Phosphonate Derivatives of Cytidine and Cytosine Arabinoside
compound 9 (5 mg). For compound 13: 1H NMR δ 10.04 (s,
(d, J ) 7.4 Hz, 1H), 5.45 (d, J ) 4.3 Hz, 1H), 4.68 (dd, J ) 4.3,
4.3 Hz, 1H), 4.19 (dd, J ) 4.5, 4.3 Hz, 1H), 4.15 (m, 1H), 4.00
(br d, J ) 11.8 Hz, 1H), 3.72 (br d, J ) 12.2 Hz, 1H), 3.70 (br
1
H), 7.69 (d, J ) 7.6 Hz, 1H), 7.46 (m, 2H), 7.36 (m, 4H), 5.81
(
d, J ) 2.5 Hz, 1H), 5.70 (dd, J ) 10.2, 5.0 Hz, 1H), 4.99 (dd,
J ) 6.7, 4.0 Hz, 1H), 4.87 (s, 1H), 4.85 (dd, J ) 6.7, 2.5 Hz,
1
3
)
(
1
5
(
3
s, 1H, exchanges with CD OD), 2.29 (s, 3H), 0.90 (s, 9H), 0.88
1
3
H), 4.50 (ddd, J ) 9.7, 5.0, 4.0 Hz, 1H), 4.00-3.64 (m, 4H),
(s, 9H), 0.08 (s, 6H), 0.06 (s, 3H), 0.03 (s, 3H); C NMR δ171.4,
163.2, 155.4, 147.9, 96.9, 96.2, 86.3, 73.5, 71.4, 61.5, 26.0 (6C),
25.2, 18.3, 18.2, -4.2, -4.5, -4.6, -4.7. Anal. Calcd for
.43 (s, 3H), 2.30 (s, 3H), 1.56 (s, 3H), 1.32 (s, 3H), 1.14 (t, J
1
3
7.2 Hz, 3H), 1.08 (t, J ) 7.4 Hz, 3H); C NMR δ 171.3, 169.2
d, J CP ) 3.8 Hz), 163.6, 154.9, 146.4, 135.7, 129.2, 128.8 (2C),
23 43 3 6 2
C H N O Si : C, 53.77; H, 8.44; N, 8.18. Found: C, 53.40;
H, 8.59; N, 8.09.
27.7 (2C), 115.0, 97.3, 94.9, 85.6, 84.6, 82.4, 81.4 (d, J CP
)
.9 Hz), 68.1 (d, J CP ) 164.4 Hz), 63.3 (d, J CP ) 7.2 Hz), 63.1
Dieth yl [1′-(5′(S)-Hyd r oxy-2′,3′-d i-O-ter t-bu tyld im eth -
4
d, J CP ) 6.4 Hz), 57.6, 27.3, 25.4, 25.2, 16.4 (d, J CP ) 4.1 Hz),
ylsilyl-â-D-r ibo-p en t a -1′,4′-fu r a n osyl)-N -a cet ylcyt osyl]-
3
1
1
6.3 (d, J CP ) 4.1 Hz); P NMR δ 15.9. Anal. Calcd for
11P: C, 53.20; H, 5.95; N, 6.89. Found: C, 53.00; H,
.16; N, 6.62.
S)-O-Meth yl Ma n d ela te Ester 14. A solution of epimeric
′-hydroxy phosphonates 9 and 10 (3:1, 143 mg, 0.31 mmol)
Cl was treated with EDC (61 mg, 0.32 mmol), DMAP
11 mg, 0.09 mmol), and (S)-(+)-O-methyl mandelic acid (41
5′-p h osp h on a te (20). DMSO (15 mL) was added to alcohol
17 (2.01 g, 3.9 mmol) and EDC (2.25 g, 11.7 mmol) suspended
in toluene (15 mL). Pyridine (0.48 mL, 5.9 mmol) and then
TFA (0.39 mL, 5.0 mmol) were added, and the reaction mixture
was allowed to stirr at room temperature for 6 h. After the
reaction was diluted by addition of diethyl ether (100 mL) and
washed with dilute acid (pH 3), the aqueous layer was
extracted with ether, and the combined organic layer was dried
27 36 3
C H N O
6
(
5
in CH
(
2
2
mg, 0.25 mmol), as described above for compound 13, to obtain
the O-methyl mandelic acid esters 13 (34 mg) and 14 (35 mg)
in a total yield of 79% based on recovered starting materials
4
(MgSO ) and concentrated in vacuo to give the crude aldehyde
18 (2.10 g).
9
1
and 10 (77 mg, 54%). For compound 14: 1H NMR δ 10.25 (s,
H), 8.26 (d, J ) 7.5 Hz, 1H), 7.58 (d, J ) 7.5 Hz, 1H), 7.30
To a stirred solution of diethyl phosphite (0.35 mL, 3.8
mmol) in THF (15 mL) at -78 °C was added LHMDS (1 M
THF solution, 3.6 mL) dropwise. After 15 min, a solution of
aldehyde 18 (925 mg, 1.8 mmol) in THF (5 mL) was added via
cannula. The reaction mixture was stirred at -78 °C for 2 h,
then allowed to warm to -20 °C and quenched by addition of
acetic acid in ether. The reaction mixture was first partitioned
between ethyl acetate and water, and the aqueous layer was
extracted with ethyl acetate. The combined ethyl acetate layer
(m, 3H), 7.23 (m, 2H), 5.72 (d, J ) 2.0 Hz, 1H), 5.61 (dd, J )
1
4
1
3.4, 3.2 Hz, 1H), 4.73 (s, 1H), 4.72 (m, 1H), 4.27-4.10 (m,
H), 4.02 (dd, J ) 6.5, 2.8 Hz, 1H), 3.72 (dd, J ) 6.5, 2.0 Hz,
H), 3.36 (s, 3H), 2.35 (s, 3H), 1.49 (s, 3H), 1.32 (m, 6H), 1.17
1
3
(
1
8
s, 3H); C NMR δ 172.0, 169.6 (d, J CP ) 3.6 Hz), 163.9, 155.6,
46.5, 136.0, 130.3, 129.8 (2C), 128.1 (2C), 114.7, 96.8, 95.8,
6.7, 86.0, 82.8, 81.5 (d, J CP ) 10.9 Hz), 68.9 (d, J CP ) 168.1
Hz), 64.1 (d, J CP ) 7.8 Hz), 64.0 (d, J CP ) 6.7 Hz), 57.8, 27.4,
4
was dried (MgSO ) and concentrated in vacuo. The residue was
2
5.8, 25.4, 17.1 (d, J CP ) 6.0 Hz), 17.0 (d, J CP ) 6.1 Hz); 31
NMR δ 16.2. Anal. Calcd for C27 11P: C, 53.20; H, 5.95;
N, 6.89. Found: C, 52.94; H, 5.98; N, 6.82.
1′-(5′(R)-Hyd r oxy-â-D-r ibo-p en ta -1′,4′-fu r a n osyl)cyto-
syl]-5′-p h osp h on ic Acid (11). To a stirred solution of phos-
phonate 9 (75 mg, 0.16 mmol) in CH Cl (10 mL) at 0 °C was
P
purified by flash chromatography with EtOAc to give 20 (403
mg), 19 (91 mg), and mixture of 20 and 19 (105.8 mg) in a
total 54% yield.
For compound 20: 1H NMR δ 10.21 (s, 1H), 8.34 (d, J ) 7.4
Hz, 1H), 7.42 (d, J ) 7.4 Hz, 1H), 5.60 (d, J ) 3.6 Hz, 1H),
4.51 (br t, J ) 3.0 Hz, 1H), 4.43 (br d, J ) 4.5 Hz, 1H), 4.27-
4.07 (m, 6H), 2.30 (s, 3H), 1.34 (t, J ) 7.2 Hz, 3H), 1.32 (t, J
) 7.2 Hz, 3H), 0.89 (s, 18H), 0.10 (s, 3H), 0.08 (s, 6H), 0.07 (s,
3H); 13C NMR δ 171.5, 163.3, 155.3, 147.2, 96.7, 94.6, 83.7,
73.8, 71.5 (d, J CP ) 13.1 Hz), 76.1 (d, J CP ) 163.1 Hz), 63.7 (d,
36 3
H N O
[
2
2
added TMSBr (0.65 mL, 4.92 mmol) dropwise via syringe and
then the reaction mixture was allowed to warm to room
temperature. The reaction mixture was stirred at room tem-
perature for 2 days, and then the volatiles were removed by
rotary evaporation. The residue was coevaporated with MeOH
three times and then washed with diethyl ether and ethyl
acetate to give a dark yellow solid. This solid was dissolved in
water and coevaporated with water three times to provide a
white solid that precipitated from cold water to afford a white
solid (49 mg, 93%). This white solid was dissolved in 100 mM
ammonium bicarbonate (1.5 mL) and lyophilized to give a
white solid. This material was dissolved in distilled water and
J
CP ) 7.5 Hz), 62.8 (d, J CP ) 7.5 Hz), 26.0 (6C), 25.1, 18.2,
18.2, 16.7 (d, J CP ) 5.2 Hz), 16.6 (d, J CP ) 5.7 Hz), -4.2, -4.3,
3
1
+
-4.8 (2C); P NMR δ 21.5; HRMS (ESI ) m/z calcd for
+
C
27
H
53
N
3
O
9
PSi
2
(M + H) 650.3058, found 650.3063.
Dieth yl [1′-(5′(S)-Hyd r oxy-â-D-r ibo-p en ta -1′,4′-fu r a n o-
4
syl)-N -a cetyl cytosyl]-5′-p h osp h on a te (21). TBAF (1 M
solution in THF, 2.75 mL, 2.75 mmol) was added to a solution
of phosphonate 20 (357 mg, 0.55 mmol) in THF (5 mL) at room
temperature. After the solution was stirred for 4 h, the solvent
was removed in vacuo and the residue was purified by flash
chromatography (15% MeOH in EtOAc) to give compound 21
lyphoilized, and the process was repeated twice to give the
1
phosphonic acid 11: H NMR (D
2
O, DSS standard) δ 8.24 (d,
J ) 7.9 Hz, 1H), 6.25 (d, J ) 7.9 Hz, 1H), 5.95 (d, J ) 5.2 Hz,
1
1
1
9
H), 4.45 (m, 2H), 4.37 (dd, J ) 5.1 Hz, 1H), 4.14 (dd, J )
2.5, 2.5 Hz, 1H); 13C NMR (D
O) δ 162.1, 151.5, 147.2, 98.1,
1.6, 88.3 (d, J CP ) 13.2 Hz), 77.6, 71.7, 71.5 (d, J CP ) 152.6
(189 mg, 82%) as a white solid: H NMR (CD OD) δ 8.70 (d, J
3
2
) 7.4 Hz, 1H), 7.41 (d, J ) 7.4 Hz, 1H), 5.87 (d, J ) 1.7 Hz,
1H), 4.39 (m, 1H), 4.25-4.15 (m, 7H), 2.18 (s, 3H), 1.35 (t, J )
3
1
13
Hz); P NMR (D
P (M - H) 322.0440, found 322.0427.
-(2′, 3′-Di-O-ter t-bu tyld im eth ylsilyl-â-D-r ibo-p en ta -1′,
2
O) δ 16.2; HRMS (ESI) m/z calcd for
6.9 Hz, 3H), 1.31 (t, J ) 6.9 Hz, 3H); C NMR (CD OD) δ
3
-
C
9
H
13
N
3
O
8
173.2, 164.5, 158.1, 147.0, 97.8, 93.8, 84.6, 76.0, 70.6 (d, J
)
CP
1
12.1 Hz), 67.3 (d, J CP ) 168.7 Hz), 64.6 (d, J CP ) 7.2 Hz), 64.2
4
(d, J CP ) 6.6 Hz), 24.7, 17.0, 16.9; 31P NMR (CD OD) δ 23.3;
4
′-fu r a n osyl)-N -a cetylcytosin e (17). To a solution of pro-
3
1
6
HRMS (ESI
found 422.1330.
+
) m/z calcd for C H N O P (M + H) 422.1328,
+
tected cytidine 16 (9.86 g, 20.9 mmol) at reflux in MeOH (200
mL) was added Ac O (29.0 mL, 307 mmol) dropwise in 5
15 25
3
9
2
batches over 1 h. The reaction mixture was heated for 3 h,
allowed to cool to room temperature, and then stirred over-
night. The volatile materials were removed in vacuo and the
residue was partitioned between EtOAc and water. The
[1′-(5′(S)-Hyd r oxy-â-D-r ibo-p en ta -1′,4′-fu r a n osyl)cyto-
syl]-5′-p h osp h on ic Acid (12). To a stirred solution of phos-
phonate 21 (162 mg, 0.38 mmol) in CH Cl (4 mL) at 0 °C was
2 2
added TMSBr (0.76 mL, 5.8 mmol) dropwise via syringe. The
reaction mixture was allowed to warm to room temperature
and stirred for 24 h, and then the volatiles were removed by
rotary evaporation. The residue was dissolved in MeOH,
stirred for 40 min, and then concentrated in vacuo. The residue
was coevaporated with MeOH three times. The residue was
dissolved in a minimum of MeOH and then precipitated by
addition of EtOAc, and this process was repeated three times.
aqueous phase was neutralized by NaHCO
EtOAc. The combined EtOAc extract was dried (MgSO
3
and extracted with
) and
4
filtered, and the filtrate was concentrated in vacuo. The
residue was purified by flash chromatography (MeOH gradient
in CH
along with recovered compound 16 (0.52 g, 5%). For the alcohol
2 2
Cl ) to afford alcohol 17 (8.08 g, 75%) as a white solid,
1
1
7: H NMR δ 9.89 (br s, 1H), 8.08 (d, J ) 7.5 Hz, 1H), 7.44
J . Org. Chem, Vol. 67, No. 26, 2002 9337