2
252 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 9
Brief Articles
(
multiplet), and dd (double of doublets). UV spectra were obtained
(-)-(2S,4S)-1-[2-(Hydroxymethyl)-1,3-dioxolan-4-yl]-4-N-de-
2
5
on a Beckman DU-650 spectrophotometer. Optical rotations were
measured on a JASCO DIP-370 digital polarimeter. TLC was
performed on Uniplates (silica gel) purchased from Analtech. Co.
and Elemental analysis were performed by Atlantic Microlab Inc.,
Norcross, GA. All commercially available anhydrides were used
without further purification. Cyclopropanecarboxylic, cyclopenthan-
ecarboxylic, and cyclohexanecarboxylic anhydrides were synthe-
sized according to a reported procedure and used without further
purification.14 4-Fluoro, 4-chloro, 4-bromobenzoic anhydride, as
well as 2,4-dichlorobenzoic anhydride, were synthesized according
canoyl-cytosine (6f): Yield ) 66%; mp 141.0-143.0 °C; [R]
D
-35.59 (c 0.028, MeOH); UV (H
246 nm (ꢀ 13056 pH 7.4), 246 nm (ꢀ 8256 pH 11); H NMR
(CDCl
2
O) λmax 246 nm (ꢀ 11850 pH 2),
1
3
) δ 8.49 (d, 1H, J ) 7.32 Hz), 7.44 (d, 1H, J ) 7.32 Hz),
6.19 (m, 1H), 5.12 (m, 1H), 4.33 (m, 1H), 4.24 (m, 1H), 3.97 (m,
2H), 2.45 (t, 2H, J ) 7.32 Hz), 1.66 (m, 2H), 1.29 (m, 12H), 0.88
(t, 3H, J ) 7.32 Hz); 13C NMR (CDCl
) δ 173.6, 162.7, 155.6,
3
145.2, 105.7, 96.3, 83.5, 72.7, 61.0, 37.8, 31.9, 29.4, 29.3, 29.2,
-1
29.1, 24.9, 22.7, 14.1; IR (neat) 1690, 1650, 1553, 1499 cm
.
(-)-(2S,4S)-1-[2-(Hydroxymethyl)-1,3-dioxolan-4-yl]-4-N-lau-
15
27
to a reported procedure.
ryl-cytosine (6g): Yield ) 54%; mp 137.0-138.5 °C; [R]
D
1
Chemical Synthesis. General Procedure for the Parallel
Solution-Phase Synthesis of 4-(N-Acyl-substituted)-L-OddC Pro-
drugs (6a-t). L-1,3-Dioxolane-cytidine 5 (2 g) was dissolved in
anhydrous MeOH (20 mL) and 1 mL of the solution (100 mg, 1
equiv of 5) was added to each microfrit-equipped reaction vessel,
followed by 9 mL of methanol. The appropriate anhydrides (3
equiv) were then added, and the reaction mixture was stirred
vigorously (upward stroke ) 50%, time ) 1 s) at 55 °C for 6 h in
an Argonaut Quest 210 organic synthesizer. After 6 h, the reaction
vessels were drained, and the collected crude material was
evaporated to dryness under reduced pressure and purified on a
short flash column (gradient elution, 60% hexane/40% ethyl
acetate-100% ethyl acetate).
-61.75 (c 0.039, MeOH); UV (MeOH) λmax 241 nm (ꢀ 7442); H
NMR (CDCl ) δ 8.48 (d, 1H, J ) 7.32 Hz), 7.45 (d, 1H, J ) 7.32
3
Hz), 6.19 (m, 1H), 5.12 (m, 1H), 4.33 (m, 1H), 4.24 (m, 1H), 3.97
(m, 2H), 2.46 (t, 2H, J ) 7.32 Hz), 1.66 (m, 2H), 1.25 (m, 16H),
0.88 (t, 3H, J ) 7.32 Hz); 13C NMR (CDCl
) δ 173.6, 162.7, 155.7,
3
145.2, 105.8, 96.3, 83.5, 72.7, 61.0, 37.7, 31.9, 29.6, 29.5, 29.4,
-
1
29.1, 24.9, 22.7, 14.1; IR (neat) 1690, 1650, 1553, 1499 cm
.
(-)-(2S,4S)-1-[2-(Hydroxymethyl)-1,3-dioxolan-4-yl]-4-N-palm-
2
9
itoyl-cytosine (6h): Yield ) 23%; mp 134.5-135.5 °C; [R]
D
1
-79.34 (c 0.02, MeOH); UV (MeOH) λmax 244 nm (ꢀ 11 145); H
NMR (CDCl ) δ 8.46 (d, 1H, J ) 7.32 Hz), 7.43 (d, 1H, J ) 7.32
3
Hz), 6.19 (m, 1H), 5.13 (m, 1H), 4.34 (m, 1H), 4.26 (m, 1H), 3.98
(m, 2H), 2.42 (t, 2H, J ) 7.32 Hz), 1.66 (m, 2H), 1.25 (m, 24H),
(
-)-(2S,4S)-1-[2-(Hydroxymethyl)-1,3-dioxolan-4-yl]-4-N-acetyl-
0.88 (t, 3H, J ) 7.32 Hz); 13C NMR (CDCl
3
) δ 162.4, 150.0, 145.0,
24
cytosine (6a): Yield ) 92%; mp 176.0-178.0 °C; [R]
(
1
(
2
1
1
D
-68.005
105.6, 96.0, 83.6, 72.8, 61.1, 37.9, 31.9, 29.7, 29.6, 29.5, 29.4, 29.3,
-
1
c 0.04, MeOH); UV (H
6 703 pH 7.4), 270 nm (ꢀ 9760 pH 11); H NMR (CDCl
2
O) λmax 246 nm (ꢀ 9033 pH 2), 246 nm (ꢀ
29.1, 24.9, 22.7, 14.1; IR (neat) 1690, 1651, 1553, 1499 cm
.
1
3
) δ 8.60
(-)-(2S,4S)-1-[2-(Hydroxymethyl)-1,3-dioxolan-4-yl]-4-N-
2
9
d, 1H, J ) 7.32 Hz), 6.24 (m, 1H), 5.12 (m, 1H), 4.33-4.25 (m,
stearoyl-cytosine (6i): Yield ) 20%; mp 131-133 °C; [R]
-9.60 (c 0.5%, CHCl ); UV (H O pH)7) λmax 240 nm (ꢀ 5593);
D
H), 3.90 (m, 2H), 2.21 (s, 3H); 13C NMR (CD
63.1, 156.8, 145.1, 106.1, 96.2, 83.4, 72.0, 60.2, 23.2; IR (neat)
3
OD) δ 180.1, 171.6,
3
2
1
H NMR (CDCl ) δ 8.46 (d, 1H, J ) 7.4 Hz), 8.19 (bs, 1H), 7.43
3
-
1
716, 1654, 1562, 1494 cm
(d, 1H, J ) 7.4 Hz), 6.19 (m, 1H), 5.14 (m, 1H), 4.35 (m, 1H),
(
-)-(2S,4S)-1-[2-(Hydroxymethyl)-1,3-dioxolan-4-yl]-4-N-bu-
4.27 (m, 1H), 3.99 (m, 2H), 2.40 (t, 2H, J ) 7.40 Hz), 1.68 (m,
24
13
tyryl-cytosine (6b): Yield ) 82%; mp 118.0-120.0 °C; [R]
48.43 (c 0.042, MeOH); UV (H O) λmax 246 nm (ꢀ 16 430 pH
), 246 nm (ꢀ 18 353 pH 7.4), 244 nm (ꢀ 10 155 pH 11); H NMR
CDCl
D
2H), 1.25 (m, 28H), 0.88 (t, 3H, J ) 7.00 Hz); C NMR (CDCl
3
)
-
2
(
6
2
δ 173.4, 162.4, 155.5, 145.1, 105.6, 96.1, 83.6, 72.7, 61.0, 37.8,
31.9, 29.8, 29.7, 29.6, 29.5, 29.4, 29.3, 29.1, 24.9, 22.7, 14.2; IR
1
-
1
3
) δ 8.49 (d, 1H, J ) 7.33 Hz), 7.44 (d, 1H, J ) 7.33 Hz),
(neat) 1689, 1650, 1553, 1497 cm
.
.20 (m, 1H), 5.12 (m, 1H), 4.34-4.23 (m, 2H), 3.97 (m, 2H),
(-)-(2S,4S)-1-[2-(Hydroxymethyl)-1,3-dioxolan-4-yl]-4-N-arachi-
2
9
2
.45 (t, 2H, J ) 7.32 Hz), 1.70 (m, 2H), 0.97 (t, 3H, J ) 7.32 Hz);
doyl-cytosine (6j): Yield ) 15%; mp 127-130 °C; [R ]
D
-6.41
1
1
3
C NMR (CDCl
3
) δ 171.6, 162.5, 155.6, 144.9, 105.7, 96.2, 83.6,
(c 0.5%, MeOH); UV (H
2
O pH)7) λmax 240 nm (ꢀ 8412); H NMR
) δ 8.47 (d, 1H, J ) 7.4 Hz), 8.36 (br s, 1H), 7.43 (d, 1H,
-1
7
2.7, 61.1, 39.6, 18.3, 13.6; IR (neat) 1693, 1651, 1554, 1500 cm
.
(CDCl
3
(
-)-(2S,4S)-1-[2-(Hydroxymethyl)-1,3-dioxolan-4-yl]-4-N-valer-
J ) 7.4 Hz), 6.19 (m, 1H), 5.14 (m, 1H), 4.35 (m, 1H), 4.26 (m,
1H), 3.99 (m, 2H), 2.41 (t, 2H, J ) 7.60 Hz), 1.66 (m, 2H), 1.25
24
yl-cytosine (6c): Yield ) 84%; mp 143.0-144.0 °C; [R]
(
(
D
-53.34
(m, 32H), 0.88 (t, 3H, J ) 6.60 Hz); 13C NMR (CDCl
) δ 173.4,
c 0.5, MeOH); UV (H
ꢀ 14 436 pH 7.4), 246 nm (ꢀ 12 188 pH 11); H NMR (CDCl
2
O) λmax 246 nm (ꢀ 13 393 pH 2), 246 nm
3
1
3
) δ
.49 (d, 1H, J ) 7.32 Hz), 7.44 (d, 1H, J ) 7.32 Hz), 6.20 (m,
H), 5.12 (m, 1H), 4.32 (m, 1H), 4.23 (m, 1H), 3.97 (m, 2H), 2.47
162.5, 155.6, 145.1, 105.7, 96.2, 83.6, 77.3, 73.7, 61.0, 37.8, 29.75,
29.73, 29.7, 29.66, 29.54, 29.5, 29.4, 29.37, 29.1, 24.9, 22.7, 14.2;
8
1
(
-
1
IR (neat) 1699, 1656, 1553, 1499 cm
.
t, 2H, J ) 7.32 Hz), 1.65 (m, 2H), 1.36 (m, 2H); 13C NMR (CDCl
(-)-(2S,4S)-1-[2-(Hydroxymethyl)-1,3-dioxolan-4-yl]-4-N-be-
3
)
2
9
δ 173.8, 162.8, 155.6, 145.2, 105.8, 96.4, 83.5, 72.6, 61.0, 37.4,
2
henoyl-cytosine (6k): Yield ) 10%; mp 128-130 °C; [R]
-79.34 (c 0.5%, CHCl ); UV (H O pH ) 7) λmax 241 nm (ꢀ 7618);
D
6.9, 22.2, 13.7; IR (neat) 1690, 1648, 1552, 1494 cm-
1
.
3
2
1
(
-)-(2S,4S)-1-[2-(Hydroxymethyl)-1,3-dioxolan-4-yl]-4-N-hep-
3
H NMR (CDCl ) δ 8.51 (br s, 1H), 8.47 (d, 1H, J ) 7.5 Hz), 7.43
25
tanoyl-cytosine (6d): Yield ) 84%; mp 151.0-153.0 °C; [R]
56.82 (c 0.044, MeOH); UV (H O) λmax 246 nm (ꢀ 14 223 pH
), 246 nm (ꢀ 15 665 pH 7.4), 246 nm (ꢀ 14 519 pH 11); H NMR
CDCl
D
(d, 1H, J ) 7.5 Hz), 6.19 (m, 1H), 5.13 (m, 1H), 4.35 (m, 1H),
-
2
(
2
4.26 (m, 1H), 3.98 (m, 2H), 2.42 (t, 2H, J ) 7.75 Hz), 1.67 (m,
1
13
2H), 1.25 (m, 36H), 0.88 (t, 3H, J ) 7.25 Hz); C NMR (CDCl
3
)
3
) δ 8.49 (d, 1H, J ) 7.32 Hz), 7.44 (d, 1H, J ) 7.32 Hz),
δ 173.2, 162.4, 145.1, 105.6, 96.1, 83.6, 83.58, 77.3, 72.8, 61.0,
37.9, 32.0, 29.8, 29.75, 29.7, 29.65, 29.5, 29.4, 29.35, 29.1, 24.9,
22.7, 14.2; IR (neat) 1691, 1654, 1554, 1500 cm
6
2
(
1
1
.19 (m, 1H), 5.12 (m, 1H), 4.33 (m, 1H), 4.23 (m, 1H), 3.97 (m,
-
1
H), 2.46 (t, 2H, J ) 7.32 Hz), 1.66 (m, 8H), 1.28 (m, 4H), 0.89
.
t, 3H, J ) 7.32 Hz); 13C NMR (CDCl
) δ 173.7, 162.7, 155.6,
(-)-(2S,4S)-1-[2-(Hydroxymethyl)-1,3-dioxolan-4-yl]-4-N-cy-
3
26
45.2, 105.8, 96.4, 83.5, 72.7, 61.0, 37.7, 31.5, 28.8, 24.8, 22.5,
4.0; IR (neat) 1693, 1649, 1553, 1494 cm-1
-)-(2S,4S)-1-[2-(Hydroxymethyl)-1,3-dioxolan-4-yl]-4-N-
clopropyl-cytosine (6l): Yield ) 66%; mp 169.0-170.5 °C; [R]
-62.83 (c 0.033, MeOH); UV (H O) λmax 247 nm (ꢀ 16 457 pH
2), 247 nm (ꢀ 18 447 pH 7.4), 247 nm (ꢀ 16 191 pH 11); H NMR
(CDCl ) δ 8.48 (d, 1H, J ) 7.32 Hz), 7.41 (d, 1H, J ) 7.32 Hz),
6.21 (m, 1H), 5.10 (m, 1H), 4.31 (m, 1H), 4.23 (m, 1H), 3.95 (m,
D
.
2
1
(
27
nonanoyl-cytosine (6e): Yield ) 72%; mp 135.0-137.0 °C; [R]
51.58 (c 0.03, MeOH); UV (H O) λmax 246 nm (ꢀ 14 101 pH 2),
46 nm (ꢀ 15 201 pH 7.4), 246 nm (ꢀ 11 582 pH 11); H NMR
CDCl
D
3
-
2
(
2
1
13
2H), 1.86 (m, 1H), 1.07 (m, 2H), 0.92 (m, 2H); C NMR (CDCl
3
)
) δ 8.49 (d, 1H, J ) 7.81 Hz), 7.45 (d, 1H, J ) 7.81 Hz),
δ 174.6, 162.7, 155.8, 145.2, 105.9, 96.7, 83.4, 72.5, 61.0, 15.9,
3
-
1
6
2
(
1
1
.19 (m, 1H), 5.12 (m, 1H), 4.33 (m, 1H), 4.23 (m, 1H), 3.97 (m,
9.7; IR (neat) 1709, 1651, 1560, 1491 cm .
H), 2.46 (t, 2H, J ) 7.32 Hz), 1.66 (m, 2H), 1.28 (m, 10H), 0.88
(-)-(2S,4S)-1-[2-(Hydroxymethyl)-1,3-dioxolan-4-yl]-4-N-cy-
t, 3H, J ) 7.32 Hz); 13C NMR (CDCl
) δ 173.7, 162.7, 155.6,
clopentyl-cytosine (6m): Yield ) 58%; mp 59.0 °C (decomposi-
3
2
7
45.2, 105.8, 96.3, 83.5, 72.7, 61.0, 37.7, 31.8, 29.1, 24.9, 22.6,
4.1; IR (neat) 1689, 1649, 1553, 1496 cm-1
tion); [R]
D
2
-31.48 (c 0.031, MeOH); UV (H O) λmax 247 nm (ꢀ
.
15 014 pH 2), 247 nm (ꢀ 16 397 pH 7.4), 247 nm (ꢀ 12 296 pH