Notes
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 17 3421
J ) 5.4 Hz, 1H), 4.69* (q, J ) 5.3 Hz, 1H), 3.79-3.42 (m, 5H),
1.32* (d, J ) 5.3 Hz, 3H), 1.31* (d, J ) 5.3 Hz, 3H), 1.19* (t,
J ) 7.1 Hz, 3H), 1.18* (t, J ) 7.0 Hz, 3H), 1.15* (d, J ) 6.4
Hz, 3H), 1.09* (t, J ) 6.4 Hz, 3H).
(Na2SO4) and evaporated in vacuo. The resulting (chlorophe-
nyl)phosphatidic acid triethylammonium salt was used with-
out further purification for the next step.
The (chlorophenyl)phosphatidic acid triethylammonium salt
obtained above was dissolved in pyridine (5 mL). 1-(2-
Mesitylenesulfonyl)-3-nitro-1,2,4-triazole (MSNT; 0.390 g, 1.34
mmol) and AZT (0.30 g, 1.12 mmol) were added, and the
mixture was stirred at room temperature for 12 h. The
reaction mixture was then worked up by addition of saturated
aqueous NaHCO3 and extraction with dichloromethane. The
organic phase was extracted with saturated aqueous CuSO4
to remove pyridine, dried (Na2SO4), and concentrated in vacuo.
The residue was purified by flash column chromatography
using a gradient of dichloromethane/acetone (90:10-85:15).
3′-Azid o-3′-d eoxyt h ym id in e 5′-(o-ch lor op h en yl (R)-2-
(d od ecyloxy)p r op yl p h osp h a te) (10a ): yield 62%; 1H NMR
δ 8.47 (bs, 1H), 7.49-7.15 (m, 5H), 6.24 (t, J ) 6.5 Hz, 1H),
4.49-4.07 (m, 5H), 4.06 (m, 1H), 3.65-3.62 (m, 1H), 3.46-
3.41 (m, 2H), 2.42-2.26 (m, 2H), 1.88 (s, 3H), 1.54 (m, 2H),
1.25 (bs, 18H), 1.15* (d, J ) 6.3 Hz, 3H), 1.16* (d, J ) 6.3 Hz,
3H), 0.88 (t, J ) 6.2 Hz, 3H); 31P NMR δ -8.31.
3′-Azid o-3′-d eoxyth ym id in e 5′-(o-ch lor op h en yl (S)-2-
(d od ecyloxy)p r op yl p h osp h a te) (10b): yield 58.5%.
3′-Azid o-3′-d eoxyt h ym id in e 5′-(o-ch lor op h en yl (R)-1-
m eth yl-2-(d od ecyloxy)eth yl p h osp h a te) (10c): yield 36%;
1H NMR δ 8.44 (bs, 1H), 7.53-7.14 (m, 5H), 6.27 (t, J ) 6.5
Hz, 1H), 4.46-4.07 (m, 5H), 3.65-3.37 (m, 4H), 2.41-2.25 (m,
2H), 1.89 (s, 3H), 1.63-1.5 (m, 2H), 1.34 (d, J ) 6.4 Hz, 3H),
1.25 (bs, 18H), 0.88 (t, J ) 6.2 Hz, 3H); 31P NMR δ -8.95,
-9.42.
(R)- or (S)-1-(Dod ecyloxy)-2-O-(1-eth oxyeth yl)p r op a n e.
The reaction was performed as above for (R)- or (S)-2-
(dodecyloxy)-1-O-(triphenylmethyl)propane using NaH (0.044
g, 1.18 mmol, washed twice with anhydrous hexane) in toluene
(2 mL), alcohol 5a or 5b (0.140 g, 0.9 mmol) in toluene (2 mL),
1-bromododecane (0.336 g, 1.35 mmol) and KI (0.022 g, 0.135
mmol), to afford, after purification using flash column chro-
matography (petroleum ether (40-60 °C)/ethyl acetate, 9:1),
the desired product in 62% yield: 1H NMR δ 4.81* (q, J ) 5.3
Hz, 1H), 4.76* (q, J ) 5.3 Hz, 1H), 3.88-3.25 (m, 7H), 1.56-
1.49 (m, 2H), 1.29 (d, J ) 5.3 Hz, 3H), 1.24 (bs, 18 H), 1.18*
(t, J ) 7.0 Hz, 3H), 1.17* (t, J ) 7.0 Hz, 3H), 1.15* (d, J ) 6.4
Hz, 3H), 1.12 (d, J ) 6.4 Hz, 3H), 0.86 (t, J ) 6.8 Hz, 3H).
(R)- or (S)-1-(Dod ecyloxy)p r op a n -2-ol (6a ,b). To a solu-
tion of (R)- or (S)-1-(dodecyloxy)-2-O-(1-ethoxyethyl)propane
(0.260 g, 0.83 mmol) in anhydrous EtOH (7 mL) was added
pyridinium toluene-4-sulfonate (0.021 g, 0.083 mmol), and the
resulting mixture was heated at 55 °C for 1.5 h. The EtOH
was then evaporated in vacuo, and the residue was taken up
in ether and washed with saturated aqueous NaHCO3, H2O,
and brine. The organic layer was dried over Na2SO4, and the
solvent was evaporated in vacuo to afford, after purification
of the residue by flash column chromatography (petroleum
ether (40-60 °C)/ethyl acetate, 80:20), the desired product 6a
or 6b in 80% yield: 1H NMR δ 3.94-3.91 (m, 1H), 3.47-3.37
(m, 3H), 3.18 (dd, J ) 9.2, 8.3 Hz, 1H), 2.35 (bs, 1H), 1.56-
1.51 (m, 2H), 1.24 (bs, 18H), 1.11 (d, J ) 6.3 Hz, 3H), 0.86 (t,
J ) 6.6 Hz, 3H); 13C NMR δ 76.3, 71.5, 66.4, 31.9, 29.6, 29.5,
29.3, 26.1, 22.7, 18.6, 14.1.
3′-Azid o-3′-d eoxyth ym id in e 5′-(o-ch lor op h en yl (S)-1-
m eth yl-2-(d od ecyloxy)eth yl p h osp h a te) (10d ): yield 53%.
3′-Azid o-3′-d eoxyth ym id in e 5′-(o-ch lor op h en yl 2-(p h e-
(R)-1-(Dod ecyloxy)p r op a n -2-ol (6a ): [R]20 ) +8.4° (c )
1
n yloxy)eth yl p h osp h a te) (10e): yield 35%; H NMR δ 9.3
D
2 g/dL, MeOH). Anal. (C15H32O2) C, H.
(bs, 1H), 7.44-6.8 (m, 10H), 6.17 (t, J ) 6.6 Hz, 1H), 4.58-
4.36 (m, 5H), 4.27-4.0 (m, 3H), 2.38-2.17 (m, 2H), 1.9 (s, 3H);
31P NMR δ -8.32, -8.38. Anal. (C24H25N5O8ClP) C, H, N.
3′-Azid o-3′-d eoxyt h ym id in e 5′-(o-ch lor op h en yl 2-(2-
(S)-1-Dod ecyloxy-p r op a n e-2-ol (6b): [R]20D ) -8.8° (c )
2 g/dL, MeOH). Anal. (C15H32O2) C, H.
Gen er a l P r oced u r e for th e P r ep a r a tion of 2-(Ar yloxy)-
eth a n ols 7-9. To a solution of the appropriate aryl alcohol
(0.05 mol) in anhydrous acetone (60 mL) were sequentially
added anhydrous K2CO3 (0.055 mol) and bromoethanol (0.045
mol), and the resulting mixture was refluxed for 12 h.
Filtration of the K2CO3 was followed by evaporation of the
solvent from the filtrate, and the residue was added to 32%
NaOH (50 mL) and stirred at room temperature for 1 h to
remove unreacted aryl alcohol. The mixture was partitioned
between ether and water, and the organic layer was washed
with 2 N HCl, H2O, and brine and dried (Na2SO4). The solvent
was evaporated in vacuo, and the residue was purified by flash
column chromatography (petroleum ether (40-60 °C)/ether,
70:30) to afford the desired product.
1
n a p h th yloxy)eth yl p h osp h a te) (10f): yield 36%; H NMR
δ 9.54 (bs, 1H), 7.81-7.72 (m, 3H), 7.53-7.12 (m, 9H), 6.21 (t,
J ) 6.5 Hz, 1H), 4.72-4.27 (m, 7H), 4.06-4.05 (m, 1H), 2.43-
2.31 (m, 1H), 2.29-2.19 (m, 1H), 1.89 (s, 3H); 31P NMR δ -8.4.
Anal. (C28H27N5O8ClP) C, H, N.
3′-Azid o-3′-d eoxyt h ym id in e 5′-(o-ch lor op h en yl 2-(1-
1
n a p h th yloxy)eth yl p h osp h a te) (10g): yield 48%; H NMR
δ 9.18 (bs, 1H), 8.27-8.23 (m, 1H), 7.83 (d, J ) 7.8 Hz, 1H),
7.55-7.30 (m, 7H), 7.20-7.11 (m, 2H), 6.82-6.38 (m, 1H), 6.16
(t, J ) 6.5 Hz, 1H), 4.82-4.66 (m, 2H), 4.53-4.32 (m, 4H),
4.38-4.11 (m, 1H), 3.99-3.98 (m, 1H), 2.33-2.08 (m, 2H), 1.88
(s, 3H); 31P NMR δ -8.19, -8.32. Anal. (C28H27N5O8ClP) C,
H, N.
Gen er a l P r oced u r e for th e P r ep a r a tion of th e F in a l
P h osph odiester s. Tetra-n-butylammonium fluoride (3 mmol,
1 M in THF) was added to a solution of the protected conjugate
in a mixture of tetrahydrofuran-pyridine-water (8:1:1, v/v/
v) (10 mL). The mixture was stirred at room temperature for
5 h and then worked up by addition of saturated aqueous
NaHCO3 and extraction with dichloromethane. The organic
phase was evaporated, and the residue was applied to a short
column and eluted with dichloromethane:methanol (gradient
95:5-50:50). The appropriate fractions were concentrated and
treated with DOWEX 50WX8 (H+) in methanol to afford the
final phosphodiesters.
2-(P h en yloxy)eth a n ol (7): yield 95%; 1NMR δ 7.28-7.23
(m, 2H), 6.97-6.88 (m, 3H), 4.03 (t, J ) 5.1 Hz, 2H), 3.94-
3.88 (m, 2H), 2.84 (t, J ) 5.3 Hz, 1H).
2-(1-Na p h th yloxy)eth a n ol (8): yield 80%; 1NMR δ 8.18-
8.15 (m, 1H), 7.81-7.78 (m, 1H), 7.50-7.42 (m, 3H), 7.31-
7.25 (m, 1H), 6.77 (d, J ) 7.4 Hz, 1H), 4.16 (t, J ) 4.9 Hz,
2H), 4.03-3.99 (m, 2H), 2.30 (bs, 1H).
2-(2-Na p h th yloxy)eth a n ol (9): yield 90%; 1NMR δ 7.76-
7.69 (m, 3H), 7.45-7.40 (m, 1H), 7.35-7.32 (m, 1H), 7.17-
7.14 (m, 2H), 4.16 (t, J ) 4.3 Hz, 2H), 4.02-3.97 (m, 2H), 2.31
(bs, 1H).
Gen er a l P r oced u r e for th e P r ep a r a tion of 2-Ch lor o-
p h en yl 5′-(3′-Azid o-2′-d eoxyth ym id in yl) 2-Alk oxyp r op yl
P h osp h a tes a n d 2-Ch lor op h en yl 5′-(3′-Azid o-2′-d eoxyth y-
m id in yl) 2-(Ar yloxy)et h yl P h osp h a t es. Triphosphates
11a -g were synthesized using the method previously de-
scribed by us.13 Briefly, to an ice-cooled solution of o-chlo-
rophenyl phosphorodichloridate (0.35 mL, 2 mmol) in aceto-
nitrile (8 mL) were sequentially added 1,2,4-triazole (0.310 g,
4.5 mmol) and triethylamine (0.6 mL), and the mixture was
stirred at room temperature for 30 min. The appropriate
alcohol (4, 6-9) (1 mmol) in pyridine (8 mL) was added, and
after a further period of 45 min triethylamine (0.7 mL) and
water (0.2 mL) were added; the mixture was stirred for 10 min.
Addition of saturated aqueous NaHCO3 was followed by
extraction with dichloromethane. The organic phase was dried
3′-Azid o-3′-d eoxyth ym id in e 5′-((R)-2-(d od ecyloxy)p r o-
p yl p h osp h a te) (11a ): yield 60%; 1H NMR δ 7.46 (s, 1H), 6.22
(t, J ) 6.4 Hz, 1H), 4.41-4.0 (m, 6H), 3.69-3.65 (m, 1H), 3.52-
3.49 (m, 2H), 2.46-2.39 (m, 2H), 1.93 (s, 3H), 1.59-1.44 (m,
2H), 1.27 (bs, 18H), 1.19 (d, J ) 6.3 Hz, 3H), 0.83 (t, J ) 6.3
Hz, 3H); 13C NMR δ 164.3, 150.3, 135.9, 111.3, 85.2, 82.4, 73.7,
70.5, 69.5, 66.1, 60.0, 37.5, 31.9, 29.9, 29.8 29.6, 29.4, 29.3,
26.1, 22.7, 16.4, 14.1, 12.3; 31P NMR
(C25H44N5O8P) C, H, N.
δ -1.19. Anal.
3′-Azid o-3′-d eoxyth ym id in e 5′-((S)-2-(d od ecyloxy)p r o-
p yl p h osp h a te)) (11b): yield 62%. Anal. (C25H44N5O8P) C,
H, N.
3′-Azid o-3′-d eoxyth ym id in e 5′-((R)-1-m eth yl-2-(d od e-
1
cyloxy)eth yl p h osp h a te) (11c): yield 65%; H NMR δ 7.47