2′-Branched Pyrimidine 2′-Deoxy Ribonucleosides
J . Org. Chem., Vol. 65, No. 26, 2000 8995
6.16 (d, 1 H, J ) 8.5), 5.39 (d, 1 H J ) 8.1), 5.31 (d, 1 H, J )
5.4), 4.40 (d, 1 H, J ) 4.9), 4.10 (m, 1 H), 3.92 (m, 2 H), 3.74
(s, 3 H), 3.22 (dd, 1 H, J ) 5.1, 10.3) 3.12 (dd, 1 H, J ) 3.7,
10.3), 2.10 (m, 1 H), 1.10 (d, 2 H, J ) 6.3); 13C NMR (100M
Hz, CDCl3) δ 162.91, 158.11, 150.33, 144.13, 143.90, 141.18,
134.65, 130.04, 127.92, 126.92, 113.26, 101.35, 86.54, 86.14,
84.88, 71.83, 64.24, 63.68, 55.21, 52.99, 22.66 (t, J ) 19.2);
HRMS (FAB, positive) calcd for C31H32DN2O7 546.2350, found
546.2352 (MH+). 22-D:1H NMR (270 MHz, CDCl3) δ 8.13 (br
s, 1 H, NH-3), 7.78 (d, 1 H, H-6, J ) 8.1) 7.40-6.83 (m, 14 H,
MMTr), 6.30 (d, 1 H, H-1′, J ) 6.1), 5.39 (d, 1 H, H-5, J ) 8.1),
4.56 (m, 1 H, H-3′), 4.00 (m, 1 H, H-4′), 3.81 (s, 3 H, OMe),
3.50 (dd, 1 H, H-5′a J ) 3.2, 10.7), 3.45 (dd, 1 H, H-5′b, J )
3.2, 10.7), 2.26 (m, 1 H, H-2′, J ) 6.1), 1.86 (br s, 1 H, OH);
13C NMR (100 MHz, CDCl3) δ 162.23, 158.42, 149.49, 143.41,
143.24, 139.72, 134.27, 130.05, 128.00, 127.72, 127.02, 113.02,
101.91, 87.17, 85.58, 84.62, 71.14, 62.66, 55.13; HRMS (FAB,
positive) calcd for C29H28DN2O6 502.2089, found 502.2061
(MH+); NOE (400 MHz, CD3OD): irradiated H-2′, observed
H-3′ (6.5%) H-6 (5.0%).
87.43, 87.30, 86.63, 75.70, 63.51, 55.28, 54.94, 30.35, 25.77,
18.16, 0.08, -4.65; LRMS (EI) m/z 640 (M+). Anal. Calcd for
C37H44N2O6Si: C, 69.35; H, 6.92; N, 4.37. Found: C, 69.37; H,
6.95; N, 4.20.
1-[5-O-(4-Meth oxytr ityl)-2-d eoxy-2-vin yl-3-O-(ter t-bu -
tyld im eth ylsilyl)-â-D-r ibo-p en tofu r a n osyl]cytosin e (26).
A mixture of 25 (4.46 g, 7.0 mmol), TPSCl (4.22 g, 14 mmol),
DMAP (1.70 g, 14 mmol), and Et3N (1.94 mL, 14 mmol) in CH3-
CN (70 mL) was stirred at room temperature for 4 h. Aqueous
NH4OH (25%, 70 mL) was added, and the resulting mixture
was stirred at the same temperature for 2 h. The mixture was
evaporated, and the residue was partitioned between AcOEt
and H2O. The organic layer was washed with brine, dried (Na2-
SO4), and evaporated. The residue was purified by column
chromatography (SiO2, 2-5% MeOH in CHCl3) to give 26 (4.14
g, 93%) as a pale yellow foam: 1H NMR (270 MHz, CDCl3) δ
7.86 (d, 1 H, H-6, J ) 7.3) 7.44-6.83 (m, 14 H, MMTr), 6.35
(d, 1 H, J ) 7.3), 5.95 (ddd, 1 H, J ) 17.2, 10.6, 8.6), 5.41 (d,
1 H, J ) 7.3), 5.20 (d, 1 H, J ) 10.6), 5.17 (d, 1 H, J ) 17.2),
4.33 (m, 1 H), 4.03 (m, 1 H), 3.80 (s, 3 H), 3.49 (dd, 1 H, J )
3.0, 11.2), 3.31 (dd, 1 H, J ) 3.0, 11.2), 2.86 (m, 1 H, J ) 7.3),
0.82 (s, 9 H), -0.01 (s, 3 H), -0.08 (s, 3 H); 13C NMR (100
MHz, CDCl3) δ 165.18, 158.62, 155.80, 143.80, 143.71, 141.27,
134.80, 131.73, 130.32, 128.34, 127.88, 127.12, 119.35, 113.17,
94.30, 88.15, 87.11, 85.56, 74.81, 63.15, 55.28, 55.16, 25.75,
18.11, 0.08, -4.60, -4.73; LRMS (EI) m/z 639 (M+). Anal. Calcd
for C37H45N3O5Si: C, 69.45; H, 7.09; N, 6.57. Found: C, 69.23;
H, 6.97; N, 6.46.
Deu ter iu m -La belin g Exp er im en t of 18a w ith Bu 3Sn D
u n d er Th er m od yn a m ic Con d ition s. The radical reaction
and subsequent Tamao oxidation were carried out by the
procedure identical to the entry 2 in Table 1, with Bu3SnD
(65 µL, 0.24 mmol) instead of Bu3SnH to give a mixture of the
reaction products as a solid. A solution of the solid obtained,
TBDPSCl (36 µL, 0.18 mmol) and imidazole (24 mg, 0.36 mmol)
in DMF (2 mL) was stirred at room temperature for 24 h. After
addition of MeOH, the mixture was evaporated, and the
residue was partitioned between AcOEt and H2O. The organic
layer was washed with brine, dried (Na2SO4), and evaporated.
The residue was purified by column chromatography (SiO2,
0-2% MeOH in CHCl3) to give crude 24-D (52 mg), which was
further purified by HPLC (YMC Pack D-ODS-5-A, 20 × 250
mm; 90% aqueous MeOH, 9.9 mL/min; room temperature; 260
nm) to give 24-D in a pure form (30 mg, 19% from 18a ) as a
solid: 1H NMR (270 MHz, CDCl3) δ 8.45 (br s, 1 H), 7.69-
6.81 (m, 25 H), 6.10 (d, 1 H, J ) 8.6), 5.36 (d, 1 H, J ) 7.9),
4.76 (m, 1 H), 4.23 (m, 1 H), 3.79 (s, 3 H), 3.76 (m, 2 H), 3.52-
3.37 (m, 3 H), 2.31 (m, 1 H), 2.16 (m, 0.6 H), 1.63 (m, 0.4 H),
1.08 (s, 9 H); 13C NMR (100 MHz, CDCl3) δ 162.66, 158.36,
150.21, 143.68, 143.31, 139.85, 135.08, 135.04, 134.41, 131.77,
131.54, 130.00, 129.79, 129.75, 127.94, 127.92, 127.72, 127.68,
126.91, 113.04, 102.37, 88.05, 86.98, 85.05, 73.46, 64.10, 63.60,
55.10, 50.59, 26.66, 26.40, 18.85; HRMS (FAB, positive) calcd
for C47H49DN2O7SiNa 806.3348, found 806.3327 (MNa+).
Gen er a l P r oced u r e for Ra d ica l Atom -Tr a n sfer Rea c-
tion of 19a or 19b for th e Syn th esis of 1-[5-O-(4-m eth -
oxytr ityl)-2-d eoxy-2-vin yl-3-O-(ter t-bu tyld im eth ylsilyl)-
â-D-r ibo-p en tofu r a n osyl]u r a cil (25). A mixture of 19a or
19b (0.20 mmol), (Me3Sn)2 (29 µL, 0.14 mmol), and AIBN (20
mg, 0.12 mmol) in benzene (2 mL) was heated under reflux
for 5 h, and then the solvent was evaporated. A mixture of
the residue and TBAF (400 µL, 0.4 mmol) in THF (2 mL) was
stirred at room temperature for 1 h. The mixture was
evaporated, and the residue was purified by column chroma-
tography (SiO2, 50-100% AcOEt in Et2O) to give the corre-
sponding desilylated compound as a solid. A mixture of the
solid, TBSCl (90 mg, 0.60 mmol), Et3N (84 µL, 0.60 mmol),
and DMAP (5 mg, 0.04 mmol) in toluene (2 mL) was stirred
at room temperature for 20 h. The mixture was partitioned
between AcOEt and H2O, and the organic layer was washed
with brine, dried (Na2SO4), and evaporated. The residue was
purified by column chromatography (SiO2, 25-33% AcOEt in
hexane) to give 25 as a white foam: 1H NMR (270 MHz, CDCl3)
δ 7.99 (br s, 1 H, NH-3), 7.70 (d, 1 H, H-6, J 6,5 ) 8.6) 7.42-
6.84 (m, 14 H, MMTr), 6.22 (d, 1 H, H-1′, J 1′,2′ ) 8.6), 5.90 (m,
1 H, -CH)CH2), 5.43 (d, 1 H, H-5, J 5,6 ) 8.6), 5.23 (d, 1 H,
-CHdCH2, J ) 10.6), 5.16 (d, 1 H, -CHdCH2, J ) 17.2), 4.33
(m, 1 H, H-3′), 4.05 (m, 1 H, H-4′), 3.81 (s, 3 H, OCH3), 3.44
(dd, 1 H, H-5′a, J ) 10.6, 3.3), 3.38 (dd, 1 H, H-5′b, J ) 10.6,
2.6), 2.90 (m, 1 H, H-2′), 0.86 (s, 9 H, tert-butyl), 0.03 (s, 3 H,
Si-CH3), -0.03 (s, 3 H, Si-CH3); 13C NMR (100 MHz, CDCl3)
δ 162.70, 158.71, 150.20, 143.68, 143.48, 139.99, 134.50,
131.04, 130.28, 128.23, 127.97, 127.26, 120.05, 113.25, 102.51,
1-(2-Deoxy-2-C-vin yl-â-D-r ibo-pen tofu r an osyl)u r acil (7).
A solution of 25 (417 mg, 0.65 mmol) in HCl/MeOH (2.6% w/v,
10 mL) was stirred at room temperature for 5 h, and then the
mixture was evaporated. After coevaporation with MeOH
several times, the residue was purified by column chromatog-
raphy (SiO2, 2-12% MeOH in CHCl3) to give 7 (153 mg, 93%)
as a white solid: 1H NMR (400 MHz, D2O) δ 7.81 (d, 1 H, H-6,
J ) 8.1), 6.15 (d, 1 H, H-1′, J ) 9.0), 5.86 (d, 1 H, H-5, J )
8.1), 5.84 (m, 1 H, -CH)CH2), 5.24 (d, 1 H, -CHdCH2, J )
10.5), 5.22 (d, 1 H, -CHdCH2, J ) 17.6), 4.31 (m, 1 H, H-3′),
4.08 (m, 1 H, H-4′), 3.76 (dd, 1 H, H-5′a, J ) 12.7, 3.9), 3.72
(dd, 1 H, H-5′b, J ) 12.7, 5.1), 3.06 (m, 1 H, H-2′, J ) 9.0); 13
C
NMR (100 MHz, D2O) δ 166.30, 152.22, 141.95, 130.08, 121.27,
103.22, 87.52, 86.92, 73.94, 62.09, 52.76; HRMS (EI) calcd for
C
11H14N2O5 254.0902, found 254.0901 (M+).
1-(2-D e o x y -2-C-v in y l-â-D -r i b o-p e n t o fu r a n o s y l)c y -
tosin e (10). A solution of 26 (1.0 g, 1.6 mmol) in HCl/MeOH
(2.6% w/v, 15 mL) was stirred at room temperature for 20 h,
and then the mixture was evaporated. After coevaporation
with MeOH several times, the residue was partitioned between
H2O and CHCl3. The aqueous layer was evaporated and
-
applied to a column of Diaion PA-312 resin (HCO3 form,
packed with water). The column was eluted with water, and
the appropriate fractions were evaporated to give 10 (336 mg,
85%) as a white solid: mp 239-240 °C (MeOH-EtOH); 1H
NMR (270 MHz, CD3OD) δ 7.94 (d, 1 H, H-6, J ) 7.9), 6.28 (d,
1 H, H-1′, J ) 9.2), 5.97 (ddd, 1 H, -CH)CH2, J ) 2.0, 17.8,
10.6), 5.91 (d, 1 H, H-5, J ) 7.9), 5.16 (d, 1 H, -CHdCH2, J )
10.6), 5.14 (d, 1 H, -CHdCH2, J ) 17.8), 4.26 (dd, 1 H, H-3′,
J ) 5.3, 1.3), 4.00 (m, 1 H, H-4′, J ) 1.3), 3.74 (m, 2 H, H-5′a,
H-5′b), 2.93 (m, 1 H, H-2′); 13C NMR (125 MHz, CD3OD) δ
168.16, 159.34, 143.87, 133.53, 120.74, 97.36, 90.13, 89.27,
76.37, 64.23, 56.33; LRMS (FAB, positive) m/z 254 (MH+).
Anal. Calcd for C11H15N3O4: C, 52.17; H, 5.97; N, 16.59.
Found: C, 51.99; H, 5.90; N, 16.61.
1-(2-Deoxy-2-C-h yd r oxym eth yl-â-D-r ibo-p en tofu r a n o-
syl)u r a cil (8). Ozone-containing oxygen was bubbled into a
solution of 7 (51 mg, 0.20 mmol) in MeOH/H2O (3:1, 2 mL) at
-78 °C for 5 min, where disappearance of the starting material
was checked by HPLC (J ’sphere ODS M80, 4 × 250 mm, YMC
Co., Ltd.; 2% aqueous MeCN, 1.0 mL/min; room temperature,
260 nm). After addition of NaBH4 (15 mg, 0.40 mmol) at the
same temperature, the resulting solution was stirred at room
temperature for 2 h. The mixture was neutralized with
saturated aqueous NH4Cl, evaporated, and purified by pre-
parative HPLC (YMC Pack D-ODS-5-A, 20 × 250 mm; 15%
aqueous CH3CN, 9.9 mL/min; room temperature; 260 nm) to