dihydrofuran 19.26 The reaction of dihydrofuran 19 with
bis(trimethylsilyl)thymine in the presence of Me3SiI gave
20 in 92% yield, although the reaction rate was much
slower. Treatment of compound 20 with Bu4NF provided
the acyclonucleoside 21 related to d4T (1) in 97% yield.
The adenine derivative 22 was similarly produced in good
yield, by treating 19 with N6-benzoyl-N,69-bis(trimeth-
ylsilyl)adenine. No traces of the E isomer were observed
in either case.
In conclusion, a new methodology has been developed
for the stereo- and regioselective synthesis of acyclo-
nucleosides analogous to the antiviral dideoxydidehydro-
nucleosides. The Z-selectivity of this process involving
the intermediacy of reactive allylic iodides of Z-configu-
ration is particularly noteworthy.
Calcd for C11H13N2O4: C, 55.46; H, 5.88; N, 11.77. Found: C,
55.56; H, 6.02; N, 11.83.
9-[(2′Z)-2′-Bu ten -4′-h ydr oxy-1′-yl]- N6-ben zoyladen in e (14).
Starting from 2,5-dihydrofuran (9, 50 µL, 0.66 mmol) and (9)
bis(trimethylsilyl)adenine (1.98 mmol), the general procedure
for synthesizing acyclonucleosides was applied. The reaction was
maintained for 30 min to obtain compound 14 as a mixture (ratio
Z/E ) 5:1). Crystallization of the mixture (methanol) provided
110 mg (54%) of compound 14 as colorless crystals. Mp 174-
176 °C. 1H NMR (CD3OD) δ 8.57 (s, 1H), 8.27 (d, 2H), 8.24 (s,
1H), 7.54-7.42 (m, 3H), 5.85 (dtt, 1H, J ) 11.2, 6.0, 1.6), 5.79
(dtt, 1H, J ) 11.2, 6.4, 1.2), 5.35 (dd, 2H, J ) 6.0, 1.2), 5.21 (dd,
2H, J ) 6.4, 1.6). 13C NMR (CD3OD) δ 150.4, 148.9, 138.3, 134.6,
133.1, 130.9, 129.1, 126.4, 58.9, 48.2 (quaternary carbons not
included, except carbonyl). Anal. Calcd for C16H15N5O2: C, 62.14;
H, 4.86; N, 22.65. Found: C, 62.29; H, 5.00; N, 22.71.
9-[(2′Z)-2′-Bu t en -4′-h yd r oxy-1′-yl]-a d en in e (15).9 Com-
pound 14 (123 mg, 0.40 mmol) was dissolved in PrNH2 (10 M in
MeOH, 2.5 mL) and heated to reflux for 24 h. After evaporation
the residue was purified by chromatography in a short column
eluting with CH2Cl2/methanol 9:1 to give compound 15 as a
syrup (56 mg, 69% yield). 1H NMR (DMSO-d6) δ 8.12 (s, 1H),
8.08 (s, 1H), 7.75 (br s, 2H), 5.65-5.52 (m, 2H), 4.15-4.05 (m,
2H). 13C NMR (DMSO-d6) δ 152.0, 139.0, 131.7, 127.2, 57.0, 37.2.
(quaternary carbons not included). Anal. Calcd for C9H11N5O:
C, 52.68; H, 5.36; N, 34.15. Found: C, 52.51; H, 5.28; N, 34.02.
Exp er im en ta l Section
Gen er a l P r oced u r es. Melting points are uncorrected. Opti-
cal rotations were measured at 25 °C in 10-cm cells. 1H NMR
and 13C NMR spectra were recorded on 300 or 400 MHz (300,
75.4 and 400, 100.5 MHz, respectively) Varian equipment, with
CDCl3 as solvent, unless otherwise specified. Coupling constants
are given in hertz (Hz). Elemental analyses were determined
at the Servei de Recursos Cient´ıfics (Universitat Rovira i Virgili).
Flash column chromatography was performed using silica gel
60 A CC (40-63 mµ). Radial chromatography was performed
on 1-, 2-, or 4-mm plates of silica gel, depending on the amount
of product. Medium-pressure chromatography (MPLC) was
performed using silica gel 60 A CC (6-35 mµ). Band separation
was monitored by UV. TLC plates were prepared by using
Kieselgel 60 PF254. Solvents for chromatography were distilled
at atmospheric pressure prior to use. Reaction solvents were
purified and dried by using standard procedures.28
Gen er a l P r oced u r e for th e Syn th esis of Acyclon u cleo-
sid es fr om 2,5-Dih yd r ofu r a n Der iva tives. The 2,5-dihydro-
furan derivative (1 mmol) in anhydrous chloroform (1 mL) was
added to a solution of the silylated base (3 mmol) in anhydrous
chloroform (2 mL). Then iodotrimethylsilane (1.3 mmol) was
added and the reaction mixture was heated to reflux. The
reaction mixture was then allowed to cool at room temperature
and was poured into an aqueous solution of sodium bicarbonate.
The aqueous layer was extracted with ethyl acetate, and the
combination of extracts was washed with an aqueous solution
of sodium thiosulfate (10%) and dried over MgSO4 and the
solvent was evaporated under vacuum. The residue was purified
by chromatography or by crystallization to obtain the acyclo-
nucleoside.
1-[(2′Z)-2′-Bu t en -4′-a cet oxy-1′-yl]t h ym in e (12). Starting
from 2,5-dihydrofuran (9, 100 µL, 1.32 mmol) and bis(trimeth-
ylsilyl)thymine (3.96 mmol), the general procedure of acyclo-
nucleoside synthesis was applied maintaining the reaction at
reflux for 10 min, to obtain an inseparable mixture of 10 and
the E isomer (ratio Z/E ) 23:1). This mixture was then dissolved
in anhydrous pyridine (1 mL) and treated with an excess of acetic
anhydride (4 mmol). When the reaction was finished the mixture
was poured into ice/water and was extracted with dichlo-
romethane. The organic extracts were dried, evaporated under
vacuum, and purified by MPLC (hexane to hexane/ethyl acetate
1:3) to obtain 241 mg (77%) of acetylated products. Crystalliza-
tion of the mixture (ethyl acetate) provided compound 12 as
colorless crystals (212 mg, 68%). Mp 113-115 °C. 1H NMR
(CDCl3) δ 9.04 (s, 1H), 7.12 (q, 1H, J ) 1.2 Hz), 5.80 (dtt, 1H, J
) 10.8, 7.2, 1.2), 5.65 (dtt, 1H, J ) 10.8, 7.2 Hz, 1.2 Hz), 4.72
(dd, 2H, J ) 7.2, 1.6 Hz), 4.47 (dd, 2H, J ) 7.2, 1.2 Hz), 2.09 (s,
3H), 1.92 (d, 3H, J ) 1.2 Hz). 13C NMR (CDCl3) δ 170.9, 164.1,
150.8, 139.8, 128.5, 127.9, 111.1, 59.4, 44.3, 20.9, 12.3. Anal.
(3S ,5R )-3-P h e n ylse le n e n yl-5-(t er t -b u t yld ip h e n yl)sil-
yloxym eth yl-tetr a h yd r ofu r a n (18a ) a n d (3R,5R)-3-P h en -
ylselen en yl-5-(ter t-b u t yld ip h en yl)silyloxym et h yl-t et r a -
h yd r ofu r a n (18b). Compound 17 (510 mg, 1.50 mmol) was
dissolved in dichloromethane (23 mL) and then camphorsulfonic
acid (104 mg, 0.45 mmol) and N-phenylselenophthalimide (544
mg, 1.80 mmol) were added. The resulting reaction mixture was
heated to reflux for 12 h and was then left to cool at room
temperature and filtered over a silica gel pad and the solvent
evaporated under vacuum. The residue was purified by MPLC
using linear gradient (hexane to hexane/ethyl acetate 5/1), to
afford compounds 18a + 18b as a diastereoemeric mixture (ratio
25:75) (624 mg, 84%). Both compounds were separated by radial
chromatography (hexane/ethyl acetate 10:1).
18a (higher Rf): [R]25D -6.6 (c 1.70. CHCl3). 1H NMR (CDCl3)
δ 7.8-7.0 (m, 15H), 4.25-4.15 (m, 2H), 4.90-3.74 (m, 2H), 3.71
(dd, 1H, J ) 10.8, 4.5), 3.63 (dd, 1H, J ) 10.8, 4.2), 2.35 (ddd,
1H, J ) 13.2, 6.9, 6.0), 2.02 (ddd, 1 H, J ) 13.2, 7.5, 5.8), 1.04
(s, 9H). 13C NMR (CDCl3) δ: 135.7, 135.6, 134.2, 133.5, 129.7,
129.3, 129.2, 127.7, 127.6, 79.0, 74.4, 65.9, 39.3, 35.1, 26.7, 19.1.
Anal. Calcd for C27H32O2SeSi: C, 65.44; H, 6.51. Found: C,
65.53; H, 6.65.
1
18b: [R]25 +19.3 (c 0.914. CHCl3). H NMR (CDCl3) δ 7.8-
D
7.2 (m, 15H), 4.12 (dd, 1H, J ) 8.4, 6.6), 4.15-4.05 (m, 1H), 3.80
(td, 1H, J ) 8.4, 8.4, 1.5), 3.8-3.6 (m, 3H), 2.40 (dt, 1H, J )
12.9, 7.0), 1.88 (dtd, 1H, J ) 12.9, 8.1, 1.5), 1.06 (s, 9H). 13C
NMR (CDCl3) δ 135.7, 134.9, 134.2, 133.5, 129.7, 129.2, 127.7,
127.7, 127.6, 127.4, 79.6, 74.1, 65.9, 38.5, 35.1, 26.7, 19.1. Anal.
Calcd for C27H32O2SeSi: C, 65.44; H, 6.51. Found: C, 65.60; H,
6.51.
(5R)-5-(ter t-Bu tyld ip h en yl)silyloxym eth yl-2,5-d ih yd r o-
fu r a n (19). A mixture of compounds 18a + 18b (624 mg, 1.26
mmol) was dissolved in THF (8 mL) and cooled in an ice bath.
Then pyridine (8 drops) and 10% H2O2 (2.4 mL, 7.56 mmol) were
added. The reaction was stirred for 1 h and was then quenched
by adding water. The reaction mixture was extracted with
dichloromethane, and the organic phase was dried with mag-
nesium sulfate and evaporated under vacuum. The residue
obtained was purified by flash chromatography eluting with
hexane/ethyl acetate 5:1, to obtain compound 19 as a white solid
1
(391 mg, 92%). Mp 39-42 °C. [R]25 +69.3 (c 0.878. CHCl3). H
D
NMR (CDCl3) δ 7.8-7.3 (m, 10H), 5.95 (ddd, 1H, J ) 6.3, 3.6,
1.8), 5.82 (ddt, 1H, J ) 6.3, 2.5, 1.5), 4.91 (dddt, 1H, J ) 4.8,
4.8, 3.6, 1.8, 1.5), 4.69 (ddd, 1H, J ) 12.8, 2.5, 1.8), 4.63 (ddd,
1H, J ) 12.8, 2.5, 1.8), 3.72 (dd, 1H, J ) 10.5, 4.8), 3.68 (dd, 1H,
J ) 10.5, 4.8), 1.05 (s, 9H). 13C NMR (CDCl3) δ 135.7, 135.6,
133.7, 133.6, 129.6 (2 C), 127.8, 127.6 (2 C), 127.4, 86.6, 75.6,
(28) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals, 3rd ed.; Pergamon Press: Oxford, UK, 1989.
1174 J . Org. Chem., Vol. 68, No. 3, 2003