Notes
J . Org. Chem., Vol. 67, No. 3, 2002 1019
saturated aqueous NaHCO3. The resulting mixture was ex-
tracted with CHCl3. The organic layer was washed with a 10%
sodium thiosulfate solution, saturated aqueous NaHCO3, and
brine and dried over Na2SO4. After concentration, the residue
was dissolved in Ac2O (10 mL), and the mixture was kept at
100 °C for 4.5 h. Then the reaction was quenched with saturated
aqueous NaHCO3. This was stirred for 10 min. The aqueous
layer was extracted with ethyl acetate. The organic layers were
combined, washed with saturated aqueous NaHCO3, water, and
brine, dried over Na2SO4, and concentrated to give a oil. The oil
was purified by silica gel column chromatography (petroleum
ether:dichloromethane ) 2:1) to give R anomer 8a 49 mg (15%
yield, two steps), â anomer 8a 137 mg (42% yield, two steps) as
a light yellowish oil: R anomer 8a 1H NMR (300 MHz, CDCl3)
δ 6.24 (d, J ) 6.0 Hz, 1H), 3.77-3.67 (m, 3H), 3.13 (m, 1H), 2.49
(m, 2H), 2.09 (s, 3H), 0.88 (s, 9H), 0.07 (s, 6H); 19F NMR (282
MHz, CDCl3) δ -6.93 (d, J ) 8.5 Hz); â anomer 8a 1H NMR
(300 MHz, CDCl3) δ 6.22 (d, J ) 4.1 Hz, 1H), 3.72 (dd, J ) 6.4
Hz, 1.3 Hz, 2H), 3.64 (m, 1H), 2.96 (m, 1H), 2.49 (m, 1H), 2.12
(m, 1H), 2.07 (s, 3H), 0.90 (s, 9H), 0.07 (s, 6H); 19F NMR (282
MHz, CDCl3) δ -11.20 (d, J ) 7.2 Hz); IR (thin film) νmax1752,
1261, 1228 cm-1; MS m/z 301 (M+ - t-Bu, 4), 167 (100), 43 (100).
HRMS Calcd for C10H16O3F3SSi (M+ - t-Bu): 301.05416.
Found: 301.05320.
Compound 9ba (59 mg, 20.5%) and 9bb (172 mg, 59.5%) were
prepared as a white foam respectively from compound 8b (200
mg, 0.559 mmol) using the same procedure as for compounds
9a a and 9a b. 9ba : [R]20 ) -8.4° (c 0.215, CHCl3); 1H NMR
D
(300 MHz, CDCl3) δ 8.15 (d, J ) 7.4 Hz, 1H), 7.93 (d, J ) 7.4
Hz, 1H), 7.64-7.53 (m, 5H), 6.85 (d, J ) 6.0 Hz, 1H), 3.97 (m,
1H), 3.69 (m, 2H), 3.49 (m, 1H), 2.45 (m, 2H), 0.93 (s, 9H), 0.11
(s, 6H); 19F NMR (282 MHz, CDCl3) δ -11.89 (d, J ) 8.6 Hz); IR
(KBr) νmax 3400, 1693, 1660, 1619, 1544 cm-1; MS m/z 514 (M+
+ 1, 2), 513 (M+, 3), 456 (M+ - t-Bu, 30),105 (100). HRMS calcd
for C19H21O3N3F3SSi (M+ - t-Bu): 456.10250. Found: 456.10096.
9bb: [R]20D ) -1.2° (c 0.215, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 8.62 (d, J ) 7.5 Hz, 1H), 7.93 (d, J ) 7.5 Hz, 1H), 7.61-7.52
(m, 5H), 6.65 (d, J ) 6.3 Hz, 1H), 3.93 (m, 2H), 3.76 (m, 1H),
3.33 (m, 1H), 2.39 (m, 2H), 0.96 (s, 9H), 0.18 (s, 6H); 19F NMR
(282 MHz, CDCl3) δ -7.23 (d, J ) 8.5 Hz); IR (KBr) νmax 3400,
3069, 1675, 1626, 1554 cm-1; MS m/z 456 (M+ - t-Bu, 34), 105
(100). Anal. Calcd for C23H30O3N3F3SSi: C, 53.78; H, 5.89; N,
8.18. Found: C, 53.70; H, 5.69; N, 8.02. HRMS Calcd for
C19H21O3N3F3SSi (M+ - t-Bu): 456.10250. Found: 456.10060.
r-L-(2′S )-2′,3′-Did e oxy-2′-t r iflu or om e t h yl-4′-t h iocyt i-
d in e (10a a ). A stirred solution of protected nucleoside 9a a (119
mg, 0.232 mmol) in anhydrous THF (10 mL) was treated with a
1.0 M solution of TBAF in THF (0.69 mL, 0.69 mmol) at room
temperature. After stirring for 1 h, the solvent was removed,
and the residue was purified by silica gel column chromatogra-
phy (petroleum ether:ethyl acetate ) 1:4) to give crude desily-
lated cytosine derivative, which was dissolved in saturated
methanolic ammonia (13 mL). The resulting reaction mixture
was stirred for 12 h. After removed the volatile materials, the
residue was purified by silica gel column chromatography (CH2-
Cl2:MeOH ) 5:1) to give 64 mg (94% yield) of 10a a as a white
solid: mp 109-111 °C; [R]20D ) -75.2° (c 0.340, MeOH); 1H NMR
(300 MHz, MeOH-d4) δ 8.11 (d, J ) 7.5 Hz, 1H), 6.75 (d, J ) 8.9
Hz, 1H), 6.17 (d, J ) 7.5 Hz, 1H), 4.29 (m, 1H), 3.94 (dd, J )
11.2 Hz, 5.4 Hz, 1H), 3.78 (dd, J ) 11.2 Hz, 6.9 Hz, 1H), 3.71
(m, 1H), 2.77 (m, 1H), 2.11 (m, 1H); 19F NMR (282 MHz, MeOH-
d4) δ -9.51 (d, J ) 6.9 Hz); IR (KBr) νmax 3346, 3207, 1653, 1613,
1526 cm-1; MS m/z 295 (M+, 4), 112 (100). HRMS Calcd for
(3R,5R)-5-(ter t-Bu t yld im et h yl-sila n yloxym et h yl)-3-t r i-
flu or om eth yl- tetr a h yd r oth iop h en -2-yl Aceta te (8b). Com-
pound 8b (222 mg, 62% yield, two steps) was prepared as a light
yellowish oil from compound 6b (300 mg, 1.00 mmol) using the
same conditions as for compound 8a : 1H NMR (300 MHz, CDCl3)
δ 6.23 (d, J ) 4.6 Hz, 0.38 H), 6.22 (d, J ) 4.3 Hz, 0.62 H), 3.71-
3.50 (m, 3H), 3.22-3.08 (m, 1H), 2.46-2.30 (m, 2H), 2.08 (s, 3H),
0.91 (s, 3.42 H), 0.90 (s, 5.58 H), 0.08 (s, 2.28 H), 0.06 (s, 3.72
H); 19F NMR (282 MHz, CDCl3) δ -11.69 (d, J ) 6.9 Hz, 1.87
F), -7.04 (d, J ) 9.0 Hz, 1.13 F); IR (thin film) νmax 1755, 1261,
1227 cm-1; MS m/z 301 (M+ - t-Bu, 6), 43 (100). HRMS Calcd
for C10H16O3F3SSi (M+ - t-Bu): 301.05415. Found: 301.05366.
(2′S)-L-N4-Ben zoyl-5′-O-(ter t-b u t yld im et h ylsilyl)-2′,3′-
d id eoxy-2′tr iflu or om eth yl-4′-th iocytid in e (9a a a n d 9a b).
To a stirred solution of compound 8a (150 mg, 0.42 mmol) and
N4-benzoylcytosine (252 mg, 1.17 mmol) in anhydrous acetoni-
trile (15 mL) was added N,O-bis(trimethylsilyl)acetamide (0.57
mL, 2.43 mmol). The reaction mixture was stirred at reflux for
30 min. After cooling to 0 °C, trimethylsilyl triflate (0.21 mL,
0.96 mmol) was added dropwise, and the solution was stirred
for 24 h at room temperature. Saturated aqueous NaHCO3 was
added to the reaction mixture. The resulting mixture was
filtered, and the solid was washed with CHCl3 three times. The
filtrate was extracted with CHCl3. Then the organic layers were
combined, washed with saturated aqueous NaHCO3 and brine,
dried over Na2SO4, and concentrated to give a yellowish oil. The
oil was purified by silica gel column chromatography (petroleum
ether:ethyl acetate ) 2:1 to 5:4) to give 141 mg (65.6% yield) of
R anomer 9a a as a white solid, and 18 mg (8.4% yield) of â
C
10H12O2N3F3S: 295.06024. Found: 295.05950. Anal. Calcd for
C10H12O2N3F3S: C, 40.86; H, 4.10. Found: C, 40.33; H, 4.60.
â-L -(2′S )-2′,3′-Did e oxy-2′-t r iflu or om e t h yl-4′-t h iocyt i-
d in e (10a b). Compound 10a b (8 mg, 72% yield) was prepared
as a white solid from 9a b (20 mg, 0.039 mmol) using the same
conditions as for compound 10a a : mp 114-117 °C; [R]20
)
D
1
-23.6° (c 0.125, MeOH); H NMR (300 MHz, MeOH-d4) δ 8.53
(d, J ) 7.6 Hz, 1H), 6.98 (d, J ) 5.6 Hz, 1H), 6.11 (d, J ) 7.6 Hz,
1H), 4.08-4.01 (m, 3H), 3.69 (m, 1H), 2.61 (m, 1H), 2.46 (m, 1H);
19F NMR (282 MHz, MeOH-d4) δ -14.14 (d, J ) 8.3 Hz).
r-L-(2′R )-2′,3′-Did e oxy-2′-t r iflu or om e t h yl-4′-t h iocyt i-
d in e (10ba ). Compound 10ba (24 mg, 77% yield) was prepared
as a white solid from 9ba (54 mg, 0.105 mmol) using the same
conditions as for compound 10a a : mp 65-67 °C; [R]20D ) -38.8°
anomer 9a b as a white foam. 9a a : [R]20 ) -25.4° (c 0.385,
1
D
(c 0.955, MeOH); H NMR (300 MHz, MeOH-d4) δ 8.13 (d, J )
1
CHCl3); H NMR (300 MHz, CDCl3) δ 7.92 (m, 3H), 7.64-7.54
7.6 Hz, 1H), 6.93 (d, J ) 6.5 Hz, 1H), 6.13 (s, 1H), 4.14 (m, 1H),
3.77 (d, J ) 6.5 Hz, 2H), 3.73 (m, 1H), 2.64 (m, 2H); 19F NMR
(282 MHz, MeOH-d4) δ -14.43 (d, J ) 8.6 Hz); IR (KBr) νmax
3344, 3206, 1653, 1612, 1526 cm-1; MS m/z 295 (M+, 9), 2112
(100).
(m, 4H), 6.35 (d, J ) 7.9 Hz, 1H), 4.21 (m, 1H), 3.82 (dd, J )
10.2 Hz, 5.8 Hz, 1H), 3.72 (dd, J ) 10.2 Hz, 6.7 Hz, 1H), 3.46
(m, 1H), 2.62 (m, 1H), 2.05 (m, 1H), 0.91 (s, 9H), 0.09 (s, 6H);
19F NMR (282 MHz, CDCl3) δ -7.18 (d, J ) 6.3 Hz); IR (KBr)
ν
max 3422, 1686, 1666, 1626, 1549 cm-1; MS m/z 456 (M+ - t-Bu,
â-L-(2′R )-2′,3′-Did e oxy-2′-t r iflu or om e t h yl-4′-t h iocyt i-
d in e (10bb). Compound 10bb (63 mg, 76% yield) was prepared
as a white solid from 9bb (144 mg, 0.281 mmol) using the same
conditions as for compound 10a a : mp 95-97 °C; [R]20D ) +38.0°
89), 272 (21),105 (100). Anal. Calcd for C23H30O3N3F3SSi: C,
53.78; H, 5.89; N, 8.18. Found: C, 53.90; H, 6.05; N, 8.12. HRMS
Calcd for C19H21O3N3F3SSi (M+ - t-Bu): 456.10250. Found:
456.10305. 9a b: [R]20 ) -27.2° (c 0.570, CHCl3); 1H NMR (300
1
D
(c 0.225, MeOH); H NMR (300 MHz, MeOH-d4) δ 8.39 (d, J )
MHz, CDCl3) δ 8.72 (d, J ) 7.19 Hz, 1H), 7.93 (d, J ) 7.19 Hz,
1H), 7.63-7.53 (m, 5H), 6.94 (d, J ) 6.0 Hz, 1H), 3.97 (d, J )
3.2 Hz, 2H), 3.83 (m, 1H), 3.28 (m, 1H), 2.40 (m, 2H), 0.99 (s,
9H), 0.19 (s, 6H); 19F NMR (282 MHz, CDCl3) δ -11.7 (d, J )
7.7 Hz); IR (KBr) νmax 3422, 1668, 1627, 1553 cm-1; MS m/z 456
(M+ - t-Bu, 100), 105 (86). HRMS Calcd for C19H21O3N3F3SSi
(M+ - t-Bu): 456.10250. Found: 456.10059.
7.5 Hz, 1H), 6.82 (d, J ) 8.2 Hz, 1H), 6.17 (d, J ) 7.5 Hz, 1H),
3.99 (d, J ) 5.2 Hz, 2H), 3.82 (m, 1H), 3.69 (m, 1H), 2.62 (m,
2H); 19F NMR (282 MHz, MeOH-d4) δ -9.72 (d, J ) 8.5 Hz); IR
(KBr) νmax 3342, 3205, 1651, 1612, 1527 cm-1; MS m/z 295 (M+,
11), 112 (100). HRMS Calcd for C10H12O2N3F3S: 295.06024.
Found: 295.06109. Anal. Calcd for C10H12O2N3F3S: C, 40.86;
H, 4.10. Found: C, 40.33; H, 4.65.
(2′R)-L-N4-Ben zoyl-5′-O-(ter t-b u t yld im et h ylsilyl)-2′,3′-
d id eoxy-2′tr iflu or om eth yl-4′-th iocytid in e (9ba a n d 9bb).
J O0159690