El-Subbagh et al.
J . Org. Chem., Vol. 61, No. 3, 1996 893
in dry DMF (10 mL) was added dropwise to this mixture and
stirred for 18 h under nitrogen. The excess solvent was then
removed in vacuo and ice-water was added to the resulting
residue. The aqueous solution was extracted with EtOAc and
the organic layer dried and then concentrated under dimin-
ished pressure. The resulting gum was column chromato-
graphed (silica gel) using EtOAc as eluant to afford 10 (1.5 g,
85%): [R]23D +18.9° (c ) 1.42, CH2Cl2); 1H NMR (CDCl3) δ 1.0-
1.48 (m, 9H), 1.5-2.0 (m, 4H), 3.35-4.2 (m, 6H), 4.3-4.7 (q, J
) 12 Hz), 5.1 (br s, 2H), 5.4-5.7 (m, 4H), 7.1-7.55 (m, 10H),
7.65 (s, 1H). Anal. Calcd for C29H38N5O6P: C, 59.68; H, 6.56;
N, 12.00; P, 5.31. Found: C, 59.44; H, 6.61; N, 11.86; P, 5.40.
9-[[(4(S)-(Ben zyloxy)-1-(d ieth ylp h osp h on yl)-3(R)-p en -
toxy]m eth yl]gu a n in e (11). Compound 10 (0.3 g, 0.5 mmol)
was dissolved in EtOH (10 mL) containing 2 mL of cyclohexene
and to this mixture was added 20% Pd(OH)2/C (0.1 g). The
resulting suspension was refluxed for 1.5 h. After this period,
the catalyst was removed by filtration (Celite) and the filtrate
and wash (EtOH) were combined and concentrated in vacuo.
4.86-5.24 (m, 2H), 6.98 (s, 1H,), 7.24 (s, 10H), 10.24 (s, 1H,
D2O exchangeable). Anal. Calcd for C27H35N2O8P: C, 59.34;
H, 6.46; N, 5.13; P, 5.67. Found: C, 59.14; H, 6.52; N, 4.97;
P, 5.59.
1-[[(4(S),5-Bis(ben zyloxy)-1-(d ieth ylp h osp h on yl)-3(R)-
p en toxy]m eth yl]th ym in e (16). Persilylated thymine [ob-
tained from 2.52 g (20 mmol) of thymine] was coupled as
described for 6 with the chloromethyl ether 5a derived from 5
(4.2 g, 10 mmol) in dry CH2Cl2 (50 mL) and in the presence of
TEAI (30 mg). The reaction mixture was stirred and heated
at reflux for 12 h. Work up and chromatography (EtOAc-
MeOH, 9:1) afforded pure 16 (3.6 g, 63%): [R]25 -6.3° (c )
D
0.615, EtOH); 1H NMR (CDCl3) δ 1.26 (t, J ) 6 Hz, 6H), 1.46-
2.12 (m, 4H), 1.82 (s, 3H), 3.59 (br s, 3H), 3.74-4.26 (m, 5H),
4.48 (s, 2H), 4.60 (d, J ) 3 Hz, 2H), 5.08 (br s, 2H), 7.06 (s,
1H), 7.26 (s, 10H), 9.74 (s, 1H, D2O exchangeable). Anal.
Calcd for C29H39N2O8P: C, 60.62; H, 6.84; N, 4.88; P, 5.39.
Found: C, 60.40; H, 6.66; N, 4.61; P, 5.51.
1-[[1-(Dieth ylp h osph on yl-4(S)-h ydr oxy)-3(R)-p en toxy]-
m eth yl]th ym in e (17). A solution of compound 6 (0.35 g, 10
mmol) in ethanol (80 mL) and cyclohexene (20 mL) was treated
with 20% palladium hydroxide on carbon (Pd(OH)2/C, 1.0 g).
The resulting suspension was stirred at reflux for 12 h. After
cooling to room temperature, the mixture was filtered and the
filtrate was concentrated at reduced pressure. The residue
was chromatographed over silica gel (ethyl acetate-methanol,
The resulting gum on standing in EtOAc solidified to provide
1
11 (0.15 g, 60%): [R]25 +18.8° (c ) 1.345, CH2Cl2); H NMR
D
(CDCl3) δ 0.95-1.45 (m, 9H), 1.5-2.0 (m, 4H), 3.3-4.2 (m, 6H),
4.3-4.6 (m, 2H), 5.25-5.60 (m, 2H), 6.75 (br s, 2H), 7.2 (s,
5H), 12.15 (br s, 1H). Anal. Calcd for C22H32N5O6P: C, 53.54;
H, 6.54; N, 14.19; P, 6.28. Found: C, 53.42; H, 6.68; N, 13.96;
P, 6.11.
1-[[(4(S)-(Ben zyloxy)-1-(diben zylph osph on yl)-3(R)-pen -
toxy]m eth yl]th ym in e (12). Thymine (0.9 g, 6.9 mmol) was
persilylated with HMDS (30 mL) and ammonium sulfate (0.1
g). The persilylated base was then dissolved in CH2Cl2 (50
mL) along with 3a (5 mmol) and TBAI (0.1 g). The crude
product was chromatographed on a silica gel column, and the
product was obtained by eluting with EtOAc-CH2Cl2 (8:2) to
9:1) to give pure 18 (2.2 g, 78%): [R]25 -3.1° (c ) 0.7, EtOH);
D
1H NMR (CDCl3) δ 1.12 (d, J ) 6 Hz, 3H), 1.28 (t, J ) 6 Hz,
6H), 1.42-2.10 (m, 2H), 1.88 (s, 3H), 3.28-4.26 (m, 7H, 1H
exchanges with D2O), 5.18 (br s, 2H), 7.16 (s, 1H), 9.84-10.46
(br m, 1H, D2O exchangeable). Anal. Calcd for C15H27N2O7P:
C, 47.62; H, 7.19; N, 7.40. Found: C, 47.54; H, 7.27; N, 7.47.
1-[[(1-(Dim et h ylp h osp h on yl)-4(S)-h yd r oxy-3(R)-p en -
toxy]m eth yl]u r a cil (18). Compound 18 was prepared from
7 (0.690 g, 1.62 mmol) by the method described for 17 using
20% Pd(OH)2/C (0.050 g), cyclohexene (8 mL), and EtOH (9
mL) to give 0.535 g (99%) of 18: [R]25D -5.5° (c ) 0.435, EtOH);
1H NMR (CDCl3) δ 1.12 (d, J ) 6 Hz, 3H), 1.46-2.06 (m, 4H),
3.44-4.02 (m, 2H), 3.72 (d, J ) 11 Hz, 6H), 5.22 (s, 2H,), 5.66
(d, J ) 8 Hz, 1H), 7.38 (d, J ) 8 Hz, 1H). Anal. Calcd for
C12H21N2O7P: C, 42.86; H, 6.29; N, 8.33. Found: C, 42.55; H,
6.42; N, 8.14.
afford pure 12 (0.7 g, 24%): [R]23 +16.1° (c ) 0.745, CH2Cl2);
D
1H NMR (CDCl3) δ 1.1 (d, J ) 6 Hz, 3H), 1.4-2.1 (m, 7H),
3.2-3.9 (m, 2H), 4.2-4.6 (q, J ) 12 Hz, 2H), 4.7-5.2 (m, 6H),
7.0 (s, 1H), 7.1-7.4 (m, 15H), 8.9 (br s, 1H, D2O exchangeable).
Anal. Calcd for C32H37N2O7P: C,, 64.85; H, 6.29; N, 4.73; P,
5.23. Found: C, 64.64; H, 6.35; N, 4.57; P, 5.41.
1-[[(4(S)-(Ben zyloxy)-1-(diben zylph osph on yl)-3(R)-pen -
toxy]m eth yl]u r a cil (13). Uracil (0.67 g, 6 mmol) was sily-
lated with HMDS (30 mL) and ammonium sulfate (0.10 g).
The persilylated base was then dissolved in CH2Cl2 (30 mL)
along with 3a (5 mmol) and TBAI (0.1 g). The crude product
was silica gel column chromatographed using CH2Cl2-EtOAc
(7.5:2.5) as eluant to provide pure 13 (0.9g, 32%): [R]25D +14.6°
(c ) 0.565, CH2Cl2); 1H NMR (CDCl3) δ 1.1 (d, J ) 6 Hz, 3H),
1.46-2.00 (m, 4H), 3.27-3.82 (m, 2H), 4.3-4.6 (q, J ) 12 Hz,
2H), 4.8-5.2 (m, 6H), 5.6 (d, J ) 7.5 Hz, 1H), 7.1-7.45 (m,
16H), 9.8 (br s, 1H, D2O exchangeable). Anal. Calcd for
C31H35N2O7P: C, 64.35; H, 6.10; N, 4.84; P, 5.35. Found: C,
64.23; H, 6.11; N, 4.63; P, 5.49.
1-[[1-(Dieth ylp h osph on yl)-4(S)-h yd r oxy-3(R)-p en toxy]-
m eth yl]u r a cil (19). Compound 19 was prepared from 8 (4.1
g, 9 mmol) by the method described for 17 using 20%
Pd(OH)2/C (1.5 g), cyclohexene (20 mL), and EtOH (100 mL)
to provide 19 (2.47 g, 75%): [R]25 -3.9° (c ) 1.275, MeOH);
D
1H NMR (CDCl3) δ 1.14 (d, J ) 6.4 Hz, 3H), 1.28-1.40 (t, J )
7.2 Hz, 6H), 1.73-1.82 (m, 4H), 3.60-3.92 (m, 2H), 4.00-4.18
(m, 4H), 5.20-5.38 (t, J ) 7.2 Hz, 2H), 5.75 (d, J ) 7.2 Hz,
1H), 6.4 (d, J ) 7.2 Hz, 1H), 10.2 (br s, 1H, D2O exchangeable).
Anal. Calcd for C14H25N2O7P: C, 46.14; H, 6.91; N, 7.69; P,
8.50. Found: C, 46.00; H, 6.79; N, 7.60; P, 8.33.
2-Am in o-6-(b e n zyloxy)-9-[[(4(S )-(b e n zyloxy)-1-(d i-
b en zylp h osp h on yl)-3(R)-p en t oxy]m et h yl]p u r in e (14).
2-Amino-6-(benzyloxy)purine (1.16 g, 4.8 mmol) in DMF (20
mL) and sodium hydride (0.38 g, 60%, 9.6 mmol) in DMF (25
mL) were combined, and the resulting sodium salt was reacted
with 3a (4.8 mmol) in dry DMF. The reaction was carried out
as described for 10. Pure 14 was obtained after column
chromatography (EtOAc-CH2Cl2, 1:1) in 32% yield (1.1 g):
1[[1-(Dieth ylp h osp h on yl)-4(S)-h yd r oxy-3(R)-p en toxy]-
m eth yl]gu a n in e (20). Compound 20 was prepared from 11
(1.52 g, 2.6 mmol) by the method described for 17 using 20%
Pd(OH)2/C (0.5 g), cyclohexene (10 mL), and EtOH (50 mL).
The catalyst was removed by filtration, and the filtrate and
wash were concentrated under diminished pressure to a
semisolid. On standing in MeOH-EtOAc (1:2) the ester
crystallized to afford 0.8 g (80%) of 20: [R]25D +4.1° (c )1.335,
[R]25 +9.4° (c ) 0.9, CH2Cl2); 1H NMR (CDCl3) δ 1.08 (d, J )
D
6.2 Hz, 3H), 1.6-2.04 (m, 4H), 3.40-3.43 (m, 1H), 3.65-3.69
(m, 1H), 4.40-4.55 (q, J ) 11.8 Hz, 2H), 4.85-5.02 (m, 6H),
5.43-5.52 (m, 4H), 7.23-7.37 (m, 18H), 7.47-7.50 (m, 2H),
7.61 (s, 1H). Anal. Calcd for C39H42N5O6P: C, 66.18; H, 5.98;
N, 9.90; P, 4.38. Found: C, 66.33; H, 6.06; N, 9.87; P, 4.44.
1-[[(4(S),5-Bis((b en zyloxy)-1-(d im et h ylp h osp h on yl)-
3(R)-p en toxy]m eth yl]th ym in e (15). Persilylated thymine
[obtained from 1.51 g (12 mmol) of thymine] was coupled as
described for 6, with the chloromethyl ether 4a derived from
4 (2.45 g, 6 mmol), in dry CH2Cl2 (50 mL) and in the presence
of TEAI (50 mg). The reaction mixture was stirred and heated
at reflux for 12 h. Work up and chromatography (EtOAc)
MeOH); UV λ
(H2O) 277.5 nm (ꢀ ) 7388), 251 nm (ꢀ )
max
11781), λ
(pH 1) 281(ꢀ ) 8946), 256 nm (ꢀ ) 13179), λ
max
max
1
(pH 11) 263 nm (ꢀ ) 11651), 257.5 nm (ꢀ ) 11661) ; H NMR
(Me2SO-d6) δ 0.94 (d, J ) 6.3 Hz, 3H), 1.10-1.20 (t, J ) 6.9
Hz, 6H), 1.21-1.60 (m, 4H), 3.00-4.10 (m, 6H), 4.77 (d, J )
4.8 Hz, 1H), 5.30-5.47 (q, J ) 11.1 Hz, 2H), 6.57 (br s, 2H,
D2O exchangeable), 7.84 (s, 1H), 10.70 (br s, 1H, D2O ex-
changeable). Anal. Calcd for C15H26N5O6P: C, 44.66; H, 6.50;
N, 17.36; P, 7.68. Found: C, 44.14; H, 6.68; N, 16.98; P, 7.48.
1-[[4(S),5-Dih ydr oxy-1-(dim eth ylph osph on yl)-3(R)-pen -
toxy]m eth yl]th ym in e (21). Compound 21 was prepared
from 15 (1.3 g, 2.38 mmol) by the method described for 17
using 20% Pd(OH)2/C (0.2 g), cyclohexene (9.2 mL), and EtOH
afforded pure 15 (3.14 g, 96%): [R]25 +5.8° (c ) 0.89, EtOH);
D
1H NMR (CDCl3) δ 1.50-2.08 (m, 4H), 1.26 (s, 3H), 3.26-4.18
(18 mL), to furnish 0.860 g (100%) of 23: [R]25 -1.6° (c )
D
(m, 4H), 3.64 (d, J ) 11 Hz, 6H), 4.46 (s, 2H), 4.62 (s, 2H),
0.94, EtOH); 1H NMR (CDCl3+D2O) δ 1.46-2.18 (m, 4H), 1.86