152 J . Org. Chem., Vol. 67, No. 1, 2002
Klein et al.
mmol) in anhydrous toluene (650 mL) at -78 °C. After 5 min,
benzyl alcohol (6.8 mL, 65.6 mmol) in toluene (300 mL) was
slowly added over a 4 h period. The reaction mixture was
stirred at 60 °C for 2 h, and the temperature was lowered again
down to -78 °C. Then another portion of triethylamine (9.2
mL, 65.6 mmol) was added followed by a slow addition of
anhydrous methanol (2.7 mL, 65.6 mmol) in toluene (300 mL)
over 4 h. The mixture was stirred for 30 min at -78 °C and
30 min at room temperature, and powdered selenium (5.7 g,
72.2 mmol) was added. The suspension was refluxed for 3 h,
cooled to room temperature, and filtered over a Celite pad.
The filtrate was reduced under vacuum, and the crude residue
acetic anhydride (2.9 mL, 30.7 mmol) were added to a suspen-
sion of compound 11 (9.90 g, 27.8 mmol) in anhydrous
acetonitrile (200 mL). The reaction mixture was stirred for 1.5
h at room temperature and the resulting clear solution reduced
in vacuo. The residual oil was poured into ether/dichlo-
romethane 9:1 (800 mL), and the precipitate that formed was
collected by filtration and washed with ether to yield 12 (7.70
g, 70%) as a white powder. TLC Rf 0.65 (CH2Cl2/EtOH 9:1).
F° ) 170-171 °C. 1H NMR (CDCl3, 200 MHz) δ 10.06 (s broad,
1H); 8.33 (s, 1H); 7.95 (s, 1H); 7.56-7.40 (m, 5H); 6.27 (d, J )
1.9 Hz, 1H); 6.06 (s, 1H); 5.55 (dd, J ) 6.6, 1.9 Hz, 1H); 5.13
(dd, J ) 6.6, 3.2 Hz, 1H); 4.72-4.62 (m, 1H); 4.38 (AB part of
ABX syst., J AB ) 12.0 Hz, J AX ) 6.1 Hz, J BX ) 4.4 Hz, ∆ν )
11.2 Hz, 2H); 2.01 (s, 3H). 13C NMR (CDCl3, 50 MHz) δ 169.9;
156.5; 147.7; 146.0; 139.0; 135.9; 129.8; 128.4; 126.9; 124.4;
106.9; 89.1; 84.3; 83.6; 82.0; 63.6; 20.3. MS (CI/NH3) m/z 399
[M + H]+; 416 [M + NH4]+. IR (film) ν 3370; 3066; 2990; 2900;
1745; 1689; 1588; 1547; 1513; 1460; 1374; 1229; 1093.
6-Ch lor o-9-[5′-O-a cetyl-2′,3′-O-(1R)-ben zylid en e-â-D-r i-
bofu r a n osyl]p u r in e 13. Protected nucleoside 12 (7.33 g, 18.4
mmol) was added to a mixture of freshly distilled phosphorus
oxychloride (48 mL) and N,N-dimethylaniline (2.35 mL, 18.4
mmol). The mixture was refluxed for 2 min and then the
temperature quickly reduced to 0 °C. Phosphorus oxychloride
was removed under vacuum, and the crude residue was poured
into iced saturated NaHCO3 solution (400 mL) and stirred for
30 min at 0 °C. The solution was extracted with dichlo-
romethane, and the organic layer was dried over MgSO4,
reduced under vacuum, and purified by silica gel chromatog-
raphy (Et2O/C6H14 8:2 to 10:0) to yield 13 (6.32 g, 82%) as a
white powder. TLC Rf 0.45 (Et2O). F° ) 112-114 °C. 1H NMR
(CDCl3, 200 MHz) δ 8.78 (s, 1H); 8.26 (s, 1H); 7.56-7.39 (m,
5H); 6.32 (d, J ) 2.1 Hz, 1H); 6.06 (s, 1H); 5.64 (dd, J ) 6.5,
2.1 Hz, 1H); 5.16 (dd, J ) 6.5, 3.1 Hz, 1H); 4.73-4.66 (m, 1H);
4.31 (AB part of ABX syst., J AB ) 20.0 Hz, J AX ) 6.0 Hz, J BX
) 4.4 Hz, ∆ν ) 12.0 Hz, 2H); 1.97 (s, 3H). 13C NMR (D2O, 50
MHz) δ 169.9; 152.0; 151.5; 150.8; 150.7; 144.2; 135.4; 131.4;
130.0; 128.5; 126.5; 108.0; 90.9; 84.6; 84.5; 82.3; 63.5; 20.4. MS
(CI/NH3) m/z 418 [M + H]+; 435 [M + NH4]+. IR (film) ν 1744;
1592; 1561; 1403; 1227; 1095.
was purified by flash chromatography over silica gel (C6H14
/
Et2O 95/5) to yield 9 (11.4 g, 73 %) as a slightly yellow oil.
TLC Rf 0.50 (C6H14/Et2O 7:3). 1H NMR (CDCl3, 200 MHz) δ
7.43-7.35 (m, 5H); 5.13 (AB part of ABX syst., J AB ) 12.5 Hz,
J AX ) 12.8 Hz, J BX ) 10.8 Hz, ∆ν ) 9.0 Hz, 2H); 3.61 (d, J )
14.7 Hz, 3H); 1.99 (d, J ) 14.7 Hz, 3H). 13C NMR (CDCl3, 50
MHz) δ 136.1 (d, J ) 6.9 Hz); 128.6; 128.5; 128.2; 69.2 (d, J )
5.7 Hz); 53.7 (d, J ) 6.5 Hz); 24.5 (d, J ) 101.7 Hz). 31P NMR
(CDCl3, 121 MHz) δ 103.38 (s; sat.: d, J ) 846 Hz). MS (CI/
NH3) m/z 263 [M + H]+; 280 [M + NH4]+. IR (film) ν 2989;
2944; 1456; 1050; 1008; 899.
Bis(O-ben zyl-O′-m eth yl p h osp h on om eth yl)p h osp h in ic
Acid Ben zyl Ester 10. Selenophosphonate 9 (5.63 g, 21.4
mmol) in anhydrous THF (90 mL) was treated dropwise with
n-BuLi (1.6 M in hexane, 13.4 mL, 21.4 mmol) at -78 °C. The
solution was stirred for 2 min, and N,N-dimethylphosphona-
midous dichloride57 (1.56 g, 10.7 mmol) in THF (20 mL) was
added. The reaction mixture was stirred for 1 h at -78 °C, for
1 h more at room temperature, and the solvent was removed
under vacuum. Toluene (40 mL) was added to the crude
residue followed by benzyl alcohol (5.6 mL, 53.4 mmol) and
1H-tetrazole (750 mg, 10.7 mmol). The solution was refluxed
for 30 min, and then cooled to -30 °C and m-CPBA (15.8 g,
64.0 mmol) in toluene (130 mL) was added dropwise. After 45
min at -30 °C and 1 h at room temperature, the red precipitate
that formed was removed by filtration. The filtrate was treated
with aqueous Na2S2O3, and the resulting solution was neutral-
ized with aqueous NaHCO3 and extracted with ethyl acetate.
The organic layer was dried over MgSO4, filtered, and reduced
under vacuum. The crude residue was purified by chromatog-
raphy over silica gel (AcOEt/MeOH 10:0 to 8:2) to yield 10 (2.5
g, 42%) as a glassy solid (dl and meso forms). TLC Rf 0.45
(AcOEt/MeOH 95:5). 1H NMR (CDCl3, 300 MHz) δ 7.40 (m,
15H); 5.18-4.97 (m, 6H); 3.72, 3.71, 3.64 and 3.63 (4d, J )
11.3 Hz, 6H); 2.86, 2.85 and 2.83 (3t, J ) 19.6 Hz, 4H). 13C
NMR (CDCl3, 50 MHz) δ 135.7 and 135.6 (2d, J ) 3.8, 6.5 Hz);
128.4; 128.3; 128.0; 127.9; 127.8; 68.1, 68.0 and 67.8 (3d, J )
6.1 Hz); 66.9 (d, J ) 6.5 Hz); 53.0; 52.9 and 52.7 (3d, J ) 6.5,
6.1, 6.5 Hz); 27.9 (dd, J ) 132.6, 88.4 Hz). 31P NMR (CDCl3,
121 MHz) δ 39.64 and 39.42 (2t, J ) 3.9, 4.1 Hz, 0.5P); 39.56
(t, J ) 4.1 Hz, 0.5P); 22.40 (d, J ) 3.9 Hz, 0.5P); 22.38, 22.37
and 22.33 (3d, J ) 4.1 Hz, 1.5P). MS (CI/NH3) m/z 570 [M +
NH4]+. IR (film) ν 2956; 2899; 1456; 1251; 1186; 1016.
6-Ch lor o-9-[2′,3′-O-(1R)-ben zylid en e-â-D-r ibofu r a n osyl]-
p u r in e 14. Compound 13 (4.00 g, 9.6 mmol) was stirred for 3
h in methanolic ammonia (70 mL) at room temperature. The
solution was reduced in vacuo and the residue chromato-
graphed over silica gel. Compound 14 (2.91 g, 80%) was
obtained as a white powder. TLC Rf 0.60 (AcOEt). F° ) 190-
191 °C. 1H NMR (CDCl3, 200 MHz) δ 8.79 (s, 1H); 8.22 (s, 1H);
7.60-7.46 (m, 5H); 6.12 (d, J ) 4.6 Hz, 1H); 6.09 (s, 1H); 5.51
(dd, J ) 6.2, 4.6 Hz, 1H); 5.23 (dd, J ) 6.2, 1.3 Hz, 1H); 4.73
(m, 1H); 3.93 (m, 2H). 13C NMR (DMSO-d6, 50 MHz) δ 151.6;
151.3; 149.3; 149.2; 145.7; 136.0; 131.4; 129.7; 128.3; 126.8,
106.4; 90.3; 87.1; 84.3; 82.6; 61.3. MS (CI/NH3) m/z 375 [M +
H]+. IR (KBr) ν 3400; 3069; 2926; 2876; 1593; 1565; 1493; 1434;
1406; 1339; 1201; 1111; 1072.
P 1,P 3-Bis-[2′,3′-O-(1R)-ben zylid en e-1′-(6-ch lor op u r in -9-
yl)-â-D-r ibofu r a n os-5′-yl]-r,â,γ-tr iben zyl r: â,â: γ-Bis-m e-
th ylen e Tr ip h osp h a te 15. Diethyl azodicarboxylate (108 µL,
687 µmol) was added to diacid 7 (60 mg, 114 µmol), protected
nucleoside 14 (86 mg, 229 µmol), and triphenylphosphine (180
mg, 687 µmol) in refluxing anhydrous THF (2 mL). After 2.5
h the solvent was removed and the residue purified by silica
gel chromatography (Et2O/AcOEt/MeOH 10:0:0 to 0:7:3) to
yield 15 (56 mg, 40%) as a yellowish solid (mixture of four
diastereomers). TLC Rf 0.55 (AcOEt/MeOH 9:1). 1H NMR
(CDCl3, 300 MHz) δ 8.75-8.41 (m, 4H); 7.62-7.17 (m, 25H);
6.45-6.26 (m, 2H); 6.10-5.94 (m, 2H); 5.65-4.92 (m, 10H);
4.73-4.51 (m, 2H); 4.49-4.07 (m, 4H); 3.09-2.49 (m, 4H).
6-Azid o-9-[2′,3′-O-(1R)-ben zylid en e-â-D-r ibofu r a n osyl]-
p u r in e 16. Compound 14 (1.00 g, 2.67 mmol) and sodium azide
(1.73 g, 2.67 mmol) in anhydrous DMF (20 mL) were stirred
at 75 °C for 1 h. DMF was removed under reduced pressure
and the residue purified by chromatography over silica gel
(AcOEt/C6H14 7:3 to 10:0) to yield 16 (923 mg, 91%) as a white
powder. TLC Rf 0.50 (AcOEt). F° ) 158-159 °C. 1H NMR (CD3-
OD, 300 MHz) δ 9.86 (s, 1H); 8.82 (s, 1H); 7.61-7.42 (m, 5H);
2′,3′-O-(1R)-Ben zyliden ein osin e 11. Freshly distilled phos-
phorus oxychloride (5.2 mL, 55.6 mmol) was added dropwise
at 0 °C to a solution of inosine (7.46 g, 27.8 mmol) and
benzaldehyde dimethyl acetal (20.9 mL, 139.0 mmol) in
anhydrous acetonitrile (210 mL). The initial suspension was
stirred for 1 h at 0 °C and for 2 h at room temperature. The
resulting solution was poured into iced saturated NaHCO3
solution (600 mL) and stirred for 1.5 h at 0 °C. The precipitate
was collected by filtration and washed with ether to yield 11
(9.91 g, 100%) as a white powder. TLC Rf 0.35 (AcOEt/EtOH
1
8:2). F° ) 254-255 °C. H NMR (DMSO-d6, 200 MHz) δ 8.34
(s, 1H); 8.09 (s, 1H); 7.58-7.45 (m, 5H); 6.26 (d, J ) 3.0 Hz,
1H); 6.01 (s, 1H); 5.40 (dd, J ) 5.0, 3.0 Hz, 1H); 5.12 (dd, J )
5.0, 2.5 Hz, 1H); 4.46-4.38 (m, 1H); 3.73-3.61 (m, 2H). 13C
NMR (DMSO-d6, 50 MHz) δ 156.4; 147.8; 146.0; 138.8; 136.1;
129.7; 128.4; 126.8; 124.4; 106.6; 89.6; 86.5; 84.4; 82.6; 61.5.
MS (CI/NH3) m/z 357 [M + H]+. IR (film) ν 3500-2500; 1700;
1589; 1550; 1508; 1419; 1214; 1098; 974.
5′-O-Acetyl-2′,3′-O-(1R)-ben zylid en ein osin e 12. Triethyl-
amine (4.7 mL, 33.5 mmol), 4-DMAP (0.34 g, 2.8 mmol), and