A Completely Diastereoselective Electrophilic Fluorination of a Chiral, Noncarbohydrate Sugar Ring Precursor: Application to the Synthesis of Several Novel 2′-Fluoronucleosides

Article abstract of DOI:10.1021/jo9717898

A new and completely diastereoselective method for the introduction of fluorine into a noncarbohydrate sugar ring precursor has been developed. The use of N-fluorodibenzenesulfonimide (5) for the electrophilic fluorination of chiral lactone 4, which is derived from L-glutamic acid, yields the key intermediate 6. This is transformed into an anomeric acetate 8 and is used for the synthesis of a number of novel α-2′-fluoronucleosides. Since glutamic acid is used as the synthetic starting material, the L enantiomer may also be synthesized simply by using D-glutamic acid. The incorporation of fluorine into the 2′ position of the nucleoside provides several advantages including acid stability of the anomeric bond and general resistance to oxidative metabolism. Further, fluorine is a close mimic of hydroxyl groups in size and polarity and in its ability to act as a hydrogen bond acceptor. This may aid in the recognition of these nucleosides by the enzymes involved in nucleoside activation.

Full text of DOI:10.1021/jo9717898

J . Org. Chem. 1998, 63, 2161-2167
2161
A Com p letely Dia ster eoselective Electr op h ilic F lu or in a tion of a
Ch ir a l, Non ca r boh yd r a te Su ga r Rin g P r ecu r sor : Ap p lica tion to
th e Syn th esis of Sever a l Novel 2′-F lu or on u cleosid es
J . J effrey McAtee,† Raymond F. Schinazi,‡,§ and Dennis C. Liotta*,†
Emory University, Departments of Chemistry and Pediatrics, Atlanta, Georgia 30322, and
Veterans Affairs Medical Center, Decatur, Georgia, 30033
Received September 26, 1997
A new and completely diastereoselective method for the introduction of fluorine into a noncarbo-
hydrate sugar ring precursor has been developed. The use of N-fluorodibenzenesulfonimide (5) for
the electrophilic fluorination of chiral lactone 4, which is derived from L-glutamic acid, yields the
key intermediate 6. This is transformed into an anomeric acetate 8 and is used for the synthesis
of a number of novel R-2′-fluoronucleosides. Since glutamic acid is used as the synthetic starting
material, the L enantiomer may also be synthesized simply by using D-glutamic acid. The
incorporation of fluorine into the 2′ position of the nucleoside provides several advantages including
acid stability of the anomeric bond and general resistance to oxidative metabolism. Further, fluorine
is a close mimic of hydroxyl groups in size and polarity and in its ability to act as a hydrogen bond
acceptor. This may aid in the recognition of these nucleosides by the enzymes involved in nucleoside
activation.
In tr od u ction
(1.35 Å) is so similar to the C-O bond length (1.43 Å)
and because fluorine is a hydrogen-bond acceptor. The
ability of fluorine to mimic a hydroxyl group makes this
atom uniquely suited to nucleoside analogues as a
replacement of OH in the sugar portion of a nucleoside.
In addition to our long standing interest in the synthesis
of novel nucleoside analogues,3 we were interested in
incorporating an R-fluorine substituent at the 2′ position
of the sugar ring for several reasons. First, the elec-
tronegativity of fluorine should stabilize the anomeric
bond and suppress a significant pathway of in vivo
decomposition,4 thereby improving the acid stability of
the nucleoside (Scheme 1).
Second, hydroxyl groups often serve as “handles” for
the first step in oxidative degradation of biomolecules in
vivo.2c By replacing OH with F, it is possible to create a
ribo-like sugar that has a substituent at the 2′ position
sterically and electronically similar to a hydroxyl group,
but which cannot undergo oxidative catabolism. Thus,
the in vivo half-life of the compound may be improved.
Finally, few of the ribo or “down” 2′-fluoro nucleoside
derivatives were known. Therefore, we endeavored to
find a simple and efficient synthesis of these compounds
in order to generate novel analogues for biological evalu-
ation.
The controlled introduction of fluorine into organic
molecules, especially biomolecules and analogues of
natural products, has received much attention from
synthetic organic chemists in recent years. A number
of excellent books and reviews on the synthetic aspects
of selective C-F bond formation1 and the biological
effects of fluorine introduction into organic molecules2
exist. Fluorine is a close steric replacement for hydrogen,
and being the most electronegative element, it is capable
of producing significant electronic changes in a molecule
with minimal steric perturbation. In combination with
the above factors, the higher strength of the C-F bond
(116 kcal/mol vs C-H ) 100 kcal/mol) can cause changes
in substrate metabolism when fluorinated biomolecules
are used as drugs.
Fluorine may also serve as an isopolar and isosteric
mimic of a hydroxyl group since the C-F bond length
* Address correspondence to this author at Emory University,
Department of Chemistry, 1515 Pierce Drive, Atlanta, GA 30322.
Telephone: (404) 727-6602. Fax: (404) 727-6586. E-mail: dliotta@
emory.edu.
† Department of Chemistry.
‡ Department of Pediatrics.
§ Veterans Affairs Medical Center.
(1) (a) Synthetic Fluorine Chemistry; Olah, G., Chambers, R.,
Prakash, G. K. S., Eds.; J ohn Wiley and Sons: New York, 1992. (b)
Welch, J . T. Tetrahedron 1987, 43, 3123. (c) Wilkinson, J . A. Chem.
Rev. (Washington, D.C.) 1992, 92, 505. (d) Purrington, S. T.; Kagen,
B. S. Chem. Rev. (Washington, D.C.) 1986, 86, 997. (e) Schlosser, M.
Tetrahedron 1978, 34, 3.
(2) (a) Filler, R. In Organofluorine Compounds in Medicinal Chem-
istry and Biomedical Applications; Filler, R., Ed.; Studies in Organic
Chemistry 48; Elsevier: New York, 1993; pp 1-386. (b) Fluorine in
Bioorganic Chemistry, Welch, J . T., Eswarakrishnan, S., Eds.; Wiley:
New York, 1991; pp 1-261. (c) Biomedicinal Aspects of Fluorine
Chemistry; Filler, R., Kobayashi, Y., Eds.; Elsevier: New York, 1982.
(d) Chambers, R. D. Fluorine in Organic Chemistry; Wiley: New York,
1973; pp 4-7. (e) Fluorine Containing Molecules; Liebman, J . F.,
Greenburg, A.; Dolbier, W. R., J r., Eds.; VCH: New York, 1988; pp
1-346.
Herein we report the development of a completely
diastereoselective reaction for effecting the introduction
of fluorine into the sugar portion of novel nucleoside
analogues. The key step in our synthetic route is the
fluorination of a chiral, noncarbohydrate sugar ring
precursor (4S)-5-(tert-butyldiphenylsiloxy)pentan-4-olide
(4) (a) York, J . L. J . Org. Chem. 1981, 46, 2171. (b) Marquez, C. K.;
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) Coderre, J . A.; Santi, D. V.; Matsuda, A.; Watanabe, K. A.;
Fox, J . J . J . Med. Chem. 1983, 26, 1149. (d) Chou, T.-C.; Feinberg, A.
J .; Vidal, P.; Reichman, U.; Watanabe, K. A.; Fox, J . J . Cancer Res.
1981, 41, 3336. (e) Marquez, V. E.; Tseng, C. K. H.; Kelley, J . A.;
Mitsuya, H.; Broder, S.; Roth, J . S.; Driscoll, J . S. Biochem. Pharmacol.
1987, 36(17), 2719.
(3) (a) Liotta, D. C.; Strange, L. E.; Hoong, L. K. J . Org. Chem. 1992,
57, 5563. (b) Choi, W. B.; Wilson, L. J .; Yeola, S.; Liotta, D. C.; Schinazi,
R. F. J . Am. Chem. Soc. 1991, 113, 9377. (c) Xia, X.; Wang, J .; Hager,
M. W.; Sisti, N.; Liotta, D. C. Tetrahedron Lett. 1997, 38(7), 1111.
S0022-3263(97)01789-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/05/1998

2162 J . Org. Chem., Vol. 63, No. 7, 1998
McAtee et al.
Sch em e 1
Sch em e 3
Sch em e 2
Resu lts a n d Discu ssion
Lactone 4 was synthesized by the route shown in
Scheme 2 from L-glutamic acid as described by Ravid et
al.7a and Taniguchi et al.7b The enolate of lactone 4,
prepared at -78 °C with LiHMDS in THF, is known to
be stable. Several syntheses using this enolate have been
performed by our group and others,8 including addition
of electrophiles such as diphenyl diselenide, diphenyl
disulfide, and alkyl halides in high yield. However,
addition of a THF solution of 5 to the enolate of 4 gave
poor yields of the desired monofluorinated product 6.
Numerous byproducts were formed including what we
surmise to be a difluorinated lactone that is inseparable
from other impurities. For this reason, the order of
addition of the reagents was altered such that lactone 4
and NFSi 5 were dissolved together in THF and cooled
to -78 °C. Slow addition of LiHMDS resulted in a
reaction yielding 6 as the only product in addition to a
small amount of unreacted starting material (Scheme 2).
Fluorolactone 6 could be obtained in 50-70% yield
after silica gel column chromatography and crystalliza-
tion. Remarkably, this reaction yielded a single diaste-
reomer of 6, presumably due to the interaction of the
sterically bulky TBDPS group and the bulky fluorinating
reagent 5. Identification of fluorolactone 6 as the R or
“down” fluoro isomer was accomplished by comparison
to previously published NMR data9 and by X-ray crystal
structure determination of its enantiomer 20.
(4) using the electrophilic fluorine source N-fluorodiben-
zenesulfonimide (5) (Scheme 2). This relatively new class
of N-fluorosulfonimide reagents was originally developed
by Barnette5 in 1984 and since then has seen much
refinement and use as a convenient and highly reactive
source of electrophilic fluorine.6 Most often, these re-
agents are used to deliver fluorine to nucleophiles such
as enolates and metalated aromatics.6a Specifically,
N-fluorodibenzenesulfonimide (NFSi) is an air stable,
easily handled solid with sufficient steric bulk to stereo-
selectively fluorinate the enolate of silyl-protected lactone
4 in 100% de. In this paper, we describe the synthesis
of fluorolactone 6 and its use as a common intermediate
in the synthesis of a number of novel R-2′-fluoro nucleo-
sides. A significant advantage of this methodology is the
ability to access separately either the “natural” (1a ) D or
the “unnatural” (1b) L enantiomer of the nucleosides by
appropriate choice of L- or D-glutamic acid starting
material, respectively.
Lactone 6 was transformed into the anomeric acetate
8 as shown in Scheme 3. It is of interest to note that
lactol 7 exists exclusively as the â anomer and that
(7) (a) Ravid, U.; Silverstein, R. M.; Smith, L. R. Tetrahedron 1978,
34, 1449. (b) Taniguchi, M.; Koga, K.; Yamada, S. Tetrahedron 1974,
30, 3547.
(8) (a) Liotta, D. C.; Wilson, L. J . Tetrahedron Lett. 1990, 31(13),
1815. (b) Chu, C. K.; Babu, J . R.; Beach, J . W.; Ahn, S. K.; Huang, H.;
J eong, L. S.; Lee, S. J . J . Org. Chem. 1990, 55, 1418. (c) Kawakami,
H.; Ebata, T.; Koseki, K.; Matsushita, H.; Naoi, Y.; Itoh, K. Chem. Lett.
1990, 1459.
(5) Barnette, W. E. J . Am. Chem. Soc. 1984, 106, 452.
(6) (a) Davis, F. A.; Han; W., Murphy, C. K. J . Org. Chem. 1995,
60, 4730. (b) Snieckus, V.; Beaulieu, F.; Mohri, K.; Han, W.; Murphy,
C. K.; Davis, F. A. Tetrahedron Lett. 1994, 35(21), 3465. (c) Differding,
E.; Ofner, H. Synth. Lett. 1991, 187. (d) Differding, E.; Lang, R. W.
Tetrahedron Lett. 1988, 29(47), 6087. (e) Singh, S.; DesMarteau, D.
D.; Zuberi, S. S.; Witz, M.; Huang, H. N. J . Am. Chem. Soc. 1987, 109,
7194.
(9) Niihata, S.; Ebata, T.; Kawakami, H.; Matsushida, H. Bull.
Chem. Soc. J pn. 1995, 68, 1509.

Synthesis of Several Novel 2′-Fluoronucleosides
J . Org. Chem., Vol. 63, No. 7, 1998 2163
Ta ble 1. An om er ic P r oton Ch em ica l Sh ift (p p m )
Ta ble 2. An tivir a l Activity a n d Cytotoxicity
compd
R
â
toxicity IC50 (µM)
14a ,b
15a ,b
16a ,b
17a ,b
18a ,b
6.11
6.08
6.09
6.05
6.11
5.89
5.92
5.90
5.92
5.93
activity
HIV-1 EC50 (µM)
vero
cell
CEM
cell
PBM
cell
compd
15b
18b
AZT
53.0
41.0
0.004
40.5
>100
29.0
>100
>100
14.0
48.4
7.2
>100
acetate 8 shows no detectable R anomer by NMR, as
reported by Niihata et al.9
Of the 10 nucleosides listed in Table 1, only 17b,13 18a ,9
and 18b11 have been synthesized previously. They, like
the numerous 2′-â or “up” fluoro nucleoside analogues14
have been synthesized from natural precursors. Fluorine
is usually introduced into these molecules through nu-
cleophilic attack on an anhydro-nucleoside15 or through
replacement and inversion of a stereochemically fixed
hydroxyl group with diethylaminosulfur trifluoride16
(DAST). The advantage of our methodology is that no
hydroxyl group is needed for fluorine introduction. Thus,
we are not limited to natural nucleosides or sugars as
starting materials, and it is easy to access the unnatural
enantiomers of the 2′-fluoro nucleosides.
Accordingly, several unnatural nucleosides were syn-
thesized using our synthetic route with D-glutamic acid
(19) as the starting material (Scheme 4). The sugar ring
precursor to 20 was fluorinated in the manner described
above and coupled with various silylated bases.
Biological evaluation of several of the nucleosides was
carried out in order to determine their activity against
human immunodeficiency virus type 1 (HIV) and to
screen them for toxicity. The results are summarized in
Table 2, and 3′-azido-3′-deoxythymidine (AZT) is shown
as a reference for comparison.
Unfortunately, only compounds 15b and 18b showed
any antiviral activity against HIV but they exhibited
toxicity as well, indicating that the compounds are
nonselective inhibitors of HIV. However, the fact that
these nucleosides are active and toxic may indicate that
they might be phosphorylated. Compounds 14b, 15a ,
16b, 26a , 26b, 27a , 27b, 28a , and 28b were also tested
but were inactive against HIV and nontoxic to all cells
at >100 µM.
In conclusion, a short and efficient synthesis of a
fluorinated noncarbohydrate sugar ring precursor for the
preparation of nucleoside analogues has been developed.
The key step in the synthesis involves the completely
diastereoselective fluorination of chiral lactone 4 derived
from inexpensive, readily available glutamic acid. This
Coupling of 8 with silylated pyrimidine bases was
performed by standard Vorbruggen methodology10 using
TMS triflate as the Lewis acid. A number of bases were
successfully coupled in high yields ranging from 72% to
100% after column chromatography.
Proton NMR indicated that the ratio of â to R nucleo-
side anomers was approximately 2:1 in all cases. The
silyl-protected nucleosides could not be resolved by
column chromatography into the separate anomers.
However, after deprotection of the 5′-oxygen with NH4F
in methanol (Scheme 3), the R and â anomers could be
readily separated.
The classification of the free nucleosides as R or â was
based on the chemical shift of the anomeric proton (Table
1) and on the polarity of the nucleosides as observed by
thin-layer chromatography. We observed a trend for all
of the R/â pairs of free nucleosides such that the less polar
compound of the two had an anomeric proton chemical
shift that was notably upfield from that of the more polar
compound.
The correlation between anomeric proton chemical
shift and absolute structure was verified by comparison
of 18a 9 and 18b11 with previously published spectral data
and through X-ray crystal structure determination of 14b
and 15b. This finding is the opposite of the usual trend
for nucleosides in which the R anomer is normally the
less polar of the two. Presumably, in the “down” 2′-
fluorinated nucleosides, the strong dipole of the C-F
bond opposes the C-N anomeric bond dipole in the â
isomer and reduces the overall molecular dipole. Con-
versely, the R anomer has a geometry that allows
reinforcement of the molecular dipole through the addi-
tion of the C-F and C-N bond dipoles. Thus, the R
anomer is more polar than the â anomer in the case of
R-2′-fluoro nucleosides.
The R and â anomers 17a and 17b could not be
separated by column chromatography because the free
amino group caused the nucleosides to streak on silica
gel. Therefore, it was necessary to use N4-acetylcytosine
to prepare 11 and then resolve 16a and 16b. The N4-
acetyl group was removed quantitatively with a saturated
solution of ammonia in methanol in order to obtain
separated 17a and 17b . It is interesting to note that
when 5-fluorocytosine was used as the base (compound
10), the anomers 15a and 15b were easily separated and
no streaking on silica gel was observed. This is presum-
ably due to the fact that the fluorine atom makes the
neighboring amino group much less basic,12 another
example of the marked effects that fluorine can have on
organic molecules.
(12) Abdelkafi, M. M.; Baklouti, A. Bull. Soc. Chim. Fr. 1977, 1044.
(13) (a) Martin, J . A.; Bushnell, D. J .; Duncan, I. B.; Dunsdon, S.
J .; Hall, M. J .; Machin, P. J .; Merrett, J . H.; Parkes, K. E. B.; Roberts,
N. A.; Thomas, G. J .; Galpin, S. A.; Kinchington, D. J . Med. Chem.
1990, 33(8), 2137. (b) Zenchoff, G. B.; Sun, R.; Okabe, M. J . Org. Chem.
1991, 56, 4392.
(14) (a) Koshida, R.; Cox, S.; Harmenberg, J .; Gilljam, G.; Wahren,
B. Antimicrob. Agents Chemother. 1989, 33(12), 2083. (b) Tann, C. H.;
Brodfuehrer, P. R.; Brundidge, S. P.; Sapino, C.; Howell, H. G. J . Org.
Chem. 1985, 50, 3644. (c) Herdewijn, P.; Pauwels, R.; Baba, M.;
Balzarini, J .; De Clercq, E. J . Med. Chem. 1987, 30, 2131. (d)
Watanabe, K. A.; Harada, K.; Ziedler, J .; Matulic-Adamic, J .; Taka-
hashi, K.; Ren, W.; Cheng, L. C.; Fox, J . J .; Chou, T. C.; Zhu, Q. Z.;
Armstrong, D.; Gold, J . W. M.; Polsky, B. J . Med. Chem. 1990, 33(8),
2145. (e) Sterzycki, R. Z.; Ghazzouli, I.; Brankovan, V.; Martin, J . C.;
Mansuri, M. M. J . Med. Chem. 1990, 33, 3(8), 2150. (f) Huang, J . T.;
Chen, L. C.; Wang, L.; Kim, M. H.; Warshaw, J . A.; Armstrong, D.;
Zhu, Q. Y.; Chou, T. C.; Watanabe, K. A.; Matulic-Adamic, J .; Su, T.-
L.; Polsky, J . J . B.; Baron, P. A.; Gold, J . W. M.; Hardy, W. D.;
Zuckerman, E. J . Med. Chem. 1991, 34(5), 1640.
(10) (a) Chemistry of Nucleosides and Nucleotides 1; Townsend, L.,
Ed.; Plenum Press: New York, 1988; pp 1-5. (b) Niedballa, U.;
Vorbruggen, H. J . Org. Chem. 1974, 39, 3654. (c) Niedballa, U.;
Vorbruggen, H. J . Org. Chem. 1976, 41, 2084. (d) Vorbruggen, H.;
Bennua, B. Tetrahedron Lett. 1978, 15, 1339.
(15) Mengel, R.; Guschlbauer, W. Angew. Chem., Int. Ed. Engl. 1978,
17, 525.
(11) Aerschot, A. V.; Herdewijn, P.; Balzarini, J .; Pauwels, R.; De
Clercq, E. J . Med. Chem. 1989, 32, 1743.
(16) Herdewijn, P.; Aerschot, A. V.; Kerremans, L. Nucleosides
Nucleotides 1989, 8(1), 65.

2164 J . Org. Chem., Vol. 63, No. 7, 1998
McAtee et al.
Sch em e 4
(d, J ) 20.5 Hz), 135.5, 135.4, 132.3, 131.7, 130.1, 128.0, 127.9,
85.6 (d, J ) 186.6 Hz), 77.3 (d, J ) 5.3 Hz), 65.0, 31.8 (d, J )
20.5 Hz), 26.7, 19.1; IR (thin film) 2958, 1796, 1252, 1192,
1111, 1016 cm-1; HRMS calcd for [M + Li] C21H25O3FSiLi
379.1717, found 379.1713. Anal. Calcd for C21H25O3FSi: C,
67.71; H, 6.76. Found: C, 67.72; H, 6.78.
route provides access to both natural and unnatural
enantiomers of these nucleosides. Currently, these com-
pounds are undergoing biological evaluation for activity
against other viruses and as potential cancer chemo-
therapeutic agents. Investigations are underway to
extend this methodology to the synthesis of purine
nucleosides as well.
5-O-(ter t-Bu t yld ip h en ylsilyl)-2,3-d id eoxy-2-flu or o-L-
er yth r o-p en tofu r a n ose (21). To a flask were added lactone
20 (12.12 g, 0.0325 mol, 1.0 equiv) and 240 mL of anhydrous
THF. The solution was cooled to - 78 °C, and 65 mL (0.065
mol, 2.0 equiv) of a 1.0 M solution of DIBALH in hexanes was
added dropwise over a period of 30 min. This was allowed to
stir at - 78 °C for 3 h, after which time the reaction was
quenched by the slow addition of 2.93 mL (0.163 mol, 5.0 equiv)
of water. The reaction was allowed to warm to room temper-
ature and stir for 1 h, after which time a clear gelatinous solid
formed throughout the entire flask. The reaction mixture was
diluted with two volumes of diethyl ether and was poured onto
an equal volume of saturated aqueous sodium potassium
tartrate solution in an Erlenmeyer flask. This was stirred for
20 min until the emulsion had broken. The organic layer was
separated, and the aqueous layer was extracted three times
with 250 mL of diethyl ether. The combined organic layers
were dried over MgSO4, filtered, and concentrated to a light
yellow oil. The product was purified by silica gel column
chromatography using a 6:1 hexanes/ethyl acetate solvent
system. The resulting clear oil was crystallized from boiling
hexanes to give 11.98 g (98% yield) of a white crystalline
solid: Rf(30% diethyl ether/70% hexanes) ) 0.33; mp 66-67
°C; 1H NMR (360 MHz, CDCl3) δ 7.68-7.66 (m, 4H), 7.55-
7.38 (m, 6H), 5.39 (t, J ) 7.6 Hz, 1H), 4.99 (dd, J ) 52.2 and
4.3 Hz, 1H), 4.52 (m, 1H), 3.88 (dd, J ) 10.8 and 2.5 Hz, 1H),
3.65 (d, J ) 7.9 Hz, 1H), 3.49 (dd, J ) 7.9 and 1.8 Hz, 1H),
2.44-2.07 (m, 2H), 1.07 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
135.7, 135.5, 132.2, 132.1, 130.2, 130.0, 129.8, 127.9, 127.7,
99.8 (d, J ) 31.1 Hz), 96.6 (d, J ) 178.3 Hz), 79.4, 64.8, 29.9
(d, J ) 21.2 Hz), 26.8, 19.2; IR (thin film) 3423, 2932, 1474,
1362, 1113 cm-1; HRMS calcd for [M + Li] C21H27O3FSiLi
381.1874, found: 381.1877. Anal. Calcd for C21H27O3FSi: C,
67.35; H, 7.27. Found: C, 67.42; H, 7.31.
Exp er im en ta l Section
Gen er a l P r oced u r es. N-Fluorodibenzenesulfonimide (5)
was obtained from AlliedSignal, courtesy of Dr. Andrew J . Poss
and Dr. George A. Shia, and was used without further
purification. All other reagents were obtained from Aldrich
Chemical Co. and were used without further purification.
Melting points were determined on a Thomas-Hoover capillary
melting point apparatus and are uncorrected. IR spectra were
obtained on a Nicolet Impact 400 FT-IR spectrometer. 1H
NMR and 13C NMR spectra were recorded on either a NT-360
or Varian 400 MHz spectrometer. TLC plates were silica gel
60 F254 (0.25 mm thickness) purchased from EM Science.
Flash chromatography was carried out with silica gel 60 (230-
400 mesh ASTM) from EM Science. All reactions were
performed in flame-dried glassware under an atmosphere of
dry argon. Solvents were removed by rotary evaporation.
Elemental analyses were performed by Atlantic Microlab, Inc.,
Atlanta, GA.
(2S,4R)-5-(ter t-Bu tyld ip h en ylsiloxy)-2-flu or op en ta n -4-
olid e (20). To a flask was added (4R)-5-(tert-butyldiphenyl-
siloxy)-pentan-4-olide (20.0 g, 0.0564 mol, 1.0 equiv) and
N-fluorodibenzenesulfonimide (NFSi, 5) (17.80 g, 0.0564 mol,
1.0 equiv) in 250 mL of anhydrous THF. The solution was
cooled to -78 °C and 68.0 mL (0.0680 mol, 1.2 equiv) of a 1.0
M solution of LiHMDS in THF was added dropwise over a
period of 1 h. This was allowed to stir at -78 °C for an
additional 2 h and was then warmed to room temperature to
stir for 1 h. After completion, the reaction was quenched with
10 mL of a saturated NH4Cl solution. The mixture was diluted
with three volumes of diethyl ether and was poured onto an
equal volume of saturated NaHCO3. The organic layer was
washed a second time with saturated NaHCO3 and once with
saturated NaCl. The organic layer was dried over MgSO4,
filtered, and concentrated to a light yellow oil. The oil was
purified by silica gel column chromatograpy using a 30%
diethyl ether/70% hexanes solvent system. The resultant
white solid was then crystallized from hot hexanes to yield
13.04 g (62% yield) of a transparent crystalline solid: Rf(30%
diethyl ether/70% hexanes) ) 0.26; mp 115-116 °C; 1H NMR
(360 MHz, CDCl3) δ 7.63-7.60 (m, 4H), 7.45-7.35 (m, 6H),
5.49 (dt, J ) 52.9 and 7.9 Hz, 1H), 4.69 (d, J ) 9.36 Hz, 1H),
3.91 (d, J ) 11.5 Hz, 1H), 3.60 (d, J ) 11.5 Hz, 1H), 2.72-
2.40 (m, 2H), 1.05 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 172.1
1-O-Acetyl-5-O-(ter t-bu tyld ip h en ylsilyl)-2,3-d id eoxy-2-
flu or o-L-er yth r o-p en tofu r a n ose (22). To a flask were added
lactol 21 (8.50 g, 0.0227 mol, 1.0 equiv) and 170 mL of
anhydrous CH2Cl2. Then, DMAP (0.277 g, 0.00227 mol, 0.1
equiv) and acetic anhydride (13.5 mL, 0.143 mol, 6.3 equiv)
were added and the solution was stirred at room temperature
overnight. Upon completion, the reaction was poured onto a
saturated NaHCO3 solution. The organic layer was separated,
and the aqueous layer was extracted three times with chlo-
roform. The combined organic layers were dried over MgSO4
and filtered, and the solvent was removed to yield a light
yellow oil. The oil was purified by silica gel column chroma-

Synthesis of Several Novel 2′-Fluoronucleosides
J . Org. Chem., Vol. 63, No. 7, 1998 2165
tography using an 8:1 hexanes/ethyl acetate solvent system
to give 9.85 g (99% yield) of a clear colorless oil: Rf(30% diethyl
ether/70% hexanes) ) 0.44; 1H NMR (360 MHz, CDCl3) δ 7.69-
7.67 (m, 4H), 7.43-7.38 (m, 6H), 6.30 (d, J ) 10.4 Hz, 1H),
5.06 (d, J ) 54.9 Hz, 1H), 4.53 (m, 1H), 3.81 (dd, J ) 10.8 and
4.3 Hz, 1H), 3.72 (dd, J ) 10.8 and 4.3 Hz, 1H), 2.38-2.12 (m,
2H), 1.89 (s, 3H), 1.07 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
169.4, 135.6, 135.5, 133.2, 133.1, 129.8, 129.7, 127.8, 127.7,
99.3 (d, J ) 34.1 Hz), 95.5(d, J ) 178.2 Hz), 81.4, 65.3, 31.6
(d, J ) 20.5 Hz), 26.8, 21.1, 19.3; IR (thin film) 3074, 2860,
1750, 1589, 1229, 1113 cm-1; HRMS calcd for [M - OCOCH3]
C21H26O2FSi 357.1686, found 357.1695. Anal. Calcd for
Hz), 31.0 (d, J ) 21.2 Hz), 26.9, 26.8, 19.2; IR (thin film) 3185,
1722, 1117 cm -1; HRMS calcd for [M + 1] C25H29N2O4SiF2
487.1866, found 487.1853. Anal. Calcd for C25H28N2O4SiF2:
C, 61.71; H, 5.80; N, 5.76. Found: C, 61.72; H, 5.86; N, 5.72.
D-5′-O-(ter t-Bu tyld ip h en ylsilyl)-2′,3′-d id eoxy-2-flu or o-
5-flu or ocytid in e (10): yield ) 99%, mixture of anomers
Rf(100% EtOAc) ) 0.36; mp 75-81 °C; 1H NMR (400 MHz,
CDCl3) δ 8.50 (bm, 1H), 8.05 (d, J ) 6.0 Hz, 0.67H), 7.67-
7.63 (m, 4H), 7.51-7.39 (m, 6.33H), 6.10 (d, J ) 20 Hz, 0.33H),
5.98 (d, J ) 16.4 Hz, 0.67H), 5.62 (bm, 1H), 5.41 (d, J ) 52.4
Hz, 0.33H), 5.23 (dd, J ) 51.6 and 4 Hz, 0.67H), 4.57 (m,
0.33H), 4.48 (m, 0.67H), 4.24 (dd, J ) 12.4 and 2.0 Hz, 0.67H),
3.89 (dd, J ) 11.2 and 3.2 Hz, 0.33 H), 3.74-3.66 (m, 1H),
2.39-1.95 (m, 2H), 1.09 (s, 6H), 1.06 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 158.4 (d, J ) 14.4 Hz), 158.3 (d, J ) 15.2 Hz),
153.8, 153.7, 136.5 (d, J ) 240.5 Hz), 136.2 (d, J ) 241.8 Hz),
135.59, 135.56, 135.4, 133.0, 132.9, 132.5, 132.4, 130.1, 130.0,
129.9, 127.9, 127.8, 124.8 (d, J ) 31.9 Hz), 96.5 (d, J ) 181.3
Hz), 91.8 (d, J ) 175.2 Hz), 90.7 (d, J ) 24.9 Hz), 87.8 (d, J )
21.2 Hz), 81.6, 79.6, 64.9, 63.0, 33.5 (d, J ) 19.7 Hz), 30.6 (d,
J ) 21.3 Hz), 26.9, 26.8, 19.2, 14.2; IR (thin film) 3304, 2959,
1680, 1621, 1508, 1105 cm -1; HRMS calcd for [M + Li]
C
23H29O4FSi: C, 66.32; H, 7.02. Found: C, 66.30; H, 7.04.
Rep r esen ta tive P r oced u r e for th e Cou p lin g of a Si-
lyla ted Ba se w ith 22: L-5′-O-(ter t-bu tyld ip h en ylsilyl)-
2′,3′-d id eoxy-2′-flu or o-5-flu or ocytid in e (25). To a flask
equipped with a short-path distillation head were added
5-fluorocytosine (2.01 g, 15.6 mmol, 5.0 equiv), 35 mL of
1,1,1,3,3,3-hexamethyldisilazane, and a catalytic amount (∼1
mg) of (NH4)2SO4. The white suspension was heated to boiling
for 1 h until the base was silylated and reaction was a clear
solution. The excess HMDS was distilled off and the oily
residue that remained was placed under vacuum for 1 h to
remove the last traces of HMDS. A white solid resulted which
was dissolved, under argon, in 5 mL of anhydrous 1,2-
dichloroethane. To this clear solution was added a solution
of acetate 22 (1.30 g, 3.12 mmol, 1.0 equiv) in 5 mL of
anhydrous 1,2-dichloroethane. To this was added, at room
temperature, trimethylsilyl trifluoromethanesulfonate (3.32
mL, 17.2 mmol, 5.5 equiv). The reaction was monitored by
TLC (10% methanol/90% CH2Cl2) and was observed to be
complete in 4 h. The reaction mixture was poured onto
saturated NaHCO3. The organic layer was then separated,
and the aqueous layer was extracted three times with chlo-
roform. The combined organic layers were dried over MgSO4
and filtered, and the solvent was removed to yield a white
foam. The compound was purified by silica gel column
chromatography using a gradient solvent system from 100%
CH2Cl2 to 10% methanol in CH2Cl2. The compound was
isolated as 1.51 g (99% yield) of a white foam: mixture of
anomers Rf(100% EtOAc) ) 0.36; mp 74-80 °C; 1H NMR (400
MHz, CDCl3) δ 8.84 (bs, 1H), 8.04 (d, J ) 6.4 Hz, 0.67H), 7.67-
7.63 (m, 4H), 7.51-7.39 (m, 6.33H), 6.11 (d, J ) 20 Hz, 0.33H),
5.98 (d, J ) 16.4 Hz, 0.67H), 5.88 (bs, 1H), 5.41 (d, J ) 52.4
Hz, 0.33H), 5.23 (dd, J ) 50.4 and 4 Hz, 0.67H), 4.56 (m,
0.33H), 4.45 (m, 0.67H), 4.23 (dd, J ) 12.0 and 1.6 Hz, 0.67H),
3.89 (dd, J ) 11.2 and 3.2 Hz, 0.33 H), 3.74-3.66 (m, 1H),
2.45-1.96 (m, 2H), 1.09 (s, 6H), 1.06 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 158.6 (d, J ) 14.4 Hz), 158.4 (d, J ) 14.4 Hz),
153.9, 153.8, 136.6 (d, J ) 240.5 Hz), 136.3 (d, J ) 239.7 Hz),
135.6, 135.56, 135.5, 135.4, 133.1, 132.9, 132.5, 132.4, 130.1,
130.0, 129.9, 127.9, 127.8, 125.8 (d, J ) 33.4 Hz), 124.6 (d, J
) 32.6 Hz), 96.5 (d, J ) 182.0 Hz), 91.7 (d, J ) 185.1), 90.7 (d,
J ) 35.6 Hz), 87.7 (d, J ) 15.2 Hz), 81.5, 79.5, 64.9, 63.0, 33.5
(d, J ) 20.5 Hz), 30.6 (d, J ) 20.4 Hz), 26.9, 26.8, 19.22, 19.18;
IR (thin film) 3300, 2960, 1682, 1608, 1513, 1109 cm -1; HRMS
calcd for [M + Li] C25H29N3O3SiF2Li; 492.2106, found 492.2085.
Anal. Calcd for C25H29N3O3SiF2‚1/2H2O: C, 60.71; H, 6.11; N,
8.50. Found: C, 60.67; H, 6.03; N, 8.44.
C
C
25H29N3O3SiF2Li 492.2106, found 492.2110. Anal. Calcd for
25H29N3O3SiF2: C, 61.84; H, 6.02; N, 8.65. Found: C, 61.86;
H, 6.09; N, 8.55.
D-N4-Acetyl-5′-O-(ter t-bu tyld ip h en ylsilyl)-2′,3′-d id eoxy-
2′-flu or ocytid in e (11): yield ) 91%, mixture of anomers
Rf(15% EtOH, 85% EtOAc) ) 0.75; mp 81-86 °C; 1H NMR
(400 MHz, CDCl3) δ 10.58 (bs, 1H), 8.40 (d, J ) 7.2 Hz, 0.61H),
7.86 (d, J ) 7.6 Hz, 0.38H), 7.67-7.65 (m, 4H), 7.51-7.41 (m,
6H), 7.27 (d, J ) 8.4 Hz, 1H), 6.12 (t, J ) 15.8 Hz, 1H), 5.51
(d, J ) 52.6 Hz, 0.38H), 5.21 (dd, J ) 50.8 and 2.9 Hz, 0.61H),
4.62 (m, 0.38H), 4.54 (m, 0.61H), 4.28 (d, J ) 11.5 Hz, 0.61H),
3.95 (dd, J ) 11.9 and 3.2 Hz, 0.38H), 3.79-3.70 (m, 1H), 2.46-
2.04 (m, 5H), 1.12 (s, 5.49H), 1.07 (s, 3.42H); 13C NMR (100
MHz, CDCl3) δ 171.5, 171.3, 163.4, 154.9, 144.9, 144.1, 135.5,
135.4, 133.0, 132.8, 132.5, 132.2, 130.2, 130.1, 129.9, 128.0,
127.8, 96.8 (d, J ) 91.1 Hz), 96.2 (d, J ) 147.9 Hz), 92.3,
91.2 (d, J ) 35.7 Hz), 90.5, 88.5 (d, J ) 15.9 Hz), 81.9, 80.1,
64.7, 62.9, 33.5 (d, J ) 20.5 Hz), 30.5 (d, J ) 20.5 Hz), 26.9,
26.8, 24.9, 24.8, 19.3, 19.2; IR (thin film) 3237, 2932, 1722,
1671, 1559, 1493, 1107 cm-1; HRMS calcd for [M + Li]
C
C
27H32N3O4FSiLi 516.2306, found 516.2310. Anal. Calcd for
27H32N3O4FSi: C, 63.63; H, 6.33; N, 8.24. Found: C, 63.45;
H, 6.42; N, 8.09.
D-5′-O-(ter t-Bu tyld ip h en ylsilyl)-2′,3′-d id eoxy-2′-flu or o-
cytid in e (12): yield ) 72%, mixture of anomers Rf(15% EtOH,
85% EtOAc) ) 0.50; mp 98-104 °C; 1H NMR (360 MHz, CDCl3)
δ 7.97 (d, J ) 7.2 Hz, 0.64H, H-6), 7.65 (m, 4H), 7.47-7.38
(m, 6.36H), 6.15 (d, J ) 20.5 Hz, 0.36H), 6.05 (d, J ) 16.6 Hz,
0.64H), 5.83 (d, J ) 7.9 Hz, 0.36H), 5.46 (d, J ) 7.2 Hz, 0.64H),
5.30-5.10 (m, 1H), 4.55 (m, 0.36H), 4.44 (m, 0.64H), 4.22 (d,
J ) 9.7 Hz, 0.64H), 3.88-3.63 (m, 1.36H), 2.38-1.95 (m, 2H),
1.09 (s, 5.76H), 1.06 (s, 3.24H); 13C NMR (100 MHz, CDCl3) δ
166.1, 155.8, 141.5, 140.5, 135.6, 135.4, 133.1, 132.9, 132.8,
132.4, 130.1, 130.0, 129.8, 128.0, 127.9, 127.8, 96.7 (d, J )
181.3 Hz), 93.4 (d, J ) 140.3 Hz), 94.5, 90.8 (d, J ) 35.6 Hz),
90.8, 87.8 (d, J ) 15.9 Hz), 81.2, 79.4, 65.0, 63.2, 33.7 (d, J )
21.2 Hz), 30.8 (d, J ) 20.4 Hz), 26.9, 26.8, 19.3, 19.2; IR (thin
film) 3470, 3339, 1644, 1487, 1113 cm-1; HRMS calcd for [M
+ Li] C25H30N3O3FSiLi 474.2201, found 474.2198. Anal. Calcd
for C25H30N3O3FSi: C, 64.21; H, 6.47; N, 8.99. Found: C,
64.04; H, 6.58; N, 8.76.
L-5′-O-(ter t-Bu t yld ip h en ylsilyl)-2′,3′-d id eoxy-2′-flu o-
r oth ym id in e (23): yield ) 87%, mixture of anomers Rf(10%
MeOH/90% CH2Cl2) ) 0.56; mp 61-65 °C; 1H NMR (360, MHz,
CDCl3) δ 9.48 (bs, 1H), 7.67 (m, 4H), 7.45-7.37 (m, 7H), 6.15
(dd, J ) 20.2 and 3.2 Hz, 0.36H), 5.99 (d, J ) 18.4 Hz, 0.64H),
5.34 (d, J ) 51.8 Hz, 0.36H), 5.24 (dd, J ) 52.2 and 4.3 Hz,
0.64H), 4.59 (m, 0.36H), 4.45 (m, 0.64H), 4.17 (dd, J ) 12.2
and 2.5 Hz, 0.64H), 3.91 (dd, J ) 11.9 and 2.9 Hz, 0.36H),
3.81 (dd, J ) 11.5 and 2.9 Hz, 0.64H), 3.68 (dd, J ) 10.8 and
3.6 Hz, 0.36H), 2.40-2.12 (m, 2H), 1.94 (s, 1.08H), 1.61 (s,
1.92H), 1.10 (s, 5.76H), 1.07 (s, 3.24H); 13C NMR (100 MHz,
CDCl3) δ 164.1, 164.0, 150.4, 150.2, 136.4, 135.6, 135.5, 135.4,
D-5′-O-(ter t-Bu tyld ip h en ylsilyl)-2′,3′-d id eoxy-2′-flu or o-
5-flu or ou r id in e (9): yield ) 87%, mixture of anomers Rf(1:1
hexanes/EtOAc) ) 0.48; mp 65-70 °C; 1H NMR (400 MHz,
CDCl3) δ 10.0 (bm, 1H), 7.99 (d, J ) 5.6 Hz, 0.63H), 7.65 (m,
4H), 7.42 (m, 6.37H), 6.12 (dd, J ) 18.0 and 1.6 Hz, 0.37H),
6.00 (d, J ) 16 Hz, 0.63H), 5.37 (dd, J ) 54.6 and 2.4 Hz,
0.37H), 5.22 (dd, J ) 50.4 and 4 Hz, 0.63H), 4.57 (m, 0.37H),
4.44 (m, 0.63H), 4.22 (dd, J ) 12.2 and 2.0 Hz, 0.63H), 3.92
(dd, J ) 11.2 and 3.2 Hz, 0.37 H), 3.70 (m, 1H), 2.22 (m, 2H),
1.09 (s, 5.67H), 1.074 (s, 3.33H); 13C NMR (100 MHz, CDCl3)
δ 157.2 (d, J ) 31.7 Hz), 157.1 (d, J ) 25.8 Hz), 149.1, 148.8,
140.4 (d, J ) 236.6 Hz), 140.1 (d, J ) 235.2 Hz), 135.6, 135.5,
135.4, 132.9, 132.7, 132.4, 132.3, 130.1, 130.0, 129.9, 127.9,
127.8, 125.1 (d, J ) 34.9 Hz), 123.6 (d, J ) 34.1 Hz), 96.4 (d,
J ) 182.0 Hz), 92.0 (d, J ) 185.9 Hz), 90.2 (d, J ) 37.2 Hz),
87.0 (d, J ) 15.2 Hz), 81.7, 79.8, 64.8, 63.0, 33.3 (d, J ) 21.2

2166 J . Org. Chem., Vol. 63, No. 7, 1998
McAtee et al.
135.3, 135.2, 133.0, 132.8, 132.6, 130.1, 130.0, 129.9, 127.94,
127.90, 127.8, 110.8, 109.8, 96.4 (d, J ) 181.3 Hz), 92.1 (d, J
) 185.8 Hz), 90.7 (d, J ) 36.4 Hz), 86.6 (d, J ) 15.2 Hz), 80.9,
79.4, 64.9, 63.6, 33.4 (d, J ) 20.5 Hz), 32.0 (d, J ) 21.2 Hz),
27.0, 26.8, 19.4, 19.2, 12.6, 12.2; IR (thin film) 3183, 3050, 1696,
1506, 1188 cm -1; HRMS calcd for [M + Li] C26H31N2O4SiF
489.2197, found 489.2175. Anal. Calcd for C26H31N2O4SiF:
C, 64.71; H, 6.47; N, 5.80. Found: C, 64.88; H, 6.56; N, 5.76.
L-5′-O-(ter t-Bu tyld ip h en ylsilyl)-2′,3′-d id eoxy-2′-flu or o-
5-flu or ou r id in e (24): yield ) 85%, mixture of anomers Rf(1:1
hexanes/EtOAc) ) 0.48; mp 65-71 °C; 1H NMR (400 MHz,
CDCl3) δ 9.08 (bs, 0.4H), 9.00 (bs, 0.6H) 8.01 (d, J ) 5.4 Hz,
0.6H), 7.65 (m, 4H), 7.42 (m, 6.4H), 6.10 (dd, J ) 20.2 and 1.4
Hz, 0.4H), 6.00 (d, J ) 16.0 Hz, 0.6H), 5.35 (dd, J ) 52.4 and
1.6 Hz, 0.4H), (5.22, dd, J ) 51.2 and 4 Hz, 0.6H), 4.57 (m,
0.4H), 4.44 (m, 0.6H), 4.22 (dd, J ) 12.4 and 2.0 Hz, 0.6H),
3.91 (dd, J ) 11.2 and 2.9 Hz, 0.4H), 3.70 (m, 1H), 2.45-2.00
(m, 2H), 1.09 (s, 5.4H), 1.07 (s, 3.6H); 13C NMR (100 MHz,
CDCl3) δ 156.9 (d, J ) 26.5 Hz), 148.8, 148.6, 140.3 (d, J )
236.7 Hz), 140.1 (d, J ) 235.1 Hz), 135.6, 135.5, 135.4, 132.9,
132.7, 132.4, 132.3, 130.2, 130.1, 129.9, 127.9, 127.8, 125.1 (d,
J ) 34.9 Hz), 123.6 (d, J ) 34.2 Hz), 96.4 (d, J ) 182.9 Hz),
92.0 (d, J ) 186.6 Hz), 90.2 (d, J ) 36.0 Hz), 86.9 (d, J ) 15.1
Hz), 81.7, 79.8, 64.8, 63.0, 33.2 (d, J ) 20.5 Hz), 30.9 (d, J )
20.4 Hz), 26.9, 26.8, 19.2; IR (thin film) 3191, 1719, 1113 cm
-1; HRMS calcd for [M + Li] C25H28N2O4SiF2Li 493.1946, found
493.1952. Anal. Calcd for C25H28N2O4SiF2: C, 61.71; H, 5.80;
N, 5.76. Found: C, 61.73; H, 5.83; N, 5.77.
185.1 Hz), 88.5 (d, J ) 15.1 Hz), 81.8, 64.3, 34.3 (d, J ) 20.5
Hz); IR (KBr) 3421, 3081, 1685, 1478, 1111 cm-1; HRMS calcd
for [M + Li] C9H10N2O4F2Li 255.0769, found 255.0778. Anal.
Calcd for C9H10N2O4F2: C, 43.56; H, 4.06; N, 11.29. Found:
C, 43.59; H, 4.11; N, 11.17.
â-D-2′,3′-Did eoxy-2′-flu or o-5-flu or ou r id in e (14b): yield
) 48%; Rf(100% EtOAc) ) 0.54; mp 152-154 °C; 1H NMR (360
MHz, CD3OD) δ 8.41 (d, J ) 7.2 Hz, 1H), 5.89 (d, J ) 16.6 Hz,
1H), 5.21 (dd, J ) 51.5 and 3.6 Hz, 1H), 4.41 (m, 1H), 4.00 (d,
J ) 12.6 Hz, 1H), 3.67 (d, J ) 12.2 Hz, 1H), 2.25-2.09 (m,
2H); 13C NMR (100 MHz, CD3OD) δ 159.7 (d, J ) 25.8 Hz),
150.7, 141.8 (d, J ) 229.8 Hz), 126.3 (d, J ) 36.4 Hz), 98.3 (d,
J ) 179 Hz), 91.9 (d, J ) 37.1 Hz), 83.6, 61.9, 31.9 (d, J )
20.5 Hz); IR (KBr) 3417, 3056, 1684, 1474, 1105 cm-1; HRMS
calcd for [M + Li] C9H10N2O4F2Li 255.0769, found 255.0764.
Anal. Calcd for C9H10N2O4F2: C, 43.56; H, 4.06; N, 11.29.
Found: C, 43.37; H, 3.98; N, 11.22.
r-D-2′,3′-Did eoxy-2′-flu or o-5-flu or ocytid in e (15a ): yield
) 27%; Rf(15% EtOH/85% EtOAc) ) 0.22; mp 198-202 °C
(dec); 1H NMR (400 MHz, CD3OD) δ 7.78 (d, J ) 6.8 Hz, 1H),
6.07 (d, J ) 18.8 Hz, 1H), 5.37 (d, J ) 54.0 Hz, 1H), 4.59 (m,
1H), 3.80 (dd, J ) 12.0 and 3.2 Hz, 1H), 3.57 (dd, J ) 12.4
and 4.4 Hz, 1H), 2.38-2.14 (m, 2H); 13C NMR (100 MHz,
CD3OD) δ 159.9 (d, J ) 13.6 Hz), 156.5, 138.3 (d, J ) 240.4
Hz), 127.5 (d, J ) 33.4 Hz), 93.6 (d, J ) 184.3 Hz), 89.5 (d,
J ) 15.9 Hz), 81.8, 64.4, 34.5 (d, J ) 20.5 Hz); IR (KBr)
3486, 3098, 1681, 1519, 1108 cm-1; HRMS calcd for [M +
Li] C9H11N3O3F2Li 254.0929, found 254.0929. Anal. Calcd for
C9H11N3O3F2‚1/2H2O: C, 42.19; H, 4.72; N, 16.40. Found: C,
41.86; H, 4.75; N, 16.36.
â-D-2′,3′-Did eoxy-2′-flu or o-5-flu or ocytid in e (15b): yield
) 51%; Rf(15% EtOH/85% EtOAc) ) 0.37; mp 181-183 °C
(dec); 1H NMR (400 MHz, CD3OD) δ 8.45 (d, J ) 7.2 Hz, 1H),
5.92 (dd, J ) 16.2 and 1.2 Hz, 1H), 5.18 (dd, J ) 50.8 and 4.0
Hz, 1H), 4.46 (m, 1H), 4.05 (dd, J ) 12.4 and 2.4 Hz, 1H), 3.72
(dd, J ) 12.8 and 2.4 Hz, 1H), 2.27-2.05 (m, 2H); 13C NMR
(100 MHz, CD3OD) δ 159.9 (d, J ) 13.6 Hz), 156.5, 138.5 (d,
J ) 240.5 Hz), 126.9 (d, J ) 33.4 Hz), 98.4 (d, J ) 179.0 Hz),
92.5 (d, J ) 36.4 Hz), 83.6, 61.9, 31.6 (d, J ) 20.5 Hz); IR (KBr)
3494, 2944, 1689, 1522, 1106 cm-1; HRMS calcd for [M +
Li] C9H11N3O3F2Li 254.0929, found 254.0936. Anal. Calcd for
C9H11N3O3F2: C, 43.73; H, 4.49; N, 17.00. Found: C, 43.84;
H, 4.47; N, 17.05.
Rep r esen ta tive P r oced u r e for th e Dep r otection of
Silyl-P r otected Nu cleosid es: r- a n d â-L-2′,3′- d id eoxy-2′-
flu or o-5-flu or ocytid in e (28a a n d 28b). Nucleoside 25
(1.098 g, 2.26 mmol, 1.0 equiv) was dissolved in 15 mL of
methanol to which was added ammonium fluoride (0.838 g,
22.6 mmol, 10.0 equiv). This was stirred vigorously for 24 h,
after which time TLC (15% ethanol/85% ethyl acetate) revealed
that the reaction was complete. The reaction mixture was
diluted with three volumes of ethyl acetate and was filtered
through a small (1 cm) silica gel plug. The plug was rinsed
with 200 mL of 15% ethanol/85% ethyl acetate solution, and
the solvent was removed to yield a white foam. The compound
was purified by silica gel column chromatography using a 15%
ethanol/85% ethyl acetate solvent system which also effected
the separation of the R and â anomers. The yield of R as a
white foam was 0.190 g (0.768 mmol, 34% yield), and the yield
of â as a white foam was 0.290 g (1.17 mmol, 52% yield). 28a :
r-D-N4-Acetyl-2′,3′-dideoxy-2′-flu or ocytidin e (16a): yield
) 17%; Rf(15% EtOH/85% EtOAc) ) 0.40; mp 208-212 °C; 1H
NMR (360 MHz, DMSO-d6) δ (10.91, bs, 1H), 8.05 (d, J ) 7.2
Hz, 1H), 7.25 (d, J ) 7.2 Hz, 1H), 6.08 (dd, J ) 19.1 and 2.9
Hz, 1H), 5.42 (d, J ) 52.2 Hz, 1H), 4.97 (bs, 1H), 4.54 (m, 1H),
3.63 (d, J ) 13.0 Hz, 1H), 3.47 (d, J ) 13.3 Hz, 1H), 2.35-
2.15 (m, 2H), 2.11 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ
171.0, 162.6, 154.3, 145.7, 94.9, 92.0 (d, J ) 183.6 Hz), 87.5
(d, J ) 15.9 Hz), 80.2, 62.6, 33.3 (d, J ) 19.7 Hz), 24.4; IR
(KBr) 3436, 3227, 1702, 1661, 1442, 1102 cm-1; HRMS calcd
for [M + Li] C11H14N3O4FLi 278.1128, found 278.1136. Anal.
Calcd for C11H14N3O4F: C, 48.71; H, 5.20; N, 15.49. Found:
C, 48.73; H, 5.23; N, 15.52.
1
Rf(15% EtOH, 85% EtOAc) ) 0.22; mp 199-203 °C (dec); H
NMR (400 MHz, CD3OD) δ 7.78 (d, J ) 6.8 Hz, 1H), 6.07 (d,
J ) 19.2 Hz, 1H), 5.37 (d, J ) 54.0 Hz, 1H), 4.60 (m, 1H), 3.80
(dd, J ) 12.0 and 3.2 Hz, 1H), 3.56 (dd, J ) 12.4 and 4.4 Hz,
1H), 2.40-2.00 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 157.7
(d, J ) 13.6 Hz), 153.2, 135.9 (d, J ) 239.0 Hz), 126.2 (d, J )
31.1 Hz), 92.4 (d, J ) 183.6 Hz), 86.7 (d, J ) 15.2 Hz), 79.6,
62.7, 33.3 (d, J ) 20.5 Hz); IR (KBr) 3343, 3100, 1683, 1517,
1104 cm-1; HRMS calcd for [M + Li] C9H11N3O3F2Li 254.0929,
found 254.0919. Anal. Calcd for C9H11N3O3F2‚1/2H2O: C,
42.19; H, 4.72; N, 16.40. Found: C, 42.44; H, 4.56; N, 16.56.
28b: Rf(15% EtOH, 85% EtOAc) ) 0.37; mp 182-186 °C (dec);
1H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J ) 7.6 Hz, 1H), 7.79
(bs, 1H), 7.53 (bs, 1H), 5.81 (d, J ) 16.8 Hz, 1H), 5.37 (t, J )
4.8 Hz), 5.18 (dd, J ) 51.6 and 3.2 Hz, 1H), 4.32 (m, 1H), 3.88
(dd, J ) 12.0 and 2.8 Hz, 1H), 3.59 (dd, J ) 12.4 and 2.4 Hz,
1H), 2.20-1.99 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 157.7
(d, J ) 13.7 Hz), 153.2, 136.1 (d, J ) 237.4 Hz), 125.3 (d, J )
33.4 Hz), 97.3 (d, J ) 176.8 Hz), 89.9 (d, J ) 35.7 Hz), 81.6,
60.2, 30.3 (d, J ) 19.7 Hz); IR (KBr) 3487, 2948, 1678, 1509,
1122 cm-1; HRMS calcd for [M + Li] C9H11N3O3F2Li 254.0929,
found: 254.0935. Anal. Calcd for C9H11N3O3F2: C, 43.73; H,
4.49; N, 17.00. Found: C, 43.69; H, 4.53; N, 16.92.
â-D-N4-Acetyl-2′,3′-dideoxy-2′-flu or ocytidin e (16b): yield
) 31%; Rf(15% EtOH/85% EtOAc) ) 0.50; mp 174-178 °C; 1H
NMR (360 MHz, DMSO-d6) δ (10.90, bs, 1H), 8.46 (d, J ) 7.2
Hz, 1H), 7.18 (d, J ) 7.2 Hz, 1H), 5.90 (d, J ) 16.9 Hz, 1H),
5.27 (d, J ) 52.9 Hz, 1H), 5.27 (bs, 1H), 4.39 (m, 1H), 3.88 (d,
J ) 13.0 Hz, 1H), 3.61 (d, J ) 13.0 Hz, 1H), 2.09 (s, 3H), 2.20-
1.85 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 171.0, 162.6,
154.4, 144.7, 97.0 (d, J ) 177.5 Hz), 95.0, 90.7 (d, J ) 36.6
Hz), 82.2, 60.3, 30.3 (d, J ) 19.7 Hz), 24.3; IR (KBr) 3447, 3245,
1703, 1656, 1497, 1122 cm-1; HRMS calcd for [M + Li]
C
C
11H14N3O4FLi 278.1128, found: 278.1133. Anal. Calcd for
11H14N3O4F: C, 48.71; H, 5.20; N, 15.49. Found: C, 48.65;
r-D-2′,3′-Did eoxy-2′-flu or o-5-flu or ou r id in e (14a ): yield
) 19%; Rf(100% EtOAc) ) 0.38; mp 153-155 °C; 1H NMR (360
MHz, CD3OD) δ 7.80 (d, J ) 6.8 Hz, 1H), 6.11 (d, J ) 18.7 Hz,
1H), 5.35 (d, J ) 52.9, 1H), 4.59 (m, 1H), 3.81 (d, J ) 11.9 Hz,
1H), 3.57 (dd, J ) 12.6 and 3.6 Hz, 1H), 2.36-2.15 (m, 2H);
13C NMR (100 MHz, CD3OD) δ 159.6 (d, J ) 25.8 Hz), 150.7,
141.5 (d, J ) 230.6 Hz), 127.0 (d, J ) 34.9 Hz), 93.9 (d, J )
H, 5.22; N, 15.46.
r-L-2′,3′-Did eoxy-2′-flu or oth ym id in e (26a ): yield ) 24%;
Rf(100% EtOAc) ) 0.25; mp 147-149 °C; 1H NMR (360 MHz,
CD3OD) δ 7.45 (s, 1H), 6.11 (dd, J ) 19.4 and 2.9 Hz, 1H),
5.30 (d, J ) 53.6 Hz, 1H), 4.58 (m, 1H), 3.79 (dd, J ) 12.2 and
2.2 Hz, 1H), 3.55 (dd, J ) 12.2 and 3.6 Hz, 1H), 2.40-2.15 (m,
2H), 1.87 (s, 3H); 13C NMR (100 MHz, CD3OD) δ 166.6, 152.3,

Synthesis of Several Novel 2′-Fluoronucleosides
J . Org. Chem., Vol. 63, No. 7, 1998 2167
138.6, 110.5, 93.9 (d, J ) 185.1 Hz), 88.3 (d, J ) 15.1 Hz),
81.7, 64.4, 34.5 (d, J ) 20.5 Hz), 12.6; IR (KBr) 3436, 3166,
1727, 1667, 1362, 1186 cm-1; HRMS calcd for [M + Li]
r-D-2′,3′-Did eoxy-2′-flu or ocytid in e (17a ): yield ) quan-
titative, Rf(15% EtOH/85% EtOAc) ) 0.08; mp 234-237 °C
(dec); 1H NMR (400 MHz, DMSO-d6) δ 7.52 (d, J ) 7.6 Hz,
1H), 7.21 (bm, 2H), 6.05 (dd, J ) 20.4 and 3.2 Hz, 1H), 5.73
(d, J ) 7.2 Hz, 1H), 5.28 (d, J ) 52.4 Hz, 1H), 4.93 (t, J ) 5.6
Hz, 1H), 4.45 (m, 1H), 3.58 (m, 1H), 3.43 (m, 1H), 2.26-2.13
(m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 165.8, 155.0, 141.6,
93.3, 92.2 (d, J ) 182.8 Hz), 86.6 (d, J ) 15.1 Hz), 79.4, 62.8,
33.3 (d, J ) 19.7 Hz); IR (KBr) 3366, 3199, 1659, 1399, 1122
cm-1; HRMS calcd for [M + Li] C9H12N3O3FLi 236.1023, found
236.1014. Anal. Calcd for C9H12N3O3F: C, 47.16; H, 5.28; N,
18.33. Found: C, 47.40; H, 5.34; N, 18.51.
An tivir a l a n d Cytotoxicity Assa ys. Anti-HIV-1 activity
of the compounds was determined in human peripheral blood
mononuclear (PBM) cells as described previously.17 Stock
solutions (20-40 mM) of the compounds were prepared in
sterile DMSO and then diluted to the desired concentration
in complete medium. 3′-Azido-3′-deoxythymidine (AZT) stock
solutions were made in water. Cells were infected with the
prototype HIV-1LAI at a multiplicity of infection of 0.01. Virus
obtained from the cell supernatant was quantitated on day 6
after infection by a reverse transcriptase assay using poly-
(rA)n‚oligo(dT)12-18 as template-primer. The DMSO present
in the diluted solution (<0.1%) had no effect on the virus yield.
The toxicity of the compounds was assessed in human PBM,
CEM, and Vero cells, as described previously.17 The antiviral
EC50 and cytotoxicity IC50 was obtained from the concentra-
tion-response curve using the median effective method de-
scribed by Chou and Talalay.18
C
10H13N2O4FLi 251.1019, found: 251.1014. Anal. Calcd for
C10H13N2O4F: C, 49.18; H, 5.37; N, 11.47. Found: C, 49.32;
H, 5.40; N, 11.29.
â-L-2′,3′-Did eoxy-2′-flu or oth ym id in e (26b): yield ) 61%,
Rf (100% EtOAc) ) 0.38; mp 186-188 °C; 1H NMR (360 MHz,
CD3OD) δ 7.94 (s, 1H), 5.93 (d, J ) 17.6 Hz, 1H), 5.20 (d, J )
51.8 Hz, 1H), 4.40 (m, 1H), 3.98 (d, J ) 11.9 Hz, 1H), 3.68 (d,
J ) 13.0 Hz, 1H), 2.37-2.10 (m, 2H), 1.83 (s, 3H); 13C NMR
(100 MHz, CD3OD) δ 166.7, 152.3, 138.2, 111.0, 98.4 (d, J )
178.3 Hz), 92.1 (d, J ) 36.4 Hz), 83.1, 62.4, 32.5 (d, J ) 20.5
Hz), 12.6; IR (KBr) 3478, 3052, 1684, 1363, 1192, 1005 cm-1
.
Anal. Calcd for C10H13N2O4F: C, 49.18; H, 5.37; N, 11.47.
Found: C, 49.29; H, 5.44; N, 11.36.
r-L-2′,3′-Did eoxy-2′-flu or o-5-flu or ou r id in e (27a ): yield
) 35%, Rf(100% EtOAc) ) 0.38; mp 155-157 °C; 1H NMR (400
MHz, CD3OD) δ 7.80 (d, J ) 6.8 Hz, 1H), 6.13 (d, J ) 20.0 Hz,
1H), 5.35 (d, J ) 54.4 Hz, 1H), 4.63 (m, 1H), 3.81 (dd, J )
11.9 and 3.2 Hz, 1H), 3.58 (dd, J ) 12.4 and 2.0 Hz, 1H), 2.41-
2.15 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 159.6 (d, J )
25.8 Hz), 150.7, 141.5 (d, J ) 230.6 Hz), 127.0 (d, J ) 34.9
Hz), 93.9 (d, J ) 184.3 Hz), 88.5 (d, J ) 15.1 Hz), 81.9, 64.3,
34.3 (d, J ) 20.5 Hz); IR (KBr) 3401, 3098, 1661, 1458, 1018
cm-1; HRMS calcd for [M + Li] C9H10N2O4F2Li 255.0769, found
255.0771. Anal. Calcd for C9H10N2O4F2: C, 43.56; H, 4.06;
N, 11.29. Found: C, 43.70; H, 4.17; N, 11.15.
â-L-2′,3′-Did eoxy-2′-flu or o-5-flu or ou r id in e (27b): yield
) 51%, Rf(100% EtOAc) ) 0.54; mp 153-156 °C; 1H NMR (400
MHz, CD3OD) δ 8.46 (d, J ) 6.8 Hz, 1H), 5.94 (d, J ) 16.4 Hz,
1H), 5.25 (dd, J ) 51.6 and 4.0 Hz, 1H), 4.41 (m, 1H), 4.05
(dd, J ) 12.8 and 2.4 Hz, 1H), 3.72 (dd, J ) 12.4 and 2.4 Hz,
1H), 2.34-2.09 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 159.7
(d, J ) 25.8 Hz), 150.7, 141.8 (d, J ) 230.6 Hz), 126.3 (d, J )
35.7 Hz), 98.3 (d, J ) 184.6 Hz), 91.9 (d, J ) 36.4 Hz), 83.6,
61.9, 31.9 (d, J ) 20.5 Hz); IR (KBr) 3482, 3037, 1702, 1654,
1402, 1103 cm-1; HRMS calcd for [M + Li] C9H10N2O4F2Li
255.0769, found: 255.0764. Anal. Calcd for C9H10N2O4F2: C,
43.56; H, 4.06; N, 11.29. Found: C, 43.59; H, 4.06; N, 11.17.
â-D-2′,3′-Did eoxy-2′-flu or ocytid in e (17b). Nucleoside 16
(0.160 g, 0.59 mmol) was dissolved in 10 mL of saturated
methanolic ammonia. After the solution was stirred for 5 min,
the reaction was complete. The methanolic ammonia was
removed, and the resultant white solid was placed under
vacuum and heated gently in a 60 °C water bath for 2 h to
remove the acetamide byproduct through sublimation. The
white solid was crystallized from 5% methanol/95% methylene
chloride to give a quantitative yield of a white crystalline
solid: Rf(15% EtOH/85% EtOAc) ) 0.18; mp 191-195 °C (dec);
1H NMR (360 MHz, CD3OD) δ 8.10 (d, J ) 7.2 Hz, 1H), 5.92
(d, J ) 17.3 Hz, 1H), 5.82 (d, J ) 7.6 Hz, 1H), 5.13 (d, J )
50.0 Hz, 1H), 4.39 (m, 1H), 3.97 (d, J ) 12.2 Hz, 1H), 3.68
(dd, J ) 13.0 and 2.5 Hz, 1H), 2.21-2.00 (m, 2H); 13C NMR
(100 MHz, CD3OD) δ 165.9, 155.0, 140.8, 97.3 (d, J ) 176.8
Hz), 93.6, 90.3 (d, J ) 35.6 Hz), 81.3, 60.7, 31.0 (d, J ) 20.5
Hz); IR (KBr) 3397, 3112, 1680, 1400, 1178, 1070 cm-1; HRMS
calcd for [M + Li] C9H12N3O3FLi 236.1024, found: 236.1028.
Anal. Calcd for C9H12N3O3F: C, 47.16; H, 5.28; N, 18.33.
Found: C, 47.01; H, 5.21; N, 18.29.
Ack n ow led gm en t. We thank Dr. Andrew J . Poss
and Dr. George A. Shia of AlliedSignal Inc. for their
generous donation of N-fluorodibenzenesulfonimide and
their helpful suggestions on the use of this reagent.
Their support is greatly appreciated. We also thank Dr.
Xiaoyang Xia and Dr. Karl Hagen for their assistance
in obtaining the X-ray crystal structures of 6, 18a , and
18b. We thank Susan Schlueter Wirtz, Sarah Kupfer,
Amy J uodawlkis, and Philip Tharnish for excellent
technical assistance. This work was supported by
Public Health Service Grant 1RO1-AI-28731-07 (D.C.L.),
1RO1-AI-41980 (R.F.S.) from the National Institute of
Allergy and Infectious Diseases, and by the Department
of Veterans Affairs (R.F.S.).
Su p p or tin g In for m a tion Ava ila ble: X-ray crystal struc-
tures of 6, 18a , and 18b; 1H and 13C NMR data with subjective
peak assignments (39 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of this journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
J O9717898
(17) (a) Schinazi, R. F.; McMillan, A.; Cannon, D.; Mathis, R.; Lloyd,
R. M. jr.; Peck, A.; Sommadossi, J .-P.; St. Clair, M.; Wilson, J .; Furman,
P. A.; Painter, G.; Choi, W.-B.; Liotta, D. C. Antimicrob. Agents
Chemother. 1992, 36, 2423. (b) Schinazi, R. F.; Sommadossi, J .-P.;
Saalmann, V.; Cannon, D.; Xie, M.-Y.; Hart, G.; Smith, G.; Hahn, E.
Antimicrob. Agents Chemother. 1990, 34, 1061.
(18) Chou, T.-C.; Talalay, P. Adv. Enzyme Regul. 1984, 22, 27.