Synthesis of 2′,3′-Dideoxy-2′-trifluoromethylnucleosides from α-Trifluoromethyl-α,β-unsaturated Ester

Article abstract of DOI:10.1021/jo005520r

The treatment of α-bromo-α,β-unsaturated esters 2 with FSO₂CF₂CO₂Me and CuI in DMF/HMPA constitutes a new synthetic scheme for the preparation of α-trifluoromethyl-α,β-unsaturated esters 3. The trifluoromethylation of (Z)/(E)-ethyl 3-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-bromo-2-propenoate (2e), which is derived from 1-(R)-glyceraldehyde acetonide, yields the key intermediate α-trifluoromethyl-αβ-unsaturated esters 3e. This is transformed into anomeric acetates 8a and 8b and is used for the synthesis of a number of 2′,3′-dideoxy-2′-trifluoromethylnucleosides.

Full text of DOI:10.1021/jo005520r

J . Org. Chem. 2000, 65, 7075-7082
7075
Syn th esis of 2′,3′-Did eoxy-2′-tr iflu or om eth yln u cleosid es fr om
r-Tr iflu or om eth yl-r,â-u n sa tu r a ted Ester
Xingang Zhang, Feng-Ling Qing,* and Yihua Yu
Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
flq@pub.sioc.ac.cn
Received May 21, 2000
The treatment of R-bromo-R,â-unsaturated esters 2 with FSO2CF2CO2Me and CuI in DMF/HMPA
constitutes a new synthetic scheme for the preparation of R-trifluoromethyl-R,â-unsaturated esters
3. The trifluoromethylation of (Z)/(E)-ethyl 3-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-bromo-2-prope-
noate (2e), which is derived from 1-(R)-glyceraldehyde acetonide, yields the key intermediate
R-trifluoromethyl-R,â-unsaturated esters 3e. This is transformed into anomeric acetates 8a and
8b and is used for the synthesis of a number of 2′,3′-dideoxy-2′-trifluoromethylnucleosides.
In tr od u ction
carbohydrate precursors were prepared via the addition
of trifluoromethyltrimethylsilane to suitably protected 2-
or 3-oxo sugars.7 This requires several synthetic steps,
including the difficult and low-yielding Barton-type
deoxygenation of the unreactive tertiary hydroxyl func-
tion. Recently, a new method for the preparation of 2′-
trifluoromethyl-2′,3′-dideoxyuridine derivatives was re-
ported via the nucleophilic substitution at the unsaturated
carbon of the difluoromethylene group with a fluoride
anion.8 In this paper, we describe a novel and general
route to R-trifluoromethyl-R,â-unsaturated ester and its
use as a key intermediate in the synthesis of 2′,3′-
dideoxy-2′-trifluoromethylnucleosides.
The need for new antiviral and anticancer agents has
led to the discovery of a class of modified nucleosides.1
Fluorinated nucleosides are attractive compounds, with
the fluorine incorporated either into the base or sugar
moiety. The introduction of a fluorine atom into the sugar
moiety of some nucleosides resulted in compounds with
a broad spectrum of antiviral and anticancer activity.2
Since fluorine and trifluoromethyl groups have similar
inductive effects, σ ) 0.5 and 0.45, respectively, we were
interested in incorporation a trifluoromethyl group at the
2′ position of the sugar ring for several reasons. First,
the electronegativity of trifluoromethyl group should
stabilize the anomeric bond and suppress a significant
pathway of in vivo decomposition,3 thereby improving the
acid stability of the nucleoside. Second, hydroxyl groups
often serve as “handles” for the first step in oxidative
degradation of biomolecules in vivo.4 By replacing OH
with CF3, it cannot undergo oxidative catabolism. Third,
the lipophilicity of the trifluoromethyl group should
improve the transport characteristics of the nucleoside.
Although monofluorinated5 and gem-difluorinated6 sugar
nucleosides have been widely studied, only a few trifluo-
romethylated sugar nucleosides have been reported,
which is probably due to the shortcomings of existing
synthetic methods. These methods are based on the
condensation of appropriate carbohydrate precursors,
bearing 2- or 3-trifluoromethyl groups, with bases. The
Resu lts a n d Discu ssion
A New Rou te to r-Tr iflu or om eth yl-r,â -Un sa tu r -
a ted Ester s 3. R-Trifluoromethyl-R,â-unsaturated esters
3 have served as building blocks for the preparation of
trifluoromethylated biologically active compounds.9 Sev-
eral years ago, Lang et al.10 reported that the Refor-
matskii reaction of methyl 2,2-dichloro-3,3,3-trifluoro-
propionate with aldehydes followed by acylation and
(5) (a) Okabe, M.; Sun, R.; Zenchoff, G. B. J . Org. Chem. 1991, 56,
4392. (b) Fleet, G. W. J .; Son, J . C.; Derome, A. E. Tetrahedron 1988,
44, 625. (c) Wysocki, R. J .; Siddiqui, M. A.; Barchi, J . J .; Driscoll, J .
S.; Marquez, V. E. Synthesis 1991, 1005. (d) Patrick, T.; Ye, W. J .
Fluorine Chem. 1998, 90, 53. (e) McAtee, J . J .; Schinazi, R. F.; Liotta,
D. D. J . Org. Chem. 1998, 63, 2161. (f) Lee, K.; Choi, Y.; Gullen, E.;
Schlueter-Wirtz, S.; Schinazi, R. F.; Cheng, Y. C.; Chu, C. K. J . Med.
Chem. 1999, 42, 1320. (g) Lee, K. C.; Choi, Y.; Hong, J . H.; Schinazi,
R. F.; Chu, C. K. Nucleosides Nucleotides 1999, 18, 537. (h) Thiba-
udeau, C.; Plavec, J .; Chattopadhyaya, J . J . Org. Chem. 1998, 63, 4967.
(i) Pankiewicz, K. W.; Kizeminski, J .; Ciszewski, L. A. Ren, W. Y.;
Watanabe, K. A. J . Org. Chem. 1992, 57, 553.
(6) (a) Hertel, L. W.; Kroin, J . S.; Misner, J . W.; Tustin, J . M. J .
Org. Chem. 1988, 53, 2406. (b) Chou, T. S.; Heath, P. C.; Patterson, L.
E.; Poteet, L. M.; Lakin, R. E.; Hunt, A. H. Synthesis 1992, 565. (c)
Xiang, Y.; Kotra, L. P.; Chu, C. K.; Schinazi, R. F. Bioorg. Med. Chem.
Lett. 1995, 5, 743. (d) Fernandez, R.; Matheu, M. I.; Echarri, R.;
Castillon, S. Tetrahedron 1998, 54, 3523.
(7) (a)J ohnson, C.; Bhumralkar, D. P.; De Clercq, E. Nucleosides
Nucleotides 1995, 14, 185. (b) Schmit, C. Synlett 1994, 241. (c) Lavaire,
S.; Plantier-Royon, R.; Portella, C.; De Monte, M.; Kirn, A.; Aubertin,
A. M. Nucleosides Nucleotides 1998, 17, 2267.
(8) Serafinowski, P. J .; Brown, C. A. Tetrahedron 2000, 56, 333.
(9) (a) Wipf, P.; Henningen, T. C.; Geib, S. J . J . Org. Chem. 1998,
63, 6088. (b) J ohnson, T. R.; Silvenman, R. B. Bioorg. Med. Chem. 1999,
7, 1625.
(1) (a) Huyn, D. M.; Okabe, M. Chem. Rev. 1992, 92, 1745. (b)
Perigaud, C.; Imbach, J . L. Nucleosides Nucleotides 1992, 11, 903. (c)
Chemistry of Nucleosides and Nucleotides; Townsend, L. B.; Ed.;
Plenum Press: New York, Vol. 1, 1988. (d) Chemistry of Nucleosides
and Nucleotides; Townsend, L. B.; Ed.; Plenum Press: New York, Vol.
2, 1991.
(2) (a) Ternansky, R. J .; Hertel, L. W. Organofluorine Compounds
in Medicinal Chemistry and Biomedical Applications; Filler, R.,
Kobayashi, Y., Yagupolski, L. M. Eds.; Elsevier: Amsterdam. 1993; p
23. (b) Herdewijn, P.; Van Aerschot, A.; Kerreman, L. Nucleosides
Nucleotides 1989, 8, 65. (c) Tsuchiya, T. Adv. Carbohydr,. Chem.
Biochem. 1990, 48, 91.
(3) (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.
(4) Biomedicinal Aspects of Fluorine Chemistry; Filler, R., Koba-
yashi, Y., Eds.; Elsevier: New York, 1982.
(10) Allmendinger, T.; Lang, R. W. Tetrahedron Lett. 1991, 32, 339.
10.1021/jo005520r CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/20/2000

7076 J . Org. Chem., Vol. 65, No. 21, 2000
Zhang et al.
Sch em e 1
Ta ble 1. Syn th esis of r-Tr iflu or om eth yl-r,â-u n sa tu r a ted Ester s 3
a
b
d
Yields were based on aldehydes. This ratio was determined by 1H NMR. c Yields were based on 2. This ratio was determined by
19F NMR. e These compounds were prepared from the Z-3.
Sch em e 2
reductive elimination gave compound 3, formed as nearly
a 1:1 mixture of E and Z isomers. We have developed a
new method for the predominant preparation of (Z)-R-
trifluoromethyl-R,â-unsaturated esters 3. The new route
to 3 was based on the trifluoromethylation of R-bromo-
R,â-unsaturated esters 2 (Scheme 1). Ylide 1 was pre-
pared from triphenylphosphine and ethyl bromoacetate
in four steps in 50% overall yield.11 The Wittig reaction
of aldehydes with ylide 1 provided the Z isomer of
R-bromo-R,â-unsaturated esters 2 as the major product
in high yield (Table 1). The Z and E isomer of compounds
2c and 2d can be separated by column chromatography.
However, other Z and E isomers of R-bromo-R,â-unsatur-
ated esters could not be separated and the mixture was
directly used in the next reaction. Although the reaction
of the in-situ generated trifluoromethylcopper reagent
(CF3Cu) with alkenyl and aryl halides is useful for direct
introduction of the trifluoromethyl group into a mol-
ecule,12 the coupling of in-situ generated CF3Cu with
R-halo-R,â-unsaturated esters has not been reported. We
were delighted to observe that the treatment of a 92:8
mixture of Z-and E-2e with FSO2CF2CO2Me and CuI in
the double bond in 3 was determined by the chemical
shifts of the alkenyl proton. The alkenyl proton in the Z
isomer appeared at lower field than in the E isomer.10
The following observations of the trifluoromethylation are
noteworthy: (1) The slow addition via syringe and an
excess of FSO2CF2CO2Me (2.0 equiv) were necessary for
the total conversion of R-bromo-R,â-unsaturated esters
2. Otherwise, the pure compound 3 was not obtained,
because 3 and 2 could not be separated by column
chromatography. Use of 1.0 or 2.5 equiv of CuI offered
no advantage over 0.2 equiv of CuI. (2) The Z isomer of
compound 3 was produced as the major product. Some
isomerization occurred when the pure Z isomers of 2c
and 2d reacted to form mixtures of Z and E isomers of
3c and 3d , respectively (entries 3 and 4). When a mixture
of Z and E isomers of compound 2 was used for the
trifluoromethylation, the Z:E ratio of compound 3 de-
creased (entries 1, 2, 3, and 6). Whereas R-iodo-R,â-
unsaturated ester 4 was subjected to the same trifluo-
romethylation conditions, the configuration of the double
bond remained intact (Scheme 2). However, the prepara-
tion of 4 proved to be quite problematical.14 (3) In the
case of compound 2d (entry 4), the isolated yield was low
(42%) because fluoro-containing byproducts were pro-
duced and detected by 19F NMR of the reaction mixture.15
13
DMF/HMPA at 75 °C gave a 89:11 mixture of Z- and
E-3e in 68% isolated yield. Various kinds of R-bromo-
R,â-unsaturated esters 2 were used for the preparation
of R-trifluoromethyl-R,â-unsaturated esters 3 under the
same reaction conditions (Table 1). The configuration of
(11) Denney, D. B.; Ross, S. T. J . Org. Chem. 1962, 27, 998.
(12) McClinton, M. A.; McClinton, D. A. Tetrahedron 1992, 48, 6555.
(13) (a) Chen, Q. Y.; Wu, S. W. J . Chem. Soc. Chem. Commun. 1989,
705. (b) Qing, F. L.; Fan, J .; Sun, H.; Yue, X. J . J . Chem. Soc., Perkin
Trans 1 1997, 3053. (c) Fei, X. X.; Tian, W. S.; Chen, Q. Y. J . Chem.
Soc., Perkin Trans 1 1998, 1139.
Syn t h esis of 2′,3′-Did eoxy-2′-t r iflu or om et h yln u -

Synthesis of 2′,3′-Dideoxy-2′-trifluoromethylnucleosides
J . Org. Chem., Vol. 65, No. 21, 2000 7077
Sch em e 3
F igu r e 2. ORTEP drawing of the X-ray crystallographic
structure of 13a b.
(Scheme 4). Similarly, the â-trifluoromethylated lactone
6b was transformed predominantly, but not exclusively,
into R anomeric acetate 8b under the same reaction
conditions (Scheme 5). The reduction of 6b with DIBAL-H
gave a higher yield of lactol than 6a . It is of interest to
note that when the lactol 7b (R/â ) 2.3:1 determined by
1H NMR) was treated with acetic anhydride, the â
anomer was converted into the R anomer (8b R/â )11.2:1
determined by 19F NMR). This difference was presumably
due to the steric interaction of trifluoromethyl group and
acetyl group. Coupling of 8a with silylated uracil, thym-
ine, and N4-benzoylcytosine under Vorbruggen conditions
(glycosylation reactions)16 gave mainly the â anomers in
high yields (Scheme 4 and Table 2). The silyl-protected
nucleosides could be resolved by column chromatography
into the separate anomers, except compounds 16ba and
16bb. This is different from other silyl-protected nucleo-
sides in that the R and â anomers could not be separated
by column chromatography.5e The removal of the 5′-silyl
group and the N4-benzoyl group with TBAF and a
saturated solution of ammonia in methanol respectively
gave 2′,3′-dideoxy-2′R-trifluoromethylnucleosides 12, 13,
and 15. The 2′â trifluoromethylated acetate 8b was
condensed with silylated pyrimidine bases, as described
for 8a , to afford the mainly R anomers of 2′,3′-dideoxy-
2′â-trifluoromethylnucleosides 19, 20, and 22 (Scheme 5
and Table 2).
F igu r e 1. NOE correlations from NOESY spectra of 13a b,
13a a , 20bb, and 20ba .
cleosid es. With the R-trifluoromethyl-R,â-unsaturated
esters 3e in hand (entry 5 in Table 1), we turned our
attention to the application of this trifluoromethyl-
containing building block to the preparation of 2′,3′-
dideoxy-2′-trifluoromethylnucleosides. Due to difficulties
in separation of (Z)-3e/(E)-3e isomers (Z:E ) 89:11), the
mixture was directly used in next reaction (Scheme 3).
Hydrogenation of 3e in the presence of palladium on
activated carbon (10% Pd), followed by deprotection and
closure in the presence of 2.0 mol % of 1 N HCl under
reduced pressure, afforded lactone 5 as a mixture of the
C-2 epimers (syn:anti ) 1.67:1, determined by 19F NMR)
in 78% yield. Protection of the hydroxyl group of 5 with
TBDMSCl gave 6a and 6b, which were readily separated
by silica gel column chromatography. Identification of
trifluoromethyllactone 6a and 6b as the R-trifluoromethyl
isomer (“down”) and â-trifluoromethyl isomer (“up”),
respectively, was accomplished by X-ray crystal structure
determination of 2′,3′-dideoxy-2′-trifluoromethylnucleo-
side 13a b (Figure 2) and the NOESY experiments of
13a b, 13a a , 20bb, and 20ba (Figure 1).
Stereochemical assignments of the final compounds
were made on the basis of 1D and 2D NMR spectroscopy
and X-ray crystallography. The configuration of the
anomeric center was assigned mainly by 1H NMR, in
which the anomers with H4′ at lower field were assigned
as the R anomers and the ones at higher field were
assigned as the â anomers on the basis of the deshielding
effect of the base moiety17 (Table 3). This assignment was
further confirmed by the NOESY experiment of 13a b,
The R-trifluoromethylated lactone 6a was reduced by
DIBAL-H in anhydrous THF to provide exclusively â
anomeric lactol 7a , which was then treated with acetic
anhydride to afford the single â anomeric acetate 8a
(16) (a) Vorbru¨ggen, H.; Krolikiewicz, K.; Bennua, B. Chem. Ber.
1981, 114, 1234. (b) Vorbru¨ggen, H.; Hofle, G. Chem. Ber. 1981, 114,
1256.
(17) Chun, B. K.; Olegen, S.; Hong, J . H.; Newton, M. G.; Chu, C.
K. J . Org. Chem. 2000, 65, 685.
(14) Chenault, J . Dupin, J . E. Synthesis 1987, 498.
(15) 19F NMR spectra were obtained on either 56.4 or 282 MHz
spectrometer using CF3CO2H as external standard, downfield shifts
being designated as negative.

7078 J . Org. Chem., Vol. 65, No. 21, 2000
Zhang et al.
Sch em e 4
Sch em e 5
13a a , 20bb, and 20ba (Figure 1) as well as X-ray
crystallography of 13a b (Figure 2). An additional key to
the assignment of configuration of the anomeric center
was the polarity of the nucleosides as observed by thin-
layer chromatography. When the 2′-trifluoromethyl group
was at the R-position (“down”) of the nucleosides, the R
anomer is more polar than the â anomer. In contrast,
the â anomer is more polar than the R anomer in the

Synthesis of 2′,3′-Dideoxy-2′-trifluoromethylnucleosides
J . Org. Chem., Vol. 65, No. 21, 2000 7079
Ta ble 2. Th e Glycosyla tion Rea ction s of 8a a n d 8b
ethyl 3-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-bromo-2-prope-
1
noate (2e) (92:8 by H NMR) as a clear colorless oil: 1H NMR
bases
uracil
sugar
â/R
yield(%)a
product
(300 MHz, CDCl3) δ 7.30 (d, J ) 7.0 Hz, 1H), 4.88 (m, 1H),
4.22 (m, 3H), 3.66 (m, 1H), 1.42-1.25 (m, 9H); IR (thin film)
2988, 1733, 1259, 1063, 1031 cm-1; MS m/z 281 (M++1, 4),
279 (M+ -1, 4), 43 (100). Anal. Calcd for C10H15O4Br: C, 43.01;
H, 5.38. Found: C, 43.25; H, 5.54. To a solution of 2e (11.00
g, 39.4 mmol) in anhydrous DMF (138 mL) and HMPA (20
mL) was added CuI (1.51 g, 7.89 mmol). Then the mixture was
heated to 75 °C, and a solution of FSO2CF2CO2Me (10.01 mL,
78.86 mmol) in DMF (20 mL) was added via syringe over a
period of 15 h. After the mixture was stirred for 14 h at 75 °C,
the reaction mixture was treated with saturated aqueous NH4-
Cl and was filtered. The filtrate was extracted with diethyl
ether. Then organic layer was washed with brine, dried over
8a
8a
8a
8b
8b
8b
1.43/1b
2.42/1c
1.67/1b
1/2.33c
1/2.88d
1/2.77b
75
90
85
77
85
73
9a b + 9a a
10a b + 10a a
11a b + 11a a
16bb + 16ba
17bb + 17ba
18bb + 18ba
thymine
N4-Bz-cytosi ne
uracil
thymine
N4-Bz-cytosi ne
a
b
Isolated yields. Determined by isolated products. c Deter-
d
mined by 1H NMR. Determined by 19F NMR.
Ta ble 3. Som e Selected 1H NMR Da ta of th e Syn th esized
Nu cleosid es
compd
H4 δ (ppm)
compd
H4 δ (ppm)
,
Na2SO4 and concentrated. The residue was purified by silica
12a b
13a b
15a b
4.23
4.44
4.46
12aa
13aa
15aa
19ba
20ba
22ba
4.59
4.85
4.78
4.78
4.79
4.81
gel column chromatography (hexane: ethyl acetate ) 40:1) to
1
give a mixture of 7.29 g (68% yield) of (Z)/(E)-3e (89:11, by H
NMR) as a yellowish oil:1H NMR (300 MHz, CDCl3) δ 7.35 (d,
J ) 7.0 Hz, 0.11H), 7.26 (d, J ) 7.0 Hz, 0.89H), 5.10 (m, 1H),
4.27 (m, 3H), 3.72 (m, 1H), 1.48-1.26 (m, 9H); 19F NMR (56.4
MHz, CDCl3) δ -11.9 (s, 0.33F), -17.6 (s, 2.67F); IR (thin film)
2991, 1737, 1375, 1264, 1149 cm-1; MS m/z 269 (M + 1,10),
43 (100). Anal. Calcd for C11H15O4F3: C, 49.25; H, 5.60.
Found: C, 49.22; H, 5.79.
20bb
22bb
4.37
4.35
“up” (â-position) 2′-trifluoromethylated nucleosides. This
is due to the dipole-dipole interaction between the dipole
of the C-CF3 bond and the dipole of the C-N bond.5e In
the “down” 2′-trifluoromethyl nucleosides, the strong
dipole of the C-CF3 bond opposes the C-N anomeric
bond dipole in the â anomer and reduces the overall
molecular dipole. Conversely, the R anomer has a geom-
etry that allows reinforcement of the molecular dipole
through the addition of the C-CF3 and C-N bond
dipoles. Thus, the R anomer is more polar than the â
anomer in R- 2′-trifluoromethyl nucleosides.
Of the 11 nucleosides listed in Table 3, only 12a b and
12a a 8 have been synthesized from natural precursors.
The 2′-trifluoromethyl group was introduced by the
nucleophilic addition of fluoride on the unsaturated
carbon of the difluoromethylene group.18,19 The advantage
of our methodology is that no carbonyl is needed for
trifluoromethyl introduction. Thus, we are not limited to
natural nucleosides as starting materials, and it is easy
to access the unnatural 2′-trifluoromethyl nucleosides.
In conclusion, a new and efficient preparation of
R-trifluoromethyl-R,â-unsaturated esters has been de-
veloped. The key step in this new route involves the
trifluoromethylation of R-bromo-R,â-unsaturated esters.
We have used R-trifluoromethyl-R,â-unsaturated ester 3e
as the key intermediate to synthesize 2′,3′-dideoxy-2′-
trifluoromethylnucleosides. Currently, these nucleosides
are undergoing biological evalution for activity against
viruses and as potential anticancer agents.
(Z)/(E)-Eth yl 3-P h en yl-2-tr iflu or om eth yl-2-p r op en oa te
(3a ). 1H NMR (300 MHz, CDCl3) δ 8.07 (s, 0.61H), 7.35(s,
0.39H), 7.34 (s, 5H), 4.31 (q, J ) 7.1 Hz, 1.22H), 4.21 (q, J )
7.1 Hz, 0.78H), 1.32 (t, J ) 7.1 Hz, 1.83H), 1.14 (t, J ) 7.1 Hz,
1.17H); 19F NMR (56.4 MHz, CDCl3) δ -19.7 (s, 1.83F), -13.7
(s, 1.17F); IR (thin film) 1733, 1641, 1400, 1279 cm-1; MS m/z
245 (M+ + 1, 12), 244 (M+ , 65), 199 (100).
(Z)/(E)-E t h yl 3-(4-Met h oxyp h en yl)-2-b r om o-2-p r op e-
n oa te (2b).1H NMR (300 MHz, CDCl3) δ 8.19 (s, 1H), 7.93 (d,
J ) 8.1 Hz, 2H), 6.97 (d, J ) 8.1 Hz, 2H), 4.36 (q, J ) 7.0 Hz,
2H), 3.88 (s, 3H), 1.40 (t, J ) 7.0 Hz, 3H); IR (thin film) 1720,
1602, 1512, 1255, 1176 cm-1; MS m/z 286 (M+ + 1,100), 285
(M+ , 81), 284 (M+ -1, 100). Anal. Calcd for C12H13O3Br: C,
50.55; H, 4.59. Found: C, 50.36; H, 4.59.
(Z)/(E)-Eth yl 3-(4-Meth oxyp h en yl)-2-tr iflu or om eth yl-
2-p r op en oa te (3b).1H NMR (300 MHz, CDCl3) δ 7.99 (s, 1H),
7.41 (d, J ) 9.5 Hz, 1.52H), 7.30 (d, J ) 9.5 Hz, 0.48H), 6.91
(m, 2H), 4.34 (m, 2H), 3.83 (s, 3H), 1.37 (t, J ) 7.1 Hz, 2.28H),
1.26 (t, J ) 7.1 Hz, 0.72H); 19F NMR (56.4 MHz, CDCl3) δ
-15.2 (s, 0.72F), -20.6 (s, 2.28F); IR (thin film) 1726, 1606,
1514, 1265, 1178 cm-1; MS m/z 275 (M+ + 1, 18), 274 (M+,
100). Anal. Calcd for C13H13O3F3: C, 56.94; H, 4.78. Found:
C, 56.88; H, 4.74.
(Z)-Eth yl 3-(4-Nitr oph en yl)-2-br om o-2-pr open oate (2c).
1H NMR (300 MHz, CDCl3) δ 8.28 (t, J ) 9.0 Hz, 3H), 7.96 (d,
J ) 9.0 Hz, 2H), 4.38 (q, J ) 7.1 Hz, 2H), 1.40 (t, J ) 7.1 Hz,
3H); IR (KBr) 1710, 1610, 1511, 1349, 1261 cm-1; MS m/z 301
(M+ + 1, 12), 299 (M+ - 1, 12), 192 (100). Anal. Calcd for
C
11H10NO4Br: C, 44.00; H, 3.33; N, 4.67. Found: C, 44.09; H,
3.24; N, 4.58.
(E)-Eth yl 3-(4-Nitr oph en yl)-2-br om o-2-pr open oate (2c).
1H NMR (300 MHz, CDCl3) δ 8.19 (d, J ) 9.0 Hz, 2H), 7.44 (t,
J ) 9.0 Hz, 3H), 4.22 (q, J ) 7.1 Hz, 2H), 1.20 (t, J ) 7.1 Hz,
3H); IR (KBr) 3109, 1728, 1598, 1521, 1347, 1220 cm-1; MS
m/z 301 (M+ + 1, 13), 299 (M+ - 1, 12), 192 (100).
(Z)-Eth yl 3-(4-Nitr op h en yl)-2-tr iflu or om eth yl-2-p r op e-
Exp er im en ta l Section
Rep r esen ta tive P r oced u r e for th e Syn th esis of r
-Tr iflu or om eth yl-r,â-u n sa tu r a ted Ester s 3. (Z)/(E)-Eth yl
3-[(S)-2,2-Dim eth yl-1,3-d ioxola n -4-yl]-2-tr iflu or om eth yl-
2-p r op en oa te (3e). A solution of triphenylcarbethoxybro-
momethylenephosphorane 1 (26.26 g, 61.5 mmol) and 1-(R)-
glyceraldehyde acetonide (8.00 g, 61.5 mmol) in CH2Cl2 (300
mL) was heated under reflux with stirring for 24 h. After the
solvent was removed, the residue was refluxed for 30 min with
a mixture of hexane/ethyl acetate (6:1,100 mL). The process
was repeated three times, the combined extracts were filtered,
and the filtrate was concentrated to yield a yellow oil. The oil
was purified by silica gel column chromatography (hexane:
ethyl acetate ) 15:1) to give 12.29 g (72% yield) of (Z)/(E)-
1
n oa te (3c). H NMR (300 MHz, CDCl3) δ 8.27 (d, J ) 9.0 Hz,
2H), 8.11 (s, 1H), 7.54 (d, J ) 9.0 Hz, 2H), 4.26 (q, J ) 7.0 Hz,
2H), 1.39 (t, J ) 7.0 Hz, 3H); 19F NMR (56.4 MHz, CDCl3) δ
-19.0 (s); IR (KBr) 1772, 1639, 1603, 1521 cm-1; MS m/z 290
(M+ + 1, 12), 289(M+, 26), 244 (100). Anal. Calcd for C12H10
-
NO4F3: C, 49.83; H, 3.49; N, 4.84. Found: C, 49.80; H, 3.59;
N, 4.84.
(E)-E t h yl 3-(4-Nit r op h en yl)-2-t r iflu or om et h yl-2-p r o-
1
p en oa te (3c). H NMR (300 MHz, CDCl3) δ 8.27 (d, J ) 9.0
Hz, 2H), 7.53 (d, J ) 9.0 Hz, 2H), 7.51 (s, 1H), 4.39 (q, J ) 7.0
Hz, 2H), 1.39 (t, J ) 7.0 Hz, 3H); 19F NMR (56.4 MHz, CDCl3)
δ -12.6 (s); IR (KBr) 1727, 1656, 1600, 1519 cm-1; MS m/z
289 (M+, 27), 244 (100). Anal. Calcd for C12H10NO4F3: C, 49.83;
H, 3.49; N, 4.84. Found: C, 49.86; H, 3.65; N,4.78.
(18) Serafinowski, P. J .; Barnes, C. L. Tetrahedron 1996, 52, 7929.
(19) Serafinowski, P. J .; Barnes, C. L. Synthesis 1997, 225

7080 J . Org. Chem., Vol. 65, No. 21, 2000
Zhang et al.
(2Z)-Eth yl 5-P h en yl-2-br om op en ta -2,4-d ien oa te (2d ).
1H NMR (300 MHz, CDCl3) δ 7.84 (d, J ) 8.9 Hz, 1H), 7.54
(m, 2H), 7.37 (m, 3H), 7.17 (m, 2H), 4.41 (q, J ) 7.1 Hz, 2H),
1.37 (t, J ) 7.1 Hz, 3H); IR (thin film) 1720, 1616, 1585, 1263
cm-1; MS m/z 282 (M+ + 1, 16), 281 (M+, 10), 280 (M+ - 1,
16), 128 (100).
(2E)-Eth yl 5-P h en yl-2-br om op en ta -2,4-d ien oa te (2d ).
1H NMR (300 MHz, CDCl3) δ 7.82 (m, 1H), 7.50 (m, 2H), 7.34
(m, 4H), 6.81 (d, J ) 15.5 Hz, 1H), 4.34 (q, J ) 7.1 Hz, 2H),
1.41 (t, J ) 7.1 Hz, 3H); IR (thin film) 2983, 1720, 1616, 1585,
1263, 1220 cm-1; MS m/z 282 (M+ + 1, 12), 280 (M+ - 1, 13),
128 (100).
3.46 (m,1H), 2.49 (m,2H), 0.89 (s, 9H), 0.09 (s, 6H); 19F NMR
(282 MHz, CDCl3) δ -8.34 (d, J ) 8.39); IR (KBr) 2935, 1760,
1263, 1127 cm-1; MS m/z 241 (2), 77 (100).
(2R,4S)-5-O-(ter t-Bu tyld im eth ylsilyl)-2,3-d id eoxy-2-tr i-
flu or om eth ylp en tof u r a n ose (7a ). To a flask were added
lactone 6a (2.74 g, 9.19 mmol) and anhydrous THF (90 mL).
The solution was cooled to -78 °C, and a 1.0 M solution of
DIBAL-H in cyclohexane (5.52 mL, 55.2 mmol) was added
dropwise over a period of 50 min. This was allowed to stir at
-78 °C for 5 h, then the reaction mixture was quenched by
the slow addition of methanol at -20 °C, until no more gas
elution occurred. The mixture was then allowed to warm
slowly to ambient temperature, and 50 mL of 1 N HCl was
added to the mixture. This was stirred for 30 min.The aqueous
layer was extracted with diethyl ether. The organic layers were
combined, washed with saturated aqueous NaHCO3 and brine,
dried over Na2SO4, and concentrated to give a oil. The oil was
purified by silica gel column chromatography (hexane:ethyl
acetate ) 8:1) to give 1.772 g (64% yield) of lactol 7a as a yellow
oil: 1H NMR (300 MHz, CDCl3) δ 5.47 (d, 1H), 4.48 (m, 1H),
3.84 (dd, J ) 11.0 Hz, 2.0 Hz, 1H), 3.54 (dd, J ) 11.0 Hz, 2.0
Hz,1H), 2.90 (m, 1H), 2.19 (m, 2H), 0.96 (s, 9H), 0.14 (s, 6H);
19F NMR (282 MHz, CDCl3) δ -5.95 (d, J ) 10.1 Hz); IR (thin
film) 3418, 2958, 1273, 1166, 1134 cm-1; MS m/z 283 (M+ -OH,
1), 75 (100). Anal. Calcd for C12H23O3F3Si: C, 47.98; H, 7.72.
Found: C, 47.91; H, 7.96.
(2Z)-Eth yl 5-P h en yl-2-tr iflu or om eth ylp en ta -2,4-d ien o-
1
a te (3d ). H NMR (300 MHz, CDCl3) δ 7.72 (d, J ) 11.9 Hz,
1H), 7.53 (m, 2H), 7.41 (m, H), 7.11 (d, J ) 15.2 Hz, 1H), 4.33
(q, J ) 7.1 Hz, 2H), 1.36 (t, J ) 7.1 Hz, 3H); 19F NMR (56.4
MHz, CDCl3) δ -20.7 (s). IR (thin film) 1724, 1623, 1290, 1257,
1140 cm-1; MS m/z 271 (M+ + 1, 49), 270 (M+, 100).
(Z)/(E)-ter t-Bu tyl (4S)-4-(3′-Eth oxyca r bon yl-2′-br om o-
pr op-1′-en yl)-2,2-dim eth yloxazolidin e-3-c ar boxylate (2f).
1H NMR (300 MHz, CD3COCD3) δ 7.26 (d, J ) 7.8 Hz, 0.93H),
6,77 (d, J ) 7.8 Hz, 0.07H), 5.11-4.76 (m, 1H), 4.71-4.29 (m,
3H), 3.87-3.80 (m, 1H), 1.59-1.30 (m, 18H); IR (thin film)
2982, 1705, 1616 cm-1; MS m/z 380 (M+ + 1, 1), 57 (100); Anal.
Calcd for C15H24BrNO5: C, 47.63; H, 6.40; N, 3.70. Found: C,
47.44; H, 6.50; N, 3.78.
(Z)/(E)-ter t-Bu tyl (4S)-4-(3′-Eth oxyca r bon yl-2′-tr iflu o-
r om et h ylp r op -1′-en yl)-2,2-d im et h yloxa zoli d in e-3-ca r -
boxyla te (3f). 1H NMR (300 MHz, CD3COCD3) δ 7.21 (d, J )
8.7 Hz, 0.67H), 6,94 (d, J ) 8.4 Hz, 0.33H), 5.19-4.97 (m, 1H),
4.36-4.26 (m, 3H), 3.91-3.85 (m, 1H), 1.61-1.20 (m, 18H);
9F NMR (56.4 MHz, CDCl3) δ -18.0 (s, 2.27F), -12.5 (s, 0.73F);
IR (thin film) 2984, 1735, 1710 cm-1; MS m/z 380 (M+ + 1, 2),
57 (100); Anal. Calcd for C16H24F3NO5: C, 52.32; H, 6.54; N,
3.81. Found: C, 52.42; H, 6.58; N, 4.07.
(2R,4S/2S,4S)-5-H yd r oxy-2-t r iflu or om et h ylp en t a n -4-
olid e (5). 10% of Pd/C (2.00 g, 1.88 mmol) was added to a
solution of (Z)/(E)-3e (7.10 g, 26.49 mmol) in ethanol (150 mL)
at room temperature under 1 atm of hydrogen. After stirring
for 24 h, the reaction mixture was filtered, and the solvent
was removed to give a colorless oil that was used in the next
step. The oil and 1 N HCl (2 mL) were stirred at 50-55 °C
under atmospheric pressure for 2 h and then under a reduced
pressure at 60 mmHg overnight. The excess water was
removed by stirring at that temperature under high vacuum
for 3 h. The residue was purified by silica gel column
chromatography (hexane:ethyl acetate ) 2:1) to give 3.80 g
(78% yield, two steps) of a mixture of (2R/2S)-trifluoromethyl
lactone 5:1H NMR (300 MHz, CDCl3) δ 4.70-4.62 (m, 1H), 3.95
(m, 1H), 3.65-3.60 (m, 2H), 3.27 (s, 1H), 2.53 (m, 1H), 2.32
(m, 1H); 19F NMR (282 MHz, CDCl3) δ -7.78 (d, J ) 8.7 Hz,
1.88F), -8.10 (d, J ) 8.7 Hz, 1.12F); IR(thin film) 3422, 2959,
1779, 1374, 1124 cm-1; MS m/z 185 (M+ + 1, 29), 77 (100).
Anal. Calcd for C6H7O3F3: C, 39.14; H, 3.83. Found: C, 39.49;
H, 3.77.
(2S,4S)-5-O-(ter t-Bu tyld im eth ylsiyl)-2,3-d id eoxy-2-tr i-
flu or om eth ylp en tofu r a n ose (7b). Compound 7b (2.046 g,
91%) was prepared as a light yellow oil from compound 6b
(2.228 g, 7.48 mmol) using the same procedure as for 7a : 1H
NMR (400 MHz, CDCl3) δ 5.63 (d, J ) 2.10 Hz, 0.7H), 5.39 (d,
J ) 4.27 Hz, 0.3H), 4.37 (m, 1H), 3.71 (m, 2H), 2.91 (m, 1H),
2.24 (m, 2H), 0.94 (s, 6.3H), 0.90 (s, 2.7H), 0.14 (s, 4.2H), 0.07
(s, 1.8H); 19F NMR (282 MHz, CDCl3) δ -6.86 (d, J ) 9.6 Hz,
2.26F), -11.31 (d, J ) 8.2 Hz, 0.74F); IR (thin film) 3420, 2958,
1261, 1170, 1141 cm-1; MS (EI) 300 (M+, 3), 43 (100). Anal.
Calcd for C12H23O3F3Si: C, 47.98; H, 7.72. Found: C, 47.77;
H, 7.74.
(2R,4S)-1-O-Acet yl-5-O-(ter t-b u t yld im et h ylsilyl)-2,3-
d id eoxy-2-tr iflu or om eth ylp en tofu r a n ose (8a ). To a flask
were added lactol 7a (1.77 g, 5.9 mmol) and anhydrous CH2-
Cl2 (70 mL). Then DMAP (0.070 g, 0.59 mmol) and acetic
anhydride (3.4 mL, 35.4 mmol) were added, and the solution
was stirred at room-temperature overnight. Upon completion,
the reaction was poured into a saturated NaHCO3 solution and
stirred for 15 min. The organic layers were washed with brine,
,
dried over Na2SO4 and concentrated to give light yellow oil.
The oil was purified by silica gel column chromatograph
(hexane:ethyl acetate ) 10:1) to give compound 8a (93% yield)
as a clear colorless oil: 1H NMR (300 MHz, CDCl3) δ 6.52 (d,
J ) 1.4 Hz, 1H), 4.52 (m, 1H), 3.80 (m, 2H), 3.18 (m, 1H), 2.35
(m, 2H), 2.19 (s, 3H), 1.03 (s, 9H), 0.20 (s, 6H); 19F NMR (282
MHz, CDCl3) δ -6.64 (d, J ) 9.5 Hz); IR (thin film) 2938, 1763,
1228, 1135 cm-1; MS m/z 283 (M+ -OAc, 6), 43 (100). Anal.
Calcd for C14H25O4F3Si: C, 49.10; H, 7.36. Found: C, 49.07;
H, 7.30.
(2R,4S/2S,4S)-5-(ter t-Bu t yld im et h ylsiloxy)-2-t r iflu o-
r om eth ylp en ta n -4-olid e (6a a n d 6b). To a solution of
lactone 5 (3.73 g, 20.29 mmol) in CH2Cl2 (50 mL) were added
tert-bytyldimethylsilyl chloride (8.84 g, 40.57 mmol) and
imidazole (4.14 g, 60.86 mmol) in CH2Cl2 (30 mL) with stirring.
After being stirred for 50 min at room temperature, the
reaction mixture was poured onto water. The organic layer
was washed with brine, dried over Na2SO4, and concentrated
to give a yellowish oil. The oil was purified by silica gel column
chromatography (hexane:ethyl acetate ) 8:1) to give 3.21 g
(53% yield)of compound 6a as a white solid and 2.23 g (37%
yield) of compound 6b as a white solid. 6a :1H NMR (300 MHz,
CDCl3) δ 4.68 (m, 1H), 3.93 (dd, J ) 11.5 Hz, 2.2 Hz, 1H),
3.69 (dd, J ) 11.5 Hz, 2.0 Hz, 1H), 3.55 (m, 1H), 2.50 (m, 1H),
0.90 (s, 9H), 0.09 (s, 6H); 19F NMR (282 MHz, CDCl3) δ -7.80
(d, J ) 8.8 Hz); IR (KBr) 2962, 1775, 1369, 1294, 1258, 1129
cm-1; MS m/z 299 (M+ + 1, 18), 298 (M+, 2), 77(100). Anal.
Calcd for C12H21O3F3Si: C, 48.30; H,7.03. Found: C,48.15; H,
7.16. 6b:1H NMR (300 MHz, CDCl3) δ 4.54 (m, 1H), 3.93 (dd,
J )11.6 Hz, 3.4 Hz, 1H), 3.75 (dd, J ) 11.6 Hz, 3.4 Hz, 1H),
(2S,4S)-1-O-Acet yl-5-O-(ter t-b u t yld im et h ylsilyl)-2,3-
d id eoxy-2-tr iflu or om eth ylp en tofu r a n ose (8b). Compound
8b (2.19 g, 100%) was prepared as a clear colorless oil from
compound 7b (1.921 g, 6.40 mmol) using the same procedure
as for compound 8a :1H NMR (300 MHz, CDCl3) δ 6.42 (d, J )
1.7 Hz, 1H), 4.31 (m, 1H), 3.75 (m, 2H), 3.06 (m, 1H), 2.30 (m,
1H), 2.06 (s, 3H), 1.98 (m, 1H), 0.90 (s, 9H), 0.08 (s, 6H); 19F
NMR (282 MHz, CDCl3) δ -6.88 (d, J ) 9.1 Hz, 2.69F), -11.48
(d, J ) 8.3 Hz, 0.31F); IR (thin film) 2959, 1759, 1226, 1108,
839 cm-1; MS m/z 283 (M+ -OAc, 7), 43 (100). Anal. Calcd for
C
14H25O4F3Si: C, 49.10; H, 7.36. Found: C, 49.26; H, 7.52.
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 Su ga r : (2′R)-D-5′-O-(ter t-Bu tyld im eth -
ylsilyl)-2′,3′-d id eoxy-2′-tr iflu or om eth ylu r id in e (9a b a n d
9a a ). To a stirred solution of compound 8a (0.250 g, 0.731
mmol) and uracil (0.229 g, 2.047 mmol) in anhydrous aceto-
nitrile (35 mL) was added N,O-bis(trimethylsilyl)acetamide
(1.05 mL, 4.240 mmol).The reaction mixture was stirred at
reflux for 30 min. After cooling to 0 °C, trimethylsilyl triflate

Synthesis of 2′,3′-Dideoxy-2′-trifluoromethylnucleosides
J . Org. Chem., Vol. 65, No. 21, 2000 7081
(0.35 mL, 1.681 mmol) was added dropwise and the solution
was stirred for 24 h at room temperature. Saturated aqueous
NaHCO3 was added to the reaction mixture, which was then
extracted with CH2Cl2. The combined extract was washed with
(2′R)-D-N4-Ben zoyl-5′-O-(ter t-Bu tyld im eth ylsilyl)-2′,3′-
dideoxy-2′-tr iflu or om eth ylcytidin e (11ab an d 11aa). Com-
pounds 11a b (194 mg, 53%) and 11a a (116 mg, 32%) were
prepared as a white solid respectively from compound 8a (250
mg, 0.731 mmol) using the same procedure as for compounds
9a b and 9a a . 11a b: 1H NMR (300 MHz, CDCl3) δ 8.51 (d, J
) 7.5 Hz, 1H), 7.93 (d, J ) 7.4 Hz, 2H), 7.62-7.52 (m, 4H),
6.32 (d, J ) 2.8 Hz, 1H), 4.45 (m, 1H), 4.14 (dd, J ) 11.8 Hz,
2.2 Hz, 1H), 3.75 (dd, J ) 11.8 Hz, 2.2 Hz, 1H), 3.17 (m, 1H),
2.40 (m, 1H), 2.20 (m, 1H), 0.96 (s, 9H), 0.16 (s, 6H); 19F NMR
(282 MHz, CDCl3) δ -7.62 (d, J ) 9.1 Hz); IR (KBr) 3222, 1674,
1625, 1486, 1259 cm-1; MS m/z 498 (M+ + 1, 1), 497 (M+, 1),
105 (100). Anal. Calcd for C23H30N3O4F3Si: C, 55.52; H, 6.08;
N, 8.44. Found: C, 55.36; H, 6.27; N, 8.35. 11a a :1H NMR (300
MHz, CDCl3) δ 7.99-7.94 (m, 3H), 7.61-7.52 (m, 4H), 6.23
(d, J ) 5.6 Hz, 1H), 4.61 (m, 1H), 3.86 (dd, J ) 11.2 Hz, 3.3
Hz, 1H), 3.67(m, 2H), 2.45 (m, 2H), 0.92 (s, 9H), 0.09 (s, 6H);
19F NMR (282 MHz, CDCl3) δ -10.04 (d, J ) 9.4 Hz).
,
brine, dried over Na2SO4 and concentrated to give a yellow
oil. The oil was purified by silica gel column chromatography
(petroleum ether:ethyl acetate ) 1:1) to give 89 mg (30.9%
yield) of R anomer 9a a as a white foam, and 127 mg (44.1%
yield) of â anomer 9a b as a white solid. 9ab:1H NMR (400
MHz, CDCl3) δ 9.04 (s, 1H), 7.91 (d, J )8.1 Hz, 1H), 6.28 (d,
J ) 4.9 Hz, 1H), 5.72 (d, J ) 8.1 Hz, 1H), 4.34 (m, 1H), 4.03
(dd, J ) 11.7 Hz, 2.2 Hz, 1H), 3.69 (dd, J ) 11.7 Hz, 2.2 Hz,
1H), 3.06 (m, 1H), 2.38 (m,1H), 2.25 (m, 1H), 0.94 (s, 9H), 0.13
(s, 6H);19F NMR (282 MHz, CDCl3) δ -7.33 (d, J ) 8.7 Hz);
IR (KBr) 3195, 2950, 1683, 1462, 1380, 1259, 1126 cm-1; MS
m/z 395 (M+ + 1, 2), 394 (M+, 1), 169 (100). Anal. Calcd for
C
16H25N2O4F3Si: C, 48.72; H, 6.39; N, 7.10. Found: C, 48.26;
H, 6.38; N, 6.69. 9a a :1H NMR (400 MHz, CDCl3) δ 8.49 (s,
1H), 7.41 (d, J ) 8.1 Hz, 1H), 6.23 (d, J ) 4.3 Hz, 1H), 5.73 (d,
J ) 8.1 Hz, 1H), 3.62 (dd, J ) 11.2 Hz, 3.1 Hz, 1H), 2.35 (m,
2H), 0.91 (s, 9H), 0.10 (s, 6H); 19F NMR (282 MHz, CDCl3) δ
-10.13 (d, J ) 9.5 Hz); IR (KBr) 3208, 3120, 2958, 1710, 1681,
1460, 1386, 1255, 1177 cm-1; MS m/z 396 (M+ + 2, 1), 395
(M+ + 1, 4), 169 (100).
(2′S)-D-N4-Ben zoyl-5′-O-(ter t-Bu tyld im eth ylsilyl)-2′,3′-
dideoxy-2′-tr iflu or om eth ylcytidin e (18bb an d 18ba). Com-
pounds 18bb (194 mg, 54%) and 18ba (70 mg, 19%) were
prepared as a white solid respectively from compound 8b (250
mg, 0.731 mmol) using the same procedure as for compounds
9a b and 9a a . 18bb: 1H NMR (300 MHz, CDCl3) δ 8.29 (d, J
) 7.6 Hz, 1H), 7.93 (d, J ) 7.3 Hz, 2H), 7.62-7.51 (m, 4H),
6.45 (d, J ) 7.0 Hz, 1H), 4.23 (m, 1H), 4.06 (dd, J ) 11.5 Hz,
2.9 Hz, 1H), 3.82 (dd, J ) 11.5 Hz, 3.2 Hz, 1H), 3.55 (m, 1H),
2.30 (m, 2H), 0.97 (s, 9H), 0.20 (s, 6H); 19F NMR (282 MHz,
CDCl3) δ -10.99 (d, J ) 8.6 Hz, 3F); IR (KBr) 3416, 1669, 1630,
1552, 1487, 1259, 838 cm-1; MS m/z 440 (M+ -57, 29), 105
(100). Anal. Calcd for C23H30N3O4F3Si: C, 55.52; H, 6.08; N,
8.44. Found: C, 55.70; H, 6.18; N,8.58. 18ba :1H NMR (300
MHz, CDCl3) δ 7.94 (d, J ) 7.5 Hz, 2H), 7.65 (m, 2H), 7.52 (m,
3H), 5.77 (d, J ) 5.2 Hz, 1H), 4.80 (m, 1H), 3.88 (m,1H), 3.78
(dd, J ) 11.3 Hz, 3.9 Hz, 1H,), 3.69 (dd, J ) 11.3 Hz,4.2 Hz,-
1H), 2.43 (m, 1H), 2.24 (m, 1H), 0.92 (s, 9H), 0.08 (s, 6H); 19F
NMR (282 MHz, CDCl3) δ -6.92 (d, J ) 8.3 Hz).
(2′S)-D-5′-O-(ter t-Bu t yld im et h ylsilyl)-2′,3′-d id eoxy-2′-
tr iflu or om eth ylu r id in e (16bb a n d 16ba ). Compounds 16bb
and 16ba (218 mg, 77%) were prepared as a white foam from
compound 8b (250 mg, 0.731 mmol) using the same procedure
as for 9a a and 9a b: 1H NMR (400 MHz, CDCl3) δ 9.21-9.08
(m, 1H), 7.92 (d, J ) 8.1 Hz, H6), 7.20 (d, J ) 8.0 Hz, H6),
6.42 (d, J ) 7.2 Hz, H1′), 5.77 (m, H5 and H1′), 5.70 (d, J )
8.1 Hz, H5), 4.61 (m, H4′), 4.18 (m, H4′), 4.10-3.60 (m, H5′),
3.54-3.39 (m, H2′), 2.40-2.16 (m, H3′), 0.94-0.92 (m, 9H),
0.12-0.07 (m, 6H); 19F NMR (282 MHz, CDCl3) δ -11.13 (d, J
) 7.8 Hz, 0.9F), -6.94 (d, J ) 7.24 Hz, 2.1F); IR (KBr) 3199,
3067, 2959, 1693, 1465, 1378, 1262, 838 cm-1; MS m/z 395 (M+
+ 1, 5), 169 (100). Anal. Calcd for C16H25N2O4F3Si: C, 48.72;
H, 6.39; N, 7.10. Found: C, 48.45; H, 6.52; N, 6.91.
Rep r esen ta tive P r oced u r e for th e Dep r otection of
Silyl-P r otected Ur a cil a n d Th ym in e Nu cleosid es: â-D-
(2′R)-2′,3′-Did eoxy-2′-t r iflu or om et h ylu r id in e (12a b ). A
stirred solution of protected nucleoside 9a b (0.107 g, 0.272
mmol) in anhydrous THF (10 mL) was treated with a 1.0 M
solution of TBAF in THF (0.54 mL, 0.54 mmol) at room
temperature. After stirring for 30 min, the solvent was
removed and the residue was purified by silica gel column
chromatography (petroleum ether:ethyl acetate ) 1:4) to give
(2′R)-D-5′-O-(ter t-Bu tyld im eth ylsilyl)-2′,3′-d id eoxy-2′-
tr iflu or om eth ylth ym id in em (10a b a n d 10a a ). Compounds
10a b (151 mg, 64%) and 10a a (63 mg, 26%) were prepared as
a white solid respectively from compound 8a (200 mg, 0.584
mmol) using the same conditions as for compounds 9a b and
9a a . 10a b: 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.40 (s,
1H), 6.24 (d, J ) 6.2 Hz, 1H), 4.28 (m, 1H), 3.98 (dd, J ) 11.5
Hz, 2.3 Hz, 1H), 3.69 (dd, J ) 11.5 Hz, 2.6 Hz, 1H), 3.05 (m,
1H), 2.36 (m, 1H), 2.27 (m, 1H), 1.93 (s, 3H), 0.96 (s, 9H), 0.16
(s, 6H); 19F NMR (282 MHz, CDCl3) δ -7.42 (d, J ) 8.42 Hz);
IR (KBr) 3187, 2932, 1681 cm-1; MS (FAB) 409 (M+ + 1), 407-
(M+ - 1). Anal. Calcd for C17H27N2O4F3Si: C, 49.98; H, 6.66;
N, 6.86. Found: C, 49.88; H, 6.58; N, 6.75. 10a a :1H NMR (400
MHz, CDCl3) δ 9.33 (s, 1H), 7.21 (s, 1H), 6.24 (d, J ) 5.8 Hz,
1H), 4.56 (m, 1H), 3.80 (dd, J ) 11.1 Hz, 3.0 Hz, 1H), 3.62
(dd, J ) 11.1 Hz, 2.6 Hz, 1H), 3.48 (m, 1H), 2.36 (m, 2H), 1.92
(s, 3H), 0.89 (s, 9H), 0.08 (s, 6H); 19F NMR (282 MHz, CDCl3)
δ -7.20 (d, J ) 9.4 Hz).
(2′S)-D-5′-O-(ter t-Bu t yld im et h ylsilyl)-2′,3′-d id eoxy-2′-
tr iflu or om eth ylth ym id in em (17bb a n d 17ba ). Compounds
17bb (39 mg, 22%) and 17ba (114 mg, 63%) were prepared as
a white solid respectively from compound 8b (150 mg, 0.439
mmol) using the same procedure as for compounds 9a b and
9a a . 17bb: 1H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 7.43 (s,
1H), 6.27 (d, J ) 7.3 Hz, 1H), 4.10 (m, 1H), 4.01 (dd, J ) 11.5
Hz, 3.0 Hz, 1H), 3.81 (dd, J ) 11.5 Hz, 3.4 Hz, 1H), 3.36 (m,
1H), 2.24 (m, 2H), 1.93 (s, 3H), 0.95 (s, 9H), 0.13 (s, 6H); 19F
NMR (282 MHz, CDCl3) δ -10.76 (d, J ) 8.5 Hz); IR (KBr)
3168, 3035, 1699, 1681, 1264, 1172 cm-1; MS m/z 409(M+ + 1,
5), 407(M+ - 1, 1), 351 (100). Anal. Calcd for C17H27N2O4F3Si:
C, 49.98; H, 6.66; N, 6.86. Found: C, 49.72; H, 6.99; N, 6.35.
17ba :1H NMR (400 MHz, CDCl3) δ 9.31 (s, 1H), 7.00 (s, 1H),
5.79 (d, J ) 6.0 Hz, 1H), 4.61(m, 1H), 3.76 (dd, J ) 11.2 Hz,
3.8 Hz, 1H), 3.65 (dd, J ) 11.2 Hz, 3.8 Hz, 1H), 3.58 (m, 1H),
0.90 (s, 9H), 0.09 (s, 6H); 19F NMR (282 MHz, CDCl3) δ -6.96
(d, J ) 8.5 Hz).
49 mg (64% yield) of 12a b as a white solid: mp 168-170 °C;
1
[R]20 +9.8° (c 0.15, MeOH); H NMR (300 MHz, MeOH-d4) δ
D
7.92 (d, J ) 8.1 Hz, 1H), 6.18 (d, J ) 5.4 Hz, 1H), 5.69 (d, J )
8.1 Hz, 1H), 4.23 (m, 1H), 3.78 (dd, J ) 12.1 Hz, 2.6 Hz, 1H),
3.60 (dd, J ) 12.1 Hz, 3.5 Hz, 1H), 3.34 (m, 1H), 2.32 (m, 1H),
2.23 (m, 1H);19F NMR (282 MHz, CDCl3) δ -9.66 (d, J ) 9.1
Hz); IR (KBr) 3473, 3042, 1675, 1117 cm-1; MS m/z 281 (M+
+ 1, 4), 113 (100). Anal. Calcd for C10H11N2O4F3: C, 42.87; H,
3.96; N, 10.00. Found: C, 43.09; H, 3.93; N, 9.90.
r-D-(2′R)-2′,3′-Dideoxy-2′-tr iflu or om eth ylu r idin e (12aa).
Compound 12a a (25 mg, 78%) was prepared as a white solid
from compound 9a a (45 mg, 0.114 mmol) using the same
conditions as for compound 12a b: mp170-172 °C; [R]20
D
-72.3° (c 0.315, MeOH);1H NMR (300 MHz, MeOH-d4) δ 7.60
(d, J ) 8.2 Hz, 1H), 6.29 (d, J ) 6.4 Hz, 1H), 5.65 (d, J ) 8.2
Hz, 1H), 4.6 (m, 1H), 3.66-3.57 (m, 2H), 3.50 (dd, J ) 12.1
Hz, 4.0 Hz, 1H), 2.34 (m, 2H); 19F NMR (282 MHz, MeOH-d4)
δ -13.12 (d, J ) 9.8 Hz).
r-D-(2′S)-2′,3′-Dideoxy-2′-tr iflu or om eth ylu r idin e (19ba).
A mixture of 16ba and 16bb (216 mg, 0.548 mmol) was treated
using the same conditions as for compound 12a b to give a
mixture of R/â anomers (138 mg, 90%), which was recrystal-
lized from ethyl acetate and hexane to give compound 19ba
(86 mg, 56% yield) as a white solid: mp197-199 °C; [R]20
D
1
+18.0° (c 0.31, MeOH); H NMR (300 MHz, MeOH-d4) δ 7.88
(d, J ) 8.1 Hz, 1H), 6.32 (d, J ) 6.6 Hz, 1H), 5.92 (d, J )8.1
Hz, 1H), 4.78 (m, 1H), 3.87 (m, 1H), 3.73 (dd, J ) 12.1 Hz, 4.7
Hz, 1H), 2.63 (m, 1H), 2.30 (m, 1H); 19F NMR (282 MHz,
MeOH-d4) δ -9.54 (d, J ) 8.7 Hz); IR (KBr) 3535, 3164, 1719,

7082 J . Org. Chem., Vol. 65, No. 21, 2000
Zhang et al.
1678 cm-1; MS m/z 282 (M+ + 2, 1), 281 (M+ + 1, 2), 280 (M+,
1), 149 (100).
After stirring for 30 min, the solvent was removed and the
residue was purified by silica gel column chromatography
(petroleum ether:ethyl acetate ) 1:4) to give crude desilylated
cytosine derivative, which was dissolved in saturated metha-
nolic ammonia (10 mL). The resulting reaction mixture was
stirred for 12 h. After removal of the volatile materials, the
residue was purified by silica gel chromatography (CH2Cl2:
MeOH ) 2:1) to give 46 mg (69% yield) of 15a b as a white
solid: mp 169-171 °C; [R]20D +28.7° (c 0.285, MeOH); 1H NMR
(300 MHz, MeOH-d4) δ 8.16 (d, J ) 7.45 Hz, 1H), 6.45 (d, J )
5.1 Hz, 1H), 6.11 (d, J ) 7.45 Hz, 1H), 4.46 (m, 1H), 4.03 (dd,
J ) 12.1 Hz, 2.8 Hz, 1H), 3.85 (dd, J ) 12.1 Hz, 3.6 Hz, 1H),
3.54 (m, 1H), 2.58 (m, 1H), 2.42 (m, 1H); 19F NMR (282 MHz,
MeOH-d4) δ -9.8 (d, J ) 9.0 Hz, 3F); IR (KBr) 3479, 3327,
3104, 1679, 1629, 1479, 1120 cm-1; MS m/z 280 (M+ + 1, 1),
â-D-(2′R)-2′,3′-Dideoxy-2′-trifluoromethylthymidine (13ab).
Compound 13a b (80 mg, 77%) was prepared as a white solid
from compound 10a b (144 mg, 0.353 mmol) using the same
conditions as for compound 12a b: mp 213-214 °C; [R]20D -1.9°
(c 0.31, MeOH); 1H NMR (400 MHz, MeOH-d4) δ 7.99 (s, 1H),
6.43 (d, J ) 5.6 Hz, 1H), 4.44 (m, 1H), 4.03 (dd, J ) 12.2 Hz,
2.9 Hz, 1H), 3.85 (dd, J )12.2 Hz, 3.6 Hz, 1H), 3.54 (m, 1H),
2.59 (m, 1H), 2.08 (s, 3H); 19F NMR (282 MHz, MeOH-d4) δ
-9.64 (d, J ) 8.9 Hz); IR (KBr) 3434, 3182, 3063, 1691, 1477,
1276 cm-1; MS m/z 263(M+ -31, 9), 126 (100). Anal. Calcd for
C
11H13N2O4F3: C, 44.90; H, 4.45; N, 9.52. Found: C, 44.97; H,
4.31; N, 9.48.
r-D-(2′R)-2′,3′-Did eoxy-2′-t r iflu or om et h ylt h ym id in e
(13a a ). Compound 13a a (33 mg, 77%) was prepared as a white
solid from compound 10a a (60 mg, 0.147 mmol) using the same
279(M+, 3),278 (M+, 2), 111 (100). HRMS Calcd for C10H12
N3O3F3: 279.2189. Found: 279.0821.
-
conditions as for compound 12a b: [R]20 -53.9° (c 0.125,
r-D-(2′R)-2′,3′-Dideoxy-2′-tr iflu or om eth ylcytidin e (15aa).
Compound 15a a (32 mg, 73%) was prepared as a white solid
from compound 11a a (59.29 mg, 0.119 mmol) using the same
D
MeOH); 1H NMR (400 MHz, MeOH-d4) δ 7.63 (s, 1H), 6.52 (d,
1H), 4.85 (m, 1H), 3.90 (dd, J ) 12.0 Hz, 3.4 Hz, 1H), 3.80 (m,
1H), 3.75 (dd, J ) 12.0 Hz, 4.1 Hz, 1H), 2.63 (m, 1H), 2.51 (m,
1H), 2.09 (s, 3H); 19F NMR (282 MHz, MeOH-d4) δ -13.13 (d,
J ) 9.3 Hz).
conditions as for compound 15a a : mp 214-216 °C; [R]20
D
-139.7° (c 0.26, MeOH); 1H NMR (300 MHz, MeOH-d4) δ 7.88
(d, J ) 7.5 Hz, 1H), 6.29 (d, J ) 6.0 Hz, 1H), 6.10 (d, J ) 7.5
Hz, 1H), 4.78 (m, 1H), 3.91 (dd, J ) 12.0 Hz, 3.2 Hz, 1H), 3.81
(m, 2H), 2.56 (m, 2H); 19F NMR (282 MHz, MeOH-d4) δ -13.01
(s).
â-D-(2′S)-2′,3′-Dideoxy-2′-trifluoromethylthymidine (20bb).
Compound 20bb (8.2 mg, 72%) was prepared as a white solid
from compound 17bb (16 mg, 0.039 mmol) using the same
conditions as for compound 12a b: mp142-144 °C; [R]20D +54.1°
(c 0.085, MeOH); 1H NMR (400 MHz, MeOH-d4) δ 8.16 (s, 1H),
6.54 (d, J ) 7.4 Hz, 1H), 4.37 (m, 1H), 4.15 (dd, J ) 12.6 Hz,
3.0 Hz, 1H), 3.92 (dd, J ) 12.6 Hz, 2.6 Hz, 1H), 3.81 (m, 1H),
2.44 (m, 2H), 2.06 (s, 3H); 19F NMR (282 MHz, MeOH-d4) δ
-13.6 (d, J ) 9.1 Hz).
â-D-(2′S)-2′,3′-Dideoxy-2′-tr iflu or om eth ylcytidin e (22bb).
Compound 22bb (35 mg, 90%) was prepared from 18bb as a
white solid (69 mg, 0.139 mmol) using the same conditions as
for compound 15a b: mp 113-116 °C; [R]20 +131.2° (c 0.24,
D
MeOH);1H NMR (300 MHz, MeOH-d4) δ 8.19 (d, J ) 7.3 Hz,
1H), 6.52 (d, J ) 7.0 Hz, 1H), 6.07 (d, J ) 7.3 Hz, 1H), 4.35
(m, 1H), 4.10 (dd, J ) 12.4 H, 2.7 Hz, 1H), 3.91 (dd, J ) 12.4
Hz, 3.8 Hz, 1H), 3.78 (m, 1H), 2.40 (m, 2H); 19F NMR (282
MHz, MeOH-d4) δ -13.45 (d, J ) 9.3 Hz).
r-D-(2′S)-2′,3′-Dideoxy-2′-trifluoromethylthymidine (20ba).
Compound 20ba (28 mg, 96%) was prepared as a white solid
from compound 17ba (41 mg, 0.100 mmol) using the same
conditions as for compound 12a b: mp 231-233 °C; [R]20
r-D-(2′S)-2′,3′-Dideoxy-2′-tr iflu or om eth ylcytidin e (22ba).
Compound 22ba (51 mg, 60%) was prepared as a white solid
from 18ba (151 mg, 0.183 mmol) using the same conditions
D
+20.0° (c 0.205, MeOH); 1H NMR (400 MHz, MeOH-d4) δ 7.70
(s, 1H), 6.34 (d, J ) 6.8 Hz, 1H), 4.79 (m, 1H), 3.87 (m, 2H),
3.73 (dd, J ) 12.1 Hz, 4.8 Hz, 1H), 2.62 (m, 1H), 2.30 (m, 1H),
2.09 (s, 3H); 19F NMR (282 MHz, MeOH-d4) δ -9.51 (d, J )
8.0 Hz); IR (KBr) 3526, 3176, 1710, 1677, 1270 cm-1; MS m/z
295 (M+ + 1, 1), 126 (100). Anal. Calcd for C11H13N2O4F3: C,
44.90; H, 4.45; N, 9.52. Found: C, 44.72; H, 4.50; N, 9.11.
Rep r esen ta tive P r oced u r e for th e Dep r otection of
Silyl-P r otected Cytosin e Nu cleosid es: â-D-(2′R)-2′,3′-
Did eoxy-2′-tr iflu or om eth ylcytid in e (15a b). A stirred solu-
tion of protected nucleoside 11a b (0.120 g, 0.241 mmol) in
anhydrous THF(10 mL) was treated with a 1.0 M solution of
TBAF in THF (0.48 mL, 0.48 mmol) at room temperature.
as for compound 15a b: mp 103-106 °C; [R]20 -6.1° (c 0.16,
D
1
MeOH); H NMR (300 MHz, MeOH-d4) δ 7.85 (d, J ) 7.4 Hz,
1H), 6.30 (d, J ) 6.3 Hz, 1H), 6.11 (d, J ) 7.4 Hz, 1H), 4.82
(m, 1H), 3.90 (m, 2H), 3.73 (dd, J ) 12.0 Hz, 4.6 Hz, 1H), 3.50
(m, 1H), 2.61 (m, 1H), 2.29 (m, 1H); 19F NMR (282 MHz,
MeOH-d4) δ -9.54 (d, J ) 8.7 Hz).
Ack n ow led gm en t. We thank the National Natural
Science Foundation of China for funding this work.
J O005520R