (0.16 g,
54.7% yield) as white needles and R-anomer 28 (0.057 g, 19.5%)
as a white solid.
Compound 30: mp 98.3-99.6 °C; [R]23 -13.37 (c 0.53,
D
acetone); 1H NMR (CDCl3) δ 8.70 (s, 1H), 8.60 (s, 1H), 8.03 (s,
1H), 7.86 (m, 2H), 7.56 (m, 1H), 7.42 (m 2H), 7.16 (d, 1H, J )
3.42 Hz), 5.87 (s, 1H), 4.74 (d, 1H, J ) 12.45 Hz), 4.67 (d, 1H,
J ) 12.45 Hz), 3.21 (m, 1H), 2.81 (s, 1H), 1.30 (d, 6H, J ) 6.83
Hz); 13C NMR (CDCl3) δ 176.4, 165.6, 159.7 (d, J ) 293.43 Hz),
153.2, 151.2, 149.6, 140.5, 133.9, 129.8, 128.8, 122.1, 101.0 (d,
J ) 10.55 Hz), 84.5 (d, J ) 13.43 Hz), 79.1 (d, J ) 23.97 Hz),
77.7, 68.4, 65.2, 36.3, 19.4; MS (ESI) m/z 450 (MH)+, 472 (M
+ Na)+. Anal. Calcd for C23H20N5O5F‚1.2H2O: C, 58.64; H,
4.79; N, 14.87. Found: C, 58.69; H, 4.72; N, 14.61.
Compound 26: mp 191.1-191.6 °C; [R]23 -36.57 (c 0.4,
D
1
acetone); H NMR (CDCl3) δ 8.05 (bs, 1H), 8.02 (m, 2H), 7.63
Compound 31: mp 81.5-83.2 °C; [R]28 -161.52 (c 1.21,
D
(m, 1H), 7.49 (m, 2H), 7.09 (m, 2H), 5.47 (s, 1H), 4.84 (d, 1H,
J ) 12.69 Hz), 4.54 (d, 1H, J ) 12.69 Hz), 2.76 (s, 1H), 1.57 (s,
3H); 13C NMR (CDCl3) δ 165.3, 162.8, 159.5 (d, J ) 293.20
Hz), 150.1, 134.4, 133.9, 129.7, 129.1, 128.9, 112.0, 101.3 (d, J
) 9.67 Hz), 84.7 (d, J ) 13.69 Hz), 65.0, 11.5; MS (ESI) m/z
371 (MH)+, 393 (M + Na)+. Anal. Calcd for C19H15N2O5F: C,
61.62; H, 4.08; N, 7.56. Found: C, 61.60; H, 4.25; N, 7.34.
acetone); 1H NMR (CDCl3) δ 8.73 (s, 1H), 8.58 (s, 1H), 8.29 (s,
1H), 8.06 (m, 2H), 7.63 (m, 1H), 7.50 (m 2H), 7.15 (dd, 1H, J
) 3.91, 1.46 Hz), 5.74 (s, 1H), 4.73 (d, 1H, J ) 12.20 Hz), 4.66
(d, 1H, J ) 12.20 Hz), 3.17 (m, 1H), 2.89 (s, 1H), 1.32 (d, 6H,
J ) 6.83 Hz); 13C NMR (CDCl3) δ 176.0, 165.4, 159.8 (d, J )
292.47 Hz), 153.1, 151.1, 149.5, 140.6, 133.7, 129.8, 128.7,
122.2, 101.0 (d, J ) 10.55 Hz), 83.9 (d, J ) 13.43 Hz), 78.9,
78.4 (d, J ) 24.93 Hz), 68.2, 64.6, 36.3, 19.2; MS (ESI) m/z
450 (MH)+, 472 (M + Na)+. Anal. Calcd for C23H20N5O5F‚
0.9H2O: C, 59.33; H, 4.72; N, 15.04. Found: C, 59.50; H, 4.56;
N, 14.67.
Compound 28: mp 71.6-73.0 °C; [R]27 -139.11 (c 1.41,
D
acetone); 1H NMR (CDCl3) δ 9.53 (m, 1H), 8.03 (d, 2H, J )
7.81 Hz), 7.60 (m, 2H), 7.46 (m, 2H), 7.05 (d, 1H, J ) 2.91
Hz), 5.48 (s, 1H), 4.62 (m, 2H), 2.94 (s, 1H), 1.95 (s, 3H); 13C
NMR (CDCl3) δ 165.4, 163.9, 158.9 (d, J ) 292.47 Hz), 150.6,
134.9, 133.7, 129.8, 129.0, 128.7, 112.2, 101.5 (d, J ) 9.59 Hz),
85.8 (d, J ) 13.43 Hz), 78.8, 78.3 (d, J ) 24.93 Hz), 77.0, 65.0,
12.7; MS (ESI) m/z 371 (MH)+, 393 (M + Na)+. Anal. Calcd
for C19H15N2O5F: C, 61.62; H, 4.08; N, 7.56. Found: C, 61.65;
H, 4.25; N, 7.36.
1-(2,3-Did eoxy-2,3-d id eh yd r o-3-flu or o-4-et h yn yl-â-D-
fu r a n osyl)th ym in e (23). Compound 17 (120 mg, 0.32 mmol)
was stirred in saturated methanolic ammonia solution (30 mL)
at room temperature overnight. Upon completion, the solvent
was removed under reduced pressure by rotary evaporation.
The resulting syrup was purified on a silica gel column (CH2-
Cl2/MeOH, 20:1) to afford pure free nucleoside 23 (78 mg,
1-(5-O-Ben zoyl-2,3-d id eoxy-2,3-d id eh yd r o-3-flu or o-4-
et h yn yl-â-L-fu r a n osyl)-N4-b en zoylcyt osin e (27) a n d It s
r-Isom er (29). Silylated N4-benzoylcytosine [prepared from
0.24 g (1.04 mmol) of N4-benzoylcytosine and 0.72 mL of N,O-
bis(trimethylsilyl)acetamide (2.92 mmol)], 16 (0.24 g, 0.79
mmol), and TMSOTf (0.16 mL, 0.86 mmol) in 10 mL of
acetonitrile were reacted at room temperature under an argon
atmosphere for 1 h. After extractive workup, isolation by silica
gel column chromatography (CH2Cl2/MeOH, 100:1) afforded
90.5%) as a white solid: mp 195.0-196.2 °C; [R]24 -90.83 (c
D
0.7, CH3OH); 1H NMR (CD3OD) δ 7.84 (s, 1H), 7.00 (dd, 1H, J
) 4.34, 1.07 Hz), 5.57 (s, 1H), 3.83 (d, 1H, J ) 12.52 Hz), 3.72
(d, 1H, J ) 12.52 Hz), 3.22 (s, 1H), 1.84 (s, 3H); 13C NMR (CD3-
OD) δ 165.3, 160.1 (d, J ) 287.55 Hz), 151.5, 137.4, 110.3,
101.0 (d, J ) 10.74 Hz), 84.9 (d, J ) 15.34 Hz), 80.7 (d, J )
23.77 Hz), 78.0, 76.6, 64.0, 11.3; UV (CH3OH) λmax 262.0 nm
(ꢀ 21280); MS (ESI) m/z 267 (MH)+, 289 (M + Na)+. Anal. Calcd
6040 J . Org. Chem., Vol. 69, No. 18, 2004

3′-Fluoro-4′-ethynyl-2′,3′-unsaturated Nucleosides
for C12H11N2O4F: C, 54.14; H, 4.16; N, 10.52. Found: C, 53.91;
H, 4.28; N, 10.33.
Hz), 84.9 (d, J ) 15.34 Hz), 80.7 (d, J ) 23.77 Hz), 78.1, 76.6,
64.1, 11.3; UV (CH3OH) λmax 262.5 nm (ꢀ 21 466); MS (ESI)
m/z 267 (MH)+, 289 (M + Na)+. Anal. Calcd for C12H11N2O4F:
C, 54.14; H, 4.16; N, 10.52. Found: C, 54.24; H, 4.16; N, 10.54.
1-(2,3-Did eoxy-2,3-d id eh yd r o-3-flu or o-4-et h yn yl-â-L-
fu r a n osyl)cytosin e (33). Conversion of 27 (120 mg, 0.26
mmol) to 33 was accomplished by using the same procedure
as described for 17. The obtained residue was purified by a
flash silica gel column chromatography with 10% MeOH in
CH2Cl2 to give 33 (59 mg, 90.4%) as a white solid.
1-(2,3-Did eoxy-2,3-d id eh yd r o-3-flu or o-4-et h yn yl-â-D-
fu r a n osyl)cytosin e (24). Conversion of 18 (150 mg, 0.33
mmol) to 24 was accomplished by using the same procedure
as described for 17. The obtained residue was purified by a
flash silica gel column chromatography with 10% MeOH in
CH2Cl2 to give 24 (74 mg, 89.3%) as a white solid: mp 219.3-
219.6 °C dec; [R]23 -88.37 (c 0.3, CH3OH); 1H NMR (CD3OD)
D
δ 8.01 (d, 1H, J ) 7.44 Hz), 7.07 (d, 1H, J ) 4.70 Hz), 5.86 (d,
1H, J ) 7.44 Hz), 5.86 (s, 1H), 3.81 (d, 1H, J ) 12.70 Hz),
3.71 (d, 1H, J ) 12.70 Hz), 3.22 (s, 1H); 13C NMR (CD3OD) δ
166.6, 159.9 (d, J ) 288.63 Hz), 157.3, 142.3, 101.4 (d, J )
9.59 Hz), 95.2, 85.9 (d, J ) 15.38 Hz), 80.7, 78.2, 76.5, 64.0;
UV (CH3OH) λmax 238.0 nm (ꢀ 11 370), 268.0 nm (ꢀ 10 893);
MS (ESI) m/z 252 (MH)+, 274 (M + Na)+. Anal. Calcd for
Compound 33: mp 218.7-219.5 °C dec; [R]23D 89.188 (c 0.25,
1
CH3OH); H NMR (CD3OD) δ 8.01 (d, 1H, J ) 7.44 Hz), 7.07
(d, 1H, J ) 4.70 Hz), 5.86 (d, 1H, J ) 7.44 Hz), 5.86 (s, 1H),
3.81 (d, 1H, J ) 12.70 Hz), 3.71 (d, 1H, J ) 12.70 Hz), 3.22 (s,
1H); 13C NMR (CD3OD) δ 166.6, 159.9 (d, J ) 288.63 Hz),
157.3, 142.3, 101.4 (d, J ) 9.59 Hz), 95.2, 85.9 (d, J ) 15.38
Hz), 80.7, 78.2, 76.5, 64.0; UV (CH3OH) λmax 238.0 nm (ꢀ
11 395), 268.0 nm (ꢀ 10 868); MS (ESI) m/z 252 (MH)+, 274
(M + Na)+. Anal. Calcd for C11H10N3O3F‚0.2H2O: C, 51.85;
H, 4.11; N, 16.49. Found: C, 51.73; H, 4.08; N, 16.21.
C
11H10N3O3F‚0.25H2O: C, 51.66; H, 4.14; N, 16.43. Found: C,
52.05; H, 4.14; N, 16.05.
9-(2,3-Did eoxy-2,3-d id eh yd r o-3-flu or o-4-et h yn yl-â-D-
fu r a n osyl)a d en in e (25). Compound 25 was prepared on a
0.35 mmol scale following the same procedure used for
compound 17. Purification on silica gel using 5% MeOH in CH2-
Cl2 as eluent gave 85 mg of 25 (88.3%) as a white solid.
9-(2,3-Did eoxy-2,3-d id eh yd r o-3-flu or o-4-et h yn yl-â-L-
fu r a n osyl)a d en in e (34). Compound 34 was prepared on a
0.30 mmol scale following the same procedure used for
compound 17. Purification on silica gel using 5% MeOH in CH2-
Cl2 as eluent gave 34 (73 mg, 88.5%) as a white solid.
Compound 25: mp 168.3-169.4 °C; [R]27 -136.61 (c 0.33,
D
1
CH3OH); H NMR (CD3OD) δ 8.35 (s, 1H), 8.20 (s, 1H), 7.10
(d, 1H, J ) 4.39 Hz), 5.82 (s, 1H), 3.85 (d, 1H, J ) 12.69 Hz),
3.74 (d, 1H, J ) 12.69 Hz), 3.29 (s, 1H); 13C NMR (CD3OD) δ
160.1 (d, J ) 288.64 Hz), 156.3, 152.8, 149.3, 140.3, 119.0,
110.9 (d, J ) 10.55 Hz), 84.2 (d, J ) 14.38 Hz), 81.7, 81.5,
77.4, 64.4; UV (CH3OH) λmax 258.0 nm (ꢀ 14 252); MS (ESI)
m/z 276 (MH)+, 298 (M + Na)+. Anal. Calcd for C12H10N2O2F‚
0.2H2O: C, 51.69; H, 3.76; N, 25.12. Found: C, 52.02; H, 3.66;
N, 24.82.
Compound 34: mp 168.8-169.5 °C; [R]24 +134.67 (c 0.42,
D
1
CH3OH); H NMR (CD3OD) δ 8.35 (s, 1H), 8.20 (s, 1H), 7.10
(d, 1H, J ) 4.39 Hz), 5.82 (s, 1H), 3.85 (d, 1H, J ) 12.69 Hz),
3.74 (d, 1H, J ) 12.69 Hz), 3.29 (s, 1H); 13C NMR (CD3OD) δ
160.1 (d, J ) 288.64 Hz), 156.3, 152.8, 149.3, 140.3, 119.0,
110.9 (d, J ) 10.55 Hz), 84.2 (d, J ) 14.38 Hz), 81.7, 81.5,
77.4, 64.4; UV (CH3OH) λmax 258.5 nm (ꢀ 14 261); MS (ESI)
m/z 276 (MH)+, 298 (M + Na)+. Anal. Calcd for C12H10N5O2F:
C, 52.37; H, 3.66; N, 25.44. Found: C, 52.51; H, 3.66; N, 25.49.
1-(2,3-Did eoxy-2,3-d id eh yd r o-3-flu or o-4-et h yn yl-â-L-
fu r a n osyl)th ym in e (32). Using the same procedure described
for compound 17, compound 26 (100 mg, 0.27 mmol) was
treated with the ammonial saturated methanol (30 mL) at
room-temperature overnight to give compound 32 (64 mg,
89.1%) as a white solid after flash column chromatography
(CH2Cl2/MeOH, 20:1).
Ack n ow led gm en t. This research was supported by
a U.S. Public Health Service Grant (AI32351) from the
National Institutes of Health and by the Department
of Veterans Affairs.
Compound 32: mp 195.2-196.7 °C; [R]23 +89.84 (c 0.95,
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
D
1
CH3OH); H NMR (CD3OD) δ 7.85 (d, 1H, J ) 1.22 Hz), 7.00
1
NMR for compounds 2, 5-11, and 17-34 and H NMR for the
(dd, 1H, J ) 1.46, 4.64 Hz), 5.57 (d, 1H, J ) 1.46 Hz), 3.83 (d,
1H, J ) 12.69 Hz), 3.72 (dd, 1H, J ) 12.69 Hz), 3.23 (s, 1H),
1.84 (d, 3H, J ) 1.22 Hz); 13C NMR (CD3OD) δ 165.3, 160.1
(d, J ) 287.54 Hz), 151.5, 137.4, 110.3, 101.0 (d, J ) 10.74
mixture E-4/Z-4. This material is available free of charge via
the Internet at http://pubs.acs.org.
J O049597H
J . Org. Chem, Vol. 69, No. 18, 2004 6041