5110 J . Org. Chem., Vol. 66, No. 15, 2001
Kværnø et al.
extracted with EtOAc (2 × 30 mL), and the combined organic
phase was evaporated to dryness under reduced pressure and
coevaporated with acetonitrile (4 × 40 mL). The residue was
purified by silica gel column chromatography (15.3 × 3.3 cm)
eluting first with a gradient of 0.5:0-10:99.5-89.5 pyridine/
EtOAc/CH2Cl2 (v/v/v) followed by 0.5:4:95.5 pyridine/MeOH/
CH2Cl2 (v/v/v) to give azide 8 (130 mg, 26%) as a yellowish
foam after coevaporation with acetonitrile (4 × 15 mL),
n-hexane/CH2Cl2 (2 × 15 mL, 4:1 (v/v)), and CH2Cl2 (2 × 15
mL): Rf (1:3 EtOAc/CH2Cl2 (v/v)) 0.64; IR (Nujol mull) ν 2106
cm-1 (strong); 1H NMR (CDCl3) δ 8.59 (1H, bs, NH), 7.89 (1H,
d, J ) 8.2 Hz, H6), 7.38-7.16 (18H, m, DMT), 6.85-6.77 (8H,
m, DMT), 5.54 (1H, dd, J ) 2.3, 8.2 Hz, H5), 4.08 (1H, m, H5′),
4.03 (1H, m, H4′), 3.78 (6H, s, OMe), 3.76 (3H, s, OMe), 3.75
(3H, s, OMe), 3.57 (1H, d, J ) 10.1 Hz, H1′), 3.48 (1H, d, J )
10.1 Hz, H1′), 3.28 (2H, dd, J ) 1.8, 4.2 Hz, H6′), 2.99 (1H,
dd, J ) 7.0, 14.9 Hz, H3′), 2.38 (1H, dd, J ) 5.4, 14.8 Hz, H3′);
13C NMR (CDCl3) δ 163.36 (C4), 158.57, 158.40 (DMT), 149.42
(C2), 144.30, 144.12 (DMT), 142.03 (C6), 135.44, 135.31,
135.10, 129.81, 129.79, 127.89, 127.84, 127.77, 127.67, 126.96,
126.75, 113.15, 113.01, 112.99 (DMT), 100.17 (C5), 98.08 (C2′),
86.68, 86.35 (Ar2PhC), 84.18 (C5′), 65.16 (C1′), 62.40 (C6′),
60.53 (C4′), 55.13, 55.07 (OMe), 39.98 (C3′).
1-[3′-Deoxy-1′,6′-d i-O-(4,4′-d im eth oxytr ityl)-â-D-sor bo-
fu r a n osyl]u r a cil (9). Compound 4 (4.353 g, 4.93 mmol) was
dissolved in anhydrous pyridine (30 mL) and cooled to 0 °C,
methanesulfonyl chloride (1.5 mL, 19.3 mmol) was added, and
stirring was continued at 0 °C for 2 h. Saturated aqueous
NaHCO3 (100 mL) and H2O (100 mL) were added, and the
suspension was extracted with EtOAc (4 × 100 mL). The
combined organic phase was washed with H2O (2 × 80 mL),
evaporated to dryness under reduced pressure, and coevapo-
rated with acetonitrile (2 × 100 mL). The crude residue 5 was
dissolved in 1,4-dioxane (200 mL), 1 M NaOH (aqueous, 100
mL) was added, and the mixture was stirred at 90 °C for 10
h. After the mixture cooled, H2O (200 mL) was added, and the
suspension was extracted with EtOAc (4 × 125 mL). The
combined organic phase was washed with saturated aqueous
NaHCO3 (80 mL) and H2O (80 mL), evaporated to dryness
under reduced pressure, and coevaporated with acetonitrile
(50 mL). The residue was purified by silica gel column
chromatography (13.5 × 5.5 cm) eluting with a gradient of 0.5:
0-3:99.5-96.5 pyridine/MeOH/CH2Cl2 (v/v/v) to yield com-
pound 9 (3.935 g, 93%) as a white foam after coevaporation
with acetonitrile (6 × 40 mL): Rf (5% MeOH in CH2Cl2 (v/v))
0.25; FAB-MS m/z 863 [M + H]+; 1H NMR (CDCl3) δ 8.75 (1H,
bs, NH), 7.88 (1H, d, J ) 8.2 Hz, H6), 7.52-7.15 (18H, m,
DMT), 6.86-6.76 (8H, m, DMT), 5.44 (1H, dd, J ) 2.3, 8.2 Hz,
H5), 4.39 (1H, bs, H4′), 4.32-4.28 (1H, m, H5′), 3.78 (3H, s,
OMe), 3.78 (3H, s, OMe), 3.73 (3H, s, OMe), 3.72 (3H, s, OMe),
3.61 (1H, dd, J ) 6.0, 10.4 Hz, H6′), 3.55 (1H, d, J ) 9.5 Hz,
H1′), 3.51 (1H, dd, J ) 4.4, 10.4 Hz, H6′), 3.42 (1H, d, J ) 9.5
Hz, H1′), 2.81 (1H, bs, OH), 2.98 (1H, d, J ) 15.0 Hz, H3′),
2.32 (1H, dd, J ) 4.6, 15.2 Hz, H3′); 13C NMR (CDCl3) δ 163.96
(C4), 158.54, 158.52, 158.34 (DMT), 149.73 (C2), 144.55, 144.34
(DMT), 141.63 (C6), 135.67, 135.53, 135.42, 129.94, 129.87,
129.81, 128.99, 127.99, 127.93, 127.85, 127.67, 126.91, 126.69,
113.15, 113.00, 112.99 (DMT), 99.92 (C5), 98.48 (C2′), 86.61,
86.06 (Ar2PhC), 84.37 (C5′), 71.23 (C4′), 65.25 (C1′), 62.16 (C6′),
phase was washed with H2O (2 × 80 mL), evaporated to
dryness under reduced pressure and coevaporated with CH2-
Cl2/n-hexane (1:4 (v/v), 2 × 100 mL). The residue was purified
by silica gel column chromatography (13.3 × 5.5 cm) eluting
with a gradient of 0.5:0-5:99.5-94.5 pyridine/EtOAc/CH2Cl2
(v/v/v) to give compound 8 (4.297 g, 97%) as a white foam after
coevaporation with acetonitrile (3 × 50 mL). Physical data
were identical with those obtained earlier.
1-[4′-Azido-3′-deoxy-â-D-psicofu r an osyl]u r acil (11). Azide
8 (4.247 g, 4.78 mmol) was dissolved in CH2Cl2 (10 mL) and
80% aqueous AcOH (50 mL), and the solution was stirred for
4 h, evaporated to dryness under reduced pressure, and
coevaporated with absolute EtOH (100 mL). MeOH (100 mL)
and silica gel (50 mL) were added, and the suspension was
evaporated under reduced pressure and coevaporated with
CH2Cl2 (100 mL). The residue was purified by silica gel column
chromatography (12 × 5.5 cm) eluting with a gradient of
5-10% MeOH in CH2Cl2 (v/v) to give nucleoside 1 (1.091 g,
81%) as a white foam: Rf (10% MeOH in CH2Cl2 (v/v)) 0.20;
1
FAB-MS m/z 284 [M + H]+; H NMR (CD3OD) δ 8.06 (1H, d,
J ) 8.2 Hz, H6), 5.60 (1H, dd, J ) 1.5, 8.0 Hz, H5), 4.19 (1H,
ddd, J ) 5.2, 5.7, 7.2 Hz, H4′), 4.10 (1H, q, J ) 4.6 Hz, H5′),
3.94 (1H, d, J ) 11.9 Hz, H1′), 3.77 (1H, d, J ) 11.9 Hz, H1′),
3.72 (1H, dd, J ) 4.0, 12.1 Hz, H6′), 3.63 (1H, dd, J ) 4.7,
12.1 Hz, H6′), 3.05 (1H, dd, J ) 7.1, 14.7 Hz, H3′), 2.41 (1H,
dd, J ) 5.8, 14.7 Hz, H3′); 13C NMR (CD3OD) δ 167.06 (C4),
152.01 (C2), 144.06 (C6), 100.58, 100.41 (C2′, C5), 87.69 (C5′),
65.69 (C1′), 62.14 (C6′), 61.66 (C4′), 40.28 (C3′).
1-[(2,1′-An h ydr o)-4′-azido-3′-deoxy-6′-O-(p-tolu en esu lfo-
n yl)-â-D-p sicofu r a n osyl]u r a cil (12). Nucleoside 11 (117 mg,
0.41 mmol) was dissolved in anhydrous CH2Cl2 (10 mL) and
anhydrous pyridine (2 mL), TsCl (510 mg, 2.68 mmol) was
added, and the mixture was stirred at room temperature for
45 h. Saturated aqueous NaHCO3 (10 mL) and H2O (10 mL)
were added, and the suspension was extracted with EtOAc (5
× 20 mL). The combined organic phase was washed with H2O
(2 × 20 mL), evaporated to dryness under reduced pressure,
and coevaporated with acetonitrile (2 × 20 mL). The residue
was purified by silica gel column chromatography (12.5 × 2.8
cm) eluting with a gradient of 2-4% MeOH in CH2Cl2 (v/v) to
give anhydronucleoside 12 (109 mg, 65%) as a light yellow
foam: Rf (20% MeOH in CH2Cl2 (v/v)) 0.72; FAB-MS m/z 420
[M + H]+; 1H NMR (CDCl3) δ 7.77 (2H, d, J ) 8.4 Hz, Ts),
7.42 (1H, d, J ) 7.7 Hz, H6), 7.39 (2H, d, J ) 7.9 Hz, Ts), 6.03
(1H, d, J ) 7.5 Hz, H5), 4.64 (1H, d, J ) 10.4 Hz, H1′), 4.60
(1H, d, J ) 10.4 Hz, H1′), 4.51 (1H, dt, J ) 3.2, 6.4 Hz, H4′),
4.25 (1H, dd, J ) 2.3, 11.1 Hz, H6′), 4.20 (1H, q, J ) 2.6 Hz,
H5′), 4.16 (1H, dd, J ) 2.8, 11.1 Hz, H6′), 2.97 (1H, dd, J )
6.6, 14.5 Hz, H3′), 2.47 (1H, dd, J ) 3.5, 14.5 Hz, H3′), 2.47
(3H, s, ArCH3); 13C NMR (CDCl3) δ 171.41 (C4), 159.85 (C2),
145.96, 132.60 (Ts), 131.59 (C6), 130.18, 127.73 (Ts), 110.70
(C5), 97.70 (C2′), 82.35 (C5′), 77.40 (C1′), 68.38 (C6′), 61.30
(C4′), 39.87 (C3′), 21.61 (ArCH3).
1-[4′-Azid o-3′-d eoxy-1′,6′-d i-O-m eth a n esu lfon yl-â-D-p si-
cofu r a n osyl]u r a cil (13). Nucleoside 11 (931 mg, 3.29 mmol)
was dissolved in anhydrous anhydrous pyridine (20 mL) at 0
°C, MsCl (1.25 mL, 16.1 mmol) was added, and stirring was
continued at 0 °C for 1 h 30 min. EtOAc (200 mL) was added,
and the mixture was washed with H2O (2 × 40 mL). The
combined aqueous phase was extracted with CH2Cl2 (3 × 40
mL), and the combined organic phase was evaporated to
dryness under reduced pressure and coevaporated with ac-
etonitrile (3 × 60 mL). The residue was purified by silica gel
column chromatography (7.5 × 5.5 cm) eluting with a gradient
of 2-3% MeOH in CH2Cl2 (v/v) to give nucleoside 13 (1329
mg, 92%) as a white foam: Rf (10% MeOH in CH2Cl2 (v/v))
0.35; IR (KBr) ν 2116 cm-1 (strong); FAB-MS m/z 440 [M +
H]+; 1H NMR (acetone-d6) δ 10.07 (1H, bs, NH), 7.91 (1H, d, J
) 8.4 Hz, H6), 5.60 (1H, d, J ) 8.4 Hz, H5), 4.78 (1H, d, J )
11.0 Hz, H1′), 4.59-4.48 (5H, m, H1′, H4′, H5′, H6′), 3.27 (1H,
dd, J ) 6.5, 14.9 Hz, H3′), 3.19 (3H, s, Me), 3.14 (3H, s, Me),
2.65 (1H, dd, J ) 4.9, 15.0 Hz, H3′); 13C NMR (acetone-d6) δ
163.94 (C4), 151.24 (C2), 141.26 (C6), 101.69 (C5), 97.26 (C2′),
84.61 (C5′), 71.10 (C1′), 68.56 (C6′), 61.25 (C4′), 41.03 (C3′),
37.69, 37.55 (Me).
55.12, 55.04 (OMe), 41.37 (C3′). Anal. Calcd for C52H50N2O10
:
C, 72.4; H, 5.8; N, 3.3. Found: C, 72.1; H, 5.8; N, 3.6.
Alter n a tive P r ep a r a tion of 8. Compound 9 (4.313 g, 5.00
mmol) was dissolved in anhydrous pyridine (30 mL) and cooled
to 0 °C, methanesulfonyl chloride (1.5 mL, 19.3 mmol) was
added, and the mixture was stirred at room temperature for
3 h. Saturated aqueous NaHCO3 (100 mL) and H2O (100 mL)
were added, and the suspension was extracted with EtOAc (4
× 100 mL). The combined organic phase was washed with H2O
(2 × 80 mL), evaporated to dryness under reduced pressure,
and coevaporated with acetonitrile (3 × 100 mL). The resulting
crude residue 10 was dissolved in anhydrous DMF (60 mL),
NaN3 (3.011 g, 46.3 mmol) was added, and the suspension was
stirred at 70 °C for 2 days. Saturated aqueous NaHCO3 (100
mL) and H2O (100 mL) were added, and the mixture was
extracted with EtOAc (4 × 100 mL). The combined organic