Ring-Expanded Nucleoside Analogues
J . Org. Chem., Vol. 63, No. 14, 1998 4579
for C45H39N3O3‚0.5H2O: C, 79.62; H, 5.94; N, 6.19. Found: C
79.50; H, 6.17; N, 6.20.
(m, 1H), 4.71 (s, 1H), 4.92 (t, 1H, J ) ca. 2 Hz, exchangeable),
5.58 (d, 1H, J ) 7.6 Hz), 7.71 (d, 1H, J ) 7.6 Hz), 11.34 (br s,
1H).
N4-Ben zoyl-O2-(2,3-d ih yd r oxyp r op yl)cytosin e (15). A
sample of 13a (1.31 g, 1.70 mmol) was dissolved in 80%
(aqueous) acetic acid (50 mL) and heated for 11 h at 60-65
°C. After removal of the solvent and re-evaporation with
added 1-butanol and then toluene, the residue was shaken
with a mixture of water and methylene chloride (50 mL each).
The aqueous layer was evaporated under reduced pressure to
give 15 (0.305 g, 62%), further purified by recrystallization
from ethyl acetate-methanol (5:1). Mp: 156-158 °C. 1H
NMR: δ 3.49 (t, 2H, J ) 5.6 Hz), 3.85 (m, 1H), 4.27 (dd, 1H,
J ) 10.8, 6.4 Hz), 4.37 (dd, 1H, J ) 6.4, 4.4 Hz), 4.70 (t, 1H,
J ) 5.6 Hz), 4.90 (d, 1H, J ) 5.2 Hz), 7.54 (t, 2H, J ) 7.6 Hz),
7.62 (t, 1H, J ) 7.2 Hz), 7.87 (d, 1H, J ) 5.4 Hz), 8.04 (d, 2H,
J ) 8.0 Hz), 8.52 (d, 1H, J ) 5.4 Hz), 11.14 (s, 1H). 13C NMR:
62.7, 68.5, 69.5, 104.3, 128.2, 128.3, 132.4, 133.3, 160.1, 160.2,
164.5, 167.0. Anal. Calcd for C14H15N3O4: C, 58.11; H, 5.23;
N, 14.53. Found: C, 57.88; H, 5.30; N, 14.37.
cis-5-F lu or o-1-(2-h yd r oxym et h yl-1,3-d ioxa n -5-yl)u r -
a cil (cis-5b): 71%. Mp: 207-208 °C. UV: λmax 266 nm. 1H
NMR: δ 3.43 (m, 2H), 4.13 (apparent d, 2H), 4.21 (apparent
d, 2H), 4.31 (s, 1H), 4.71 (t, 1H, J ) 4.0 Hz), 4.98 (t, 1H, J )
6.0 Hz), 8.39 (d, 1H, J ) 7.6 Hz), 11.94 (s, 1H). 13C NMR: δ
47.5, 62.5, 67.7, 101.0, 128.3 (d, 2J ) 34 Hz), 139.3 (d, 1J )
2
227 Hz), 149.6, 156.9 (d, J ) 26 Hz). Anal. Calcd for C9H11
-
FN2O5: C, 43.91; H, 4.50; N, 11.38. Found: C, 43.99; H, 4.51;
N, 11.36.
tr a n s-5-F lu or o-1-(2-h yd r oxym et h yl-1,3-d ioxa n -5-yl)-
u r a cil (tr a n s-5b) (estimated, 15%). 1H NMR: δ 3.94 (t, 2H,
J ) 11.0 Hz), 4.04 (dd, 2H, J ) 10.8, 4.8 Hz), 4.50 (m, 1H),
4.58 (t, 1H, J ) 4.4 Hz, exchangeable), 4.95 (t, 1H, J ) 6.4
Hz), 8.16 (d, 1H, J ) 7.2 Hz), 11.85 (s, 1H).
cis-1-(2-Hyd r oxym eth yl-1,3-d ioxa n -5-yl)th ym in e (cis-
5c): 76%. Mp: 230-231 °C. UV: λmax 271 nm. 1H NMR: δ
1.79 (s, 3H), 3.43 (m, 2H), 4.08 (apparent d, 2H), 4.22 (apparent
d, 2H), 4.30 (s, 1H), 4.71 (t, 1H, J ) 4.0 Hz), 4.97 (t, 1H, J )
6.4 Hz), 8.08 (s, 1H), 11.33 (s, 1H). 13C NMR: δ 12.3, 47.1,
62.5, 67.8, 101.0, 107.9, 139.4, 151.0, 163.7. Anal. Calcd for
O2-(2,3-Dih yd r oxyp r op yl)cytosin e (16). Compound 15
(0.134 g, 0.464 mmol) treated with methanolic ammonia as
for 14 gave a quantitative yield of 16, mp ) 129-131 °C from
ethyl acetate-MeOH (4:1). 1H NMR: δ 7.84 (d, 1H, J ) 7.2
Hz), 6.81 (br s, 2H), 6.06 (d, 1H, J ) 7.2 Hz), 4.89 (d, 1H, J )
4.8 Hz), 4.61 (t, 1H, J ) 6.0 Hz) 4.16 (dd, 1H, J ) 10.8, 4.4
Hz), 4.05 (dd, 2H, J ) 10.4, 6.0 Hz), 3.73 (m, 1H), 3.40 (t, 2H,
J ) 6.0 Hz). 13C NMR: δ 62.7, 67.6, 69.6, 99.1, 156.0, 164.8,
165.1. Anal. Calcd for C7H11N3O3: C, 45.40; H, 5.99; N, 22.69.
Found: C, 45.47; H, 5.99; N, 22.74.
C
10H14N2O5: C, 49.58; H, 5.83; N, 11.56. Found: C, 49.47; H,
5.77; N, 11.49.
tr a n s-1-(2-H yd r oxym et h yl-1,3-d ioxa n -5-yl)t h ym in e
(tr a n s-5c) (estimated, 18%). 1H NMR: δ 1.74 (s, 3H), 3.40
(m, 2H), 3.88-4.10 (m, 4H), 4.53 (m, 1H), 4.59 (t, 1H, J ) 4.6
Hz), ∼5 (v br s), 7.53 (s, 1H). 13C NMR: δ 12.2, 47.0, 62.4,
66.5, 100.9, 109.0, 137.6, 151.7, 164.9.
Gen er a l P r oced u r e for Cycloa ceta liza tion a n d Dep r o-
tection . cis-1-(2-Hyd r oxym eth yl-1,3-d ioxa n -5-yl)p yr im -
id in es (cis-5a -c). In a one-necked 10 mL flask with a
vacuum takeoff adapter, a stirred mixture of a 1-(1,3-dihy-
droxy-2-propyl)pyrimidine (9, 5.00 mmol), freshly distilled
benzoyloxyacetaldehyde22 (2.46 g, 15.0 mmol), and ca. 25 mg
of p-toluenesulfonic acid was heated (oil bath) at 75-80 °C
and 1-2 mmHg. The suspension became clear after about 1
h. When TLC of the mixture (chloroform-methanol, 9.5:0.5)
showed no pyrimidine starting material and a new product
spot (2-3 h), heating was discontinued, and the cooled mixture
was taken up in methylene chloride (50 mL), extracted with
saturated NaHCO3 solution (25 mL) and water (25 mL), and
dried over MgSO4. Removal of the solvent gave ca. 3.9 g of
crude material (product + aldehyde) that was chromato-
graphed over silica gel (75 g), affording 11 (3.1-4.6:1, cis:trans,
by NMR) on elution with 2% methanol in methylene chloride.
Product 11, a cis/trans mixture, was dissolved in methanol (200
mL), cooled to 0 °C, saturated with ammonia, and stirred at
room temperature for 15-22 h. Evaporation of the solvent
gave a mixure of 5 and benzamide, separated easily by passage
through a silica gel column (60 g) and elution with 2%
methanol in methylene chloride. Pure cis-5 eluted first,
followed by mixtures of cis- and trans-5. The cis products were
recrystallized from chloroform-methanol mixtures. A small
sample (∼2 mg) of trans-5c was obtained by thick layer
chromatography (silica gel, eluent chloroform-methanol 9:1,
100 mL + 2 mL benzene and 1 drop of acetic acid); similar
attempts to isolate pure samples of the other trans-5 com-
pounds were unsuccessful. Isolated yields of cis-5 are given
below; yields of trans-5 are estimated from the NMR spectra
of the crude cis/trans mixtures, using the integrated values of
the pyrimidinyl C-5 signals of the cis and trans compounds
and the isolated yields of the cis. NMR data for the trans
compounds were obtained from binary mixtures rich in trans-
5, by subtraction of the pure cis isomer.
Gen er a l P r oced u r e for th e P r ep a r a tion of Cytosin -1-
yl Der iva tives (cis-5d ,e). A solution of 11a or 11b (7.10
mmol) and 1,2,4-triazole (6.83 g, 98.9 mmol) in anhydrous
pyridine (45 mL) was cooled to 0 °C. Under an atmosphere of
dry nitrogen, 4-chlorophenyl dichlorophosphate (5.0 g, 20.4
mmol) was added dropwise over 5 min to the cold, stirred
solution. After 4 h at 0 °C the ice bath was removed and the
orange solution was stirred at room temperature for 20 h.
Removal of solvent under reduced pressure gave tarry dark
material that was re-evaporated three times with added
toluene, dissolved in methylene chloride (100 mL), and ex-
tracted with four portions of water (50 mL each). The aqueous
layers were re-extracted twice with methylene chloride (50 mL
each), and the combined organic layers were dried (MgSO4)
and evaporated to give a brownish solid. Chromatography
(silica gel, 50 g) gave the triazole derivative cis/trans-12 which
was used without additional purification. Product 12 was
stirred at room temperature with concentrated ammonium
hydroxide (15 mL) and 1,4-dioxane (30 mL) for 20 h; solvent
was removed and the residue treated with saturated metha-
nolic ammonia (50 mL) for 24 h and then evaporated to give
cis/trans-5. Pure samples of cis-5d ,e were obtained by chro-
matography and elution with 2% methanol in methylene
chloride, along with cis/trans mixtures. Small amounts of the
uracil derivatives cis-5a and cis-5b were also isolated.
cis-1-(2-Hyd r oxym eth yl-1,3-d ioxa n -5-yl)cytosin e (cis-
5d ): 38%. Mp: 245-247 °C. UV: λmax 275 nm. 1H NMR: δ
3.37 (m, 2H), 4.05 (apparent d, 2H), 4.18 (apparent d, 2H),
4.32 (s, 1H), 4.69 (t, 1H, J ) 10.2 Hz), 4.94 (t, 1H, J ) 6.4 Hz),
5.73 (d, 1H, J ) 7.2 Hz), 6.99, 7.16 (br s’s, 2H, exchangeable),
8.12 (d, 1H, J ) 7.2 Hz). 13C NMR: δ 47.8, 62.7, 67.9, 93.0,
101.2, 144.0, 155.4, 165.4. Anal. Calcd for C9H13N3O4: C,
47.57; H, 5.77; N, 18.49. Found: C, 47.63; H, 5.74; N, 18.46.
tr a n s-1-(2-H yd r oxym et h yl-1,3-d ioxa n -5-yl)cyt osin e
(tr a n s-5d ) (estimated, 7%). 1H NMR: δ ∼3.4 (ca. 2H, partially
covered), 3.85 (t, 2H, J ) 10.4 Hz), 3.93 (dd, 2H, J ) 10.4, 7.2
Hz), 4.59 (t, 1H, J ) 4.8 Hz), 4.60 (m, 1H), 4.93 (t, 1H, J ) 4.8
Hz), 5.71 (d, 1H, J ) 7.4 Hz), 7.13, 7.26 (br s’s, 2H, exchange-
able), 7.65 (d, 1H, J ) 7.4 Hz).
cis-1-(2-Hyd r oxym eth yl-1,3-d ioxa n -5-yl)u r a cil (cis-5a ):
62%. Mp: 191-192 °C. UV: λmax 266 nm. 1H NMR: δ 3.39
(m, 2H), 4.14 (apparent d, 2H), 4.21 (apparent d, 2H), 4.29 (br
s, 1H), 4.70 (t, 1H, J ) 3.7 Hz), 4.92 (t, 1H, J ) ca. 2 Hz,
exchangeable), 5.60 (d, 1H, J ) 7.9 Hz), 8.16 (d, 1H, J ) 7.9
Hz), 11.32 (s, 1H). 13C NMR: δ 47.5, 62.4, 67.7, 100.6, 101.1,
143.7, 150.9, 163.2. Anal. Calcd for C9H12N2O5: C, 47.35; H,
5.30; N, 12.28. Found: C, 47.47; H, 5.30; N, 12.18.
cis-5-F lu or o-1-(2-h yd r oxym et h yl-1,3-d ioxa n -5-yl)cy-
tosin e (cis-5e): 39%. Mp: 253-255 °C. UV: λmax 283 nm.
1H NMR: δ 3.42 (dd, 2H, J ) 4.0, 6.0 Hz), 4.08 (apparent d,
2H), 4.19 (apparent d, 2H), 4.30 (s, 1H), 4.70 (t, 1H, J ) 4.0
Hz), 4.94 (t, 1H, J ) 6.2 Hz), 7.50, 7.65 (br s’s, 2H), 8.27 (d,
1H, J ) 7.6 Hz). 13C NMR: δ 48.2, 62.5, 67.8, 101.1, 128.8 (d,
tr a n s-1-(2-Hydr oxym eth yl-1,3-dioxan -5-yl)u r acil (tr an s-
5a ) (estimated, 11%). 1H NMR: δ 3.89-4.05 (m, 4H), 4.51