Synthesis of 2',3'-didehydro-2',3'-dideoxy-2'-fluoro apionucleosides as potential antiviral agents

Article abstract of DOI:10.1039/b203126d

Synthesis of novel 2',3'-didehydro-2',3'-dideoxy-2'-fluoro apionucleosides which combine the properties of 2',3'-didehydro-2',3'-dideoxy nucleosides and apionucleosides on the basis of a bioisosteric rationale is described.

Full text of DOI:10.1039/b203126d

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Synthesis of 2Ј,3Ј-didehydro-2Ј,3Ј-dideoxy-2Ј-fluoro apionucleosides
as potential antiviral agents
Hyung Ryong Moon,a Hea Ok Kimb and Lak Shin Jeong*a
1
a Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University,
Seoul 120-750, Korea. E-mail: lakjeong@ewha.ac.kr
b Division of Chemistry and Molecular Engineering, Seoul National University, Seoul 151-742,
Korea
Received (in Cambridge, UK) 28th March 2002, Accepted 18th June 2002
First published as an Advance Article on the web 3rd July 2002
Synthesis of novel 2Ј,3Ј-didehydro-2Ј,3Ј-dideoxy-2Ј-fluoro apionucleosides which combine the properties of 2Ј,3Ј-
didehydro-2Ј,3Ј-dideoxy nucleosides and apionucleosides on the basis of a bioisosteric rationale is described.
sides and apio nucleosides based on a bioisosteric rationale.
Introduction
While synthesizing our target nucleosides, we encountered
different chemistry from that experienced in the synthesis of 2.
Herein, we report the synthesis of 2Ј,3Ј-didehydro-2Ј,3Ј-
dideoxy-2Ј-fluoro apionucleosides and their related chemistry.
2Ј,3Ј-Didehydro-2Ј,3Ј-dideoxynucleosides1 have played
a
major role in the development of antiviral agents, especially
anti-AIDS agents. Among this class of compounds, 2Ј,3Ј-
didehydro-2Ј,3Ј-dideoxythymidine (d4T, Stavudine)2 is being
clinically used for the treatment of AIDS and AIDS-related
complex (ARC). This compound exhibits anti-AIDS activity by
inhibiting reverse transcriptase and/or terminating the viral
DNA chain, after being converted into its corresponding
triphosphate.3 However, this compound suffers from side effects
such as peripheral neuropathy and from the appearance of
d4T-resistant strains.4
Results and discussion
Our original plan to synthesize the target nucleosides was to
utilize the method used in the synthesis of 2Ј,3Ј-didehydro-
2Ј,3Ј-dideoxy apionucleosides (2),8 as shown in Scheme 1, but
this was not successful.
Recently, Chu and coworkers have published the synthesis
and antiviral activity of - and -2Ј,3Ј-didehydro-2Ј,3Ј-
dideoxy-2Ј-fluoro nucleosides (1)5 (Fig. 1). Among them, the
Fig. 1 The rationale for the design of the desired nucleosides.
-cytidine, -thymidine, and -uridine analogues showed weak
to moderate anti-HIV-1 activity, while -cytidine, -5-fluoro-
cytidine and -adenosine derivatives exhibited moderate to
potent anti-HIV-1 activity in PBM cells.
A nucleoside resulting from moving the 4Ј-hydroxymethyl
group of 2Ј,3Ј-dideoxynucleosides to the C3Ј-position is called
an apiodideoxynucleoside.6 Among this class of nucleosides,
the adenine derivative was reported to show anti-HIV-1 activity
comparable to 2Ј,3Ј-dideoxyadenosine (ddA)7 and the 2Ј,3Ј-
didehydro-2Ј,3Ј-dideoxy apio analogue (2)8 was found to show
potent anti-HCMV activity.
Scheme 1
1,3-Dihydroxyacetone dimer was protected as the disilyl
ether 4, which was converted into the fluoro ester 59 (87%),
using a Horner–Emmons olefination. However, lactonisation
of 5 under aqueous acidic conditions or in the presence of
n-tetrabutylammonium fluoride failed to give the desired
α,β-unsaturated fluorolactone 6, but instead resulted in
extensive decomposition. This finding is in sharp contrast with
the case of no fluorine at the α position of α,β-unsaturated
fluoroester 5.
Therefore, based on these findings, it was of interest to us to
synthesize the target compound 3 which would combine the
properties of 2Ј,3Ј-didehydro-2Ј,3Ј-dideoxy-2Ј-fluoro nucleo-
Since the unsuccessful lactonisation is probably due to the
low reactivity of the ester group, we decided to change the ester
group to the more reactive aldehyde, as shown in Scheme 2.
1800
J. Chem. Soc., Perkin Trans. 1, 2002, 1800–1804
This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b203126d

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acetylcytosine in the presence of TMSOTf at 0 ЊC to give the
protected nucleosides 10 (23%) and 11 (31%), respectively
(Scheme 3). Low yields of condensation are attributed to the
Scheme 2
Reduction of ester 5 with DIBAL-H gave the aldehyde 7 in
quantitative yield. Cyclisation of 7 using p-TsOH in aqueous
THF gave the dihydrofuran derivative as the main product,
instead of producing the desired lactol 8. Use of n-
tetrabutylammonium fluoride in the cyclisation resulted in
many spots due to decomposed products on TLC, and in low
yield; however, the use of triethylamine trihydrofluoride gave
the desired lactol 8 in 63% yield. The lactol 8 was treated with
acetic anhydride and triethylamine to afford the diacetate 9
(67%). Since the diacetate 9 was unstable during storage or
during the silica gel column purification, it was used directly for
the condensation after aqueous work-up or purification by
short-pad silica gel column chromatography. It is interesting to
note that phenylselenenyl chemistry was utilised to insert the
double bond when the fluorine atom was absent at α position of
fluorolactone 6 as the reduction of this lactone with DIBAL-H
yielded the linear allylic alcohol, instead of giving the required
lactol. This clearly indicates that the electronegative fluorine
atom in this case reported herein played a major role in lactol
formation.8
Scheme 3
aromatisation of the diacetate 9, forming the dihydrofuran
derivative 12 as the major product. Treatment of 10 and 11 with
methanolic ammonia at RT afforded the final nucleosides 13
and 14, respectively.
For the synthesis of the purine nucleoside (Scheme 4),
diacetate 9 was condensed with silylated N6-benzoyladenine in
the presence of TMSOTf at 0 ЊC to give the protected nucleo-
side 15a (24%) and the N-7 isomer 15b (7%). As in the case of
pyrimidine nucleosides, the aromatized compound 12 was also
produced as a major product (45%). Deprotection of 15a and
15b with methanolic ammonia afforded the desired N-9 isomer
16a and the N-7 isomer 16b, respectively. The regioisomers were
easily confirmed by the comparison of the UV literature data10
of N-9 isomer 16a [λmax(MeOH)/nm 258] and N-7 isomer 16b
[λmax(MeOH)/nm 270]. It is also of interest to note that in the
case of 2Ј,3Ј-dideoxy-2Ј,3Ј-didehydro apionucleosides, cytosine
Diacetate 9 was condensed with silylated thymine and N4-
Scheme 4
J. Chem. Soc., Perkin Trans. 1, 2002, 1800–1804
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and adenine derivatives could not be obtained due to the
decomposition at the final deprotection step,8 indicating that
the electronegative fluorine played a major role in stabilizing the
final nucleosides in the 2Ј-fluoro substituted nucleosides.11
The final nucleosides 13, 14, and 16a were tested for antiviral
activity against several viruses such as HIV-1, HSV-1, HSV-2,
and polio virus. All tested compounds exhibited neither anti-
(2 H, d, J 3.6, TBSOCH2), 4.74 (2 H, d, J 2.0, TBSOCH2); m/z
(EI-LR) 349 (Mϩ Ϫ C4H9), 115, 105, 91, 73; δF(376 MHz;
MeOH-d4) Ϫ124.73.
4-(tert-Butyldimethylsilyloxy)-3-(tert-
butyldimethylsilyloxymethyl)-2-fluorobut-2-enal (7)
Diisobutylaluminium hydride (1.6 cm3, 1.6 mmol, 1.0 M
solution in toluene) was added dropwise to a stirred solution of
compound 5 (572 mg, 1.41 mmol) in toluene (6 cm3) at Ϫ78 ЊC
and the reaction mixture was stirred at the same temperature
for 1 h. After the successive addition of methanol (1.6 cm3),
hexane (3 cm3) and ethyl acetate (3 cm3), the mixture was
allowed to warm to RT and stirred for 5 h. The mixture was
then filtered through Celite and the filtrate evaporated under
reduced pressure. The colourless oil was purified by silica gel
column chromatography using hexane and ethyl acetate (25 : 1)
as the eluent to give the title compound 7 (509 mg, 100%) as a
colourless oil. (Found: C, 56.45; H, 9.98. C17H35FO3Si2 requires
C, 56.31; H, 9.73%); δH(400 MHz; CDCl3; Me4Si) 0.09 (6 H, s,
2 × CH3), 0.11 (6 H, s, 2 × CH3), 0.91 [18 H, s, 2 × (CH3)3C],
4.48 (2 H, d, J 3.2, TBSOCH2), 4.65 (2 H, d, J 3.6, TBSOCH2),
9.99 [1 H, d, J 18.4, C(O)H].
viral activity nor cytotoxicity up to 100 µg mlϪ1
.
In summary we have synthesized novel 2Ј,3Ј-didehydro-2Ј,3Ј-
dideoxy-2Ј-fluoro apionucleosides via lactol formation from an
α,β-unsaturated fluoroaldehyde as a key step, starting from 1,3-
dihydroxyacetone. While synthesizing the final nucleosides, we
found that the synthetic method is very different from that of
the reported 2Ј,3Ј-didehydro-2Ј,3Ј-dideoxy apionucleosides
with regard to lactonisation, lactol formation and stability of
the final nucleosides, which are caused by the presence of the
electronegative fluorine atom.
Experimental
General methods
1H NMR (250, 400 MHz), 13C NMR (100 MHz), and 19F NMR
(376 MHz) spectra were measured for samples in CDCl3 or
MeOH-d4 and chemical shifts are reported in parts per million
(δ) downfield from tetramethylsilane as internal standard.
Coupling constants (J) are given in Hz. Elemental analyses
were performed at the general instrument laboratory of
Ewha Womans University, Korea. TLC was performed on
Merck precoated 60F254 plates. Column chromatography
was performed using silica gel 60 (230–400 mesh, Merck).
All anhydrous solvents were distilled over CaH2, P2O5 or
Na-benzophenone prior to use.
( )-Acetic acid 5-acetoxy-4-fluoro-2,5-dihydrofuran-3-ylmethyl
ester (9)
Triethylamine trihydrofluoride (2.71 cm3, 16.63 mmol) was
added dropwise to a stirred solution of compound 7 (1.004 g,
2.77 mmol) in methylene chloride (22 cm3) at 0 ЊC and the
reaction mixture was stirred at RT overnight to produce the
lactol 8 (239 mg, 63%) as a colourless syrup. (Found: C, 44.38;
H, 5.07. C5H7FO3 requires C, 44.78; H, 5.26%); δH(400 MHz;
MeOH-d4; Me4Si) 4.16 (1 H, d, J 13.2, HOCHH), 4.23 (1 H, d,
J 13.2, HOCHH ), 4.47 (1 H, dd, J 5.6 and 12.0, OCHH), 4.62
(1 H, dt, J 4.8 and 12.0, OCHH ), 5.69 (1 H, t, J 4.4, anomeric
H).
1,3-Bis-(tert-butyldimethylsilyloxy)propan-2-one (4)
Triethylamine (15.3 cm3, 110.49 mmol) and acetic anhydride
(5.3 cm3, 56.17 mmol) were added to 8 (239 mg, 1.78 mmol) at
0 ЊC and the reaction mixture was stirred at RT overnight. The
mixture was extracted with ethyl acetate (100 cm3). The organic
layer was dried and evaporated under reduced pressure. The
pale yellow syrup was purified by short-pad silica gel column
chromatography using hexane and ethyl acetate (3 : 1) as the
eluent to give the title compound 9 (260 mg, 67%) as a colourless
oil and the monoacetylated lactol (107 mg) as a colourless oil.
(Found: C, 49.32; H, 4.87. C9H11FO5 requires C, 49.54; H,
5.08%); δH(400 MHz; CDCl3; Me4Si) 2.09 (3 H, s, COCH3), 2.12
(3 H, s, COCH3), 4.60 (1 H, dd, J 6.0, and 12.4, OCHH), 4.73–
4.82 (3 H, m, OCHH, AcOCH2), 6.71 (1 H, t, J 3.6, anomeric
H); δF(376 MHz; MeOH-d4) Ϫ142.55.
tert-Butyldimethylsilyl chloride (8.25g, 55 mmol) was added to
a stirred solution of 1,3-dihydroxyacetone dimer (2 g, 11 mmol)
and imidazole (6.0 g, 28 mmol) in N,N-dimethylformamide (40
cm3) at RT and the mixture was stirred at RT for 48 h. Water
(100 cm3) and hexane (300 cm3) were added to the reaction
mixture and the organic layer was washed with brine (20 cm3),
dried and evaporated under reduced pressure. The residue was
purified by column chromatography on silica using hexane and
ethyl acetate (15 : 1) as the eluent to give the title compound 4
(3.1 g, 90%) as a colourless oil. δH(250 MHz; CDCl3; Me4Si)
0.09 (12 H, s, 4 × CH3), 0.92 [18 H, s, 2 × (CH3)3C], 4.41 (4 H, s,
2 × TBSOCH2); m/z (EI-LR) 319 (Mϩ ϩ 1), 261, 115, 103, 89,
73.
4-(tert-Butyldimethylsilyloxy)-3-(tert-butyldimethylsilyloxy-
methyl)-2-fluorobut-2-enoic acid ethyl ester (5)
( )-Acetic acid 4-fluoro-5-(5-methyl-2,4-dioxo-1,2,3,4-tetro-
hydropyrimidin-1-yl)-2,5-dihydrofuran-3-ylmethyl ester (10)
n-Butyllithium (13.5 cm3, 21.6 mmol, 1.6 M solution in hexane)
was added dropwise to a stirred solution of triethyl 2-fluoro-2-
phosphonoacetate (4.2 cm3, 20.71 mmol) in tetrahydrofuran (30
cm3) at Ϫ78 ЊC and the reaction mixture was stirred for 30 min
at the same temperature. A solution of compound 4 (5.981 g,
18.77 mmol) in tetrahydrofuran (10 cm3) was added to the
above reaction mixture and the mixture was stirred at Ϫ78 ЊC
for 30 min and allowed to warm slowly to RT. The mixture was
quenched carefully with water (10 cm3) and then extracted with
ethyl acetate (100 cm3). The extracts were dried and evaporated
under reduced pressure. The residue was purified by column
chromatography on silica using hexane and ethyl acetate (50:1)
as the eluent to give the title compound 5 (6.776 g, 87%) as a
colourless oil. (Found: C, 56.12; H, 9.87. C19H39FO4Si2 requires
C, 56.11; H, 9.67%); δH(400 MHz; CDCl3; Me4Si) 0.08 (6 H, s, 2
× CH3), 0.08 (6 H, s, 2 × CH3), 0.90 [18 H, s, 2 × (CH3)3C], 1.35
(3 H, t, J 7.2, OCH2CH3), 4.30 (2 H, q, J 7.2, OCH2CH3), 4.44
A solution of compound 9 (77 mg, 0.35 mmol) in dichloro-
ethane (3 cm3) and trimethylsilyl trifluoromethanesulfonate
(0.13 cm3, 0.71 mmol) were added dropwise at 0 ЊC successively
to a stirred solution of persilylated thymine in dichloroethane
(3 cm3) [prepared from refluxing thymine (89 mg, 0.71 mmol)
and hexamethyldisilazane (5 cm3) in the presence of catalytic
amount of ammonium sulfate] and the reaction mixture was
stirred at the same temperature for 30 min. After being
quenched with saturated aqueous sodium bicarbonate (2 cm3),
the mixture was filtered through a Celite and the filtrate
extracted with methylene chloride (3 × 50 cm3). The organic
layer was dried and evaporated under reduced pressure. The
residue was purified by silica gel column chromatography using
hexane and ethyl acetate (1 : 1.5) as the eluent to give the title
compound 10 (23 mg, 23%) as a white solid and the dihydro-
furan derivative 12 (19 mg, 34%) as a colourless oil.
1802
J. Chem. Soc., Perkin Trans. 1, 2002, 1800–1804

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Compound 10. Mp 124–126 ЊC; (Found: C, 50.75; H, 4.87; N,
9.47. C12H13FN2O5 requires C, 50.71; H, 4.61; N, 9.86%);
λmax(MeOH)/nm 272; νmax/cmϪ1 1696 (COO); δH(400 MHz;
CDCl3; Me4Si) 1.95 (3 H, s, CH3), 2.12 (3 H, s, COCH3), 4.68
(1 H, ddd, J 2.4, 5.6, and 12.4, OCHH), 4.74–4.79 (2 H, m,
HOCHH, AcOCHH), 4.85 (1 H, d, J 13.6, AcOCHH ), 6.88
(1 H, br s, anomeric H), 6.92 (1 H, s, H-6), 8.97 (1 H, br s, NH);
m/z (FAB-LR) 285 (Mϩ ϩ 1), 225, 154, 136, 127, 99, 77.
the title compound 14 (26 mg, 90%) as a white solid. Mp 82–83
ЊC; (Found: C, 47.99; H, 4.14; N, 18.11. C9H10FN3O3 requires
C, 47.58; H, 4.44; N, 18.50%); λmax(MeOH)/nm 266; δH(400
MHz; MeOH-d4; Me4Si) 4.30 (1H, d, J 14.0, HOCHH), 4.34
(1H, d, J 14.8, HOCHH ), 4.72 (1 H, ddd, J 2.0, 5.6, and 12.0,
OCHH), 4.82–4.88 (1 H, m, OCHH ), 5.95 (1 H, d, J 7.6, H-5),
6.91 (1 H, br s, anomeric H), 7.52 (1 H, d, J 7.2, H-6);
δC(100 MHz; MeOH-d4; Me4Si) 53.99, 73.26 (d, J 8.3), 86.62
(d, J 28.5), 97.55, 120.36 (d, J 6.2), 142.24, 148.48 (d, J 275.1),
158.71, 167.89; δF(376 MHz; MeOH-d4) Ϫ148.24.
Compound 12. δH(400 MHz; CDCl3; Me4Si) 2.08 (3 H, s,
COCH3), 4.97 (2 H, s, CH2), 7.30–7.31 (1 H, m, vinylic H), 7.36
(1 H, dd, J 1.6 and 5.2, vinylic H).
( )-Acetic acid 5-(6-benzamidopurin-9-yl)-4-fluoro-2,5-
dihydrofuran-3-ylmethyl ester (15a)
( )-Acetic acid 5-(4-acetamido-2-oxo-1,2-dihydropyrimidin-1-
yl)-4-fluoro-2,5-dihydrofuran-3-ylmethyl ester (11)
A solution of compound 9 (72 mg, 0.33 mmol) in dichloro-
ethane (3 cm3) and trimethylsilyl trifluoromethanesulfonate
(0.09 cm3, 0.50 mmol) were added dropwise at 0 ЊC successively
to a stirred solution of persilylated N 6-benzoyladenine in
dichloroethane (3 cm3) [prepared from refluxing N 6-
benzoyladenine (119 mg, 0.50 mmol) and hexamethyldisilazane
(5 cm3) in the presence of catalytic amount of ammonium
sulfate], and the reaction mixture was stirred at the same
temperature for 20 min. After being quenched with saturated
aqueous sodium bicarbonate (2 cm3), the mixture was filtered
through a pad of Celite, and extracted with methylene chloride
(3 × 50 cm3). The organic layer was dried and evaporated
under reduced pressure to give a syrup, which was purified by
silica gel column chromatography using methylene chloride and
methanol (30 : 1) as the eluent to give the title compound 15a
(23 mg, 24%) as a sticky syrup, N-7 glycosylated nucleoside 15b
(7 mg, 7%) as a sticky syrup and the dihydrofuran derivative 12
(45%).
A solution of compound 9 (120 mg, 0.55 mmol) in dichloro-
ethane (4 cm3), and trimethylsilyl trifluoromethanesulfonate
(0.22 cm3, 1.24 mmol) were added dropwise at 0 ЊC successively
to a stirred solution of persilylated N 4-acetylcytosine in dichloro-
ethane (3 cm3) [prepared from refluxing N 4-acetylcytosine (190
mg, 1.24 mmol) and hexamethyldisilazane (6 cm3) in the
presence of a catalytic amount of ammonium sulfate] and the
reaction mixture was stirred at the same temperature for 20
min. After being quenched with saturated aqueous sodium
bicarbonate (3 cm3), the mixture was filtered through a pad of
Celite and the filtrate extracted with methylene chloride (3 × 50
cm3). The organic layer was dried and evaporated under
reduced pressure. The residue was purified by silica gel column
chromatography using methylene chloride and methanol (25 :
1) as the eluent to give the title compound 11 (52.4 mg, 31%) as a
white solid and the dihydrofuran derivative 12 (36.5 mg, 42%)
as a colourless oil.
Compound 15a. (Found: C, 57.44; H, 4.25; N, 17.32.
C19H16FN5O4 requires C, 57.43; H, 4.06; N, 17.62%);
λmax(MeOH)/nm 279; δH(400 MHz; MeOH-d4; Me4Si) 2.12 (3
H, s, COCH3), 4.79–4.84 (1 H, m, OCHH), 4.91 (2 H, br s,
AcOCH2), 5.01–5.06 (1 H, m OCHH ), 7.04 (1 H, br t, J 3.8,
anomeric H), 7.55–8.10 (5 H, m, Ph), 8.52 (1 H, s, H-2), 8.74 (1
H, s, H-8).
Compound 11. Mp 249 ЊC (decomp.); (Found: C, 50.23; H,
4.44; N, 13.65. C13H14FN3O5 requires C, 50.16; H, 4.53; N,
13.50%); λmax(MeOH)/nm 249 and 299; νmax/cmϪ1 1732 (COO);
δH(400 MHz; MeOH-d4; Me4Si) 2.09 (3 H, s, COCH3), 2.19
(3 H, s, NHCOCH3), 4.74 (1 H, ddd, J 2.4, 6.0, and 12.4,
OCHH), 4.83 (2 H, s, AcOCH2), 4.85–4.92 (1 H, m, OCHH ),
6.96 (1 H, br s, anomeric H), 7.48 (1 H, d, J 8.0, H-5), 7.90 (1 H,
d, J 7.2, H-6); m/z (FAB-LR) 312 (Mϩ ϩ 1), 252, 136, 99, 77.
Compound 15b. λmax(MeOH)/nm 279; δH(400 MHz; MeOH-
d4; Me4Si) 2.02 (3 H, s, COCH3), 4.68–4.86 (4 H, m, OCH2,
AcOCH2), 7.44–8.08 (6 H, m, anomeric H, and Ph), 8.63 (2 H,
br s, H-2 and H-8).
( )-1-(3-Fluoro-4-hydroxymethyl-2,5-dihydrofuran-2-yl)-5-
methylpyrimidine-2(1H),4(3H)-dione (13)
A solution of compound 10 (22 mg, 0.08 mmol) in saturated
methanolic ammonia (3 cm3) was stirred at RT for 2 h and the
mixture was evaporated under reduced pressure to give an oil.
This was purified by silica gel column chromatography using
hexane and ethyl acetate (1 : 3.5) as the eluent to give the title
compound 13 (17.6 mg, 94%) as a white solid. Mp 175–177 ЊC;
(Found: C, 49.99; H, 4.17; N, 11.33. C10H11FN2O4 requires C,
49.59; H, 4.58; N, 11.57%); λmax(MeOH)/nm 263; δH(400 MHz;
MeOH-d4; Me4Si) 1.90 (3 H, d, J 1.2, CH3), 4.31 (1 H, d, J 13.6,
HOCHH), 4.37 (1 H, d, J 13.2, HOCHH ), 4.72 (1 H, ddd, J
2.4, 5.6, and 12.0, OCHH), 4.86–4.90 (1 H, m, OCHH ), 6.83
(1 H, br s, anomeric H), 7.31 (1 H, s, H-6); δC(100 MHz;
MeOH-d4; Me4Si) 11.05, 52.66, 71.99 (d, J 8.4), 84.44 (d, J
28.8), 111.75, 119.44 (d, J 6.3), 135.59, 146.32 (d, J 274.9),
151.49, 164.94; δF(376 MHz; MeOH-d4) Ϫ150.11; m/z (FAB-
LR) 243 (Mϩ ϩ 1), 154, 136, 117, 89, 77.
( )-[5-(6-Aminopurin-9-yl)-4-fluoro-2,5-dihydrofuran-3-
yl]methanol (16a)
A solution of the N 9-isomer 15 (30 mg, 0.08 mmol) in saturated
methanolic ammonia (5 cm3) was stirred at RT for 1.5 h. The
mixture was evaporated under reduced pressure to give an oil,
which was purified by silica gel column chromatography using
methylene chloride and methanol (12:1) as the eluent to give the
title compound 16a (17 mg, 90%) as a white solid. Mp 205–206
ЊC; (Found: C, 47.88; H, 4.03; N, 27.91. C10H10FN5O2 requires
C, 47.81; H, 4.01; N, 27.88%); λmax(MeOH)/nm 258; δH(400
MHz; MeOH-d4; Me4Si) 4.39 (2 H, s, HOCH2), 4.80–4.84 (1 H,
m, OCHH), 4.97–5.02 (1 H, m, OCHH ), 6.90 (1 H, br t, J 4.4,
anomeric H), 8.22 (1 H, s, H-2), 8.25 (1 H, s, H-8); δC(100 MHz;
MeOH-d4; Me4Si) 51.13, 73.77 (d, J 8.3), 84.80 (d, J 29.1),
120.49, 120.55, 140.79, 147.37 (d, J 274.5), 150.81, 154.48,
157.59; δF(376 MHz; MeOH-d4) –148.84 (s); m/z (FAB-LR) 252
(Mϩ ϩ 1), 176, 136, 107, 89.
( )-4-Amino-1-(3-fluoro-4-hydroxymethyl-2,5-dihydrofuran-
2-yl)pyrimidin- 2(1H)-one (14)
( )-[5-(6-Aminopurin-7-yl)-4-fluoro-2,5-dihydrofuran-3-yl]
methanol (16b)
A solution of the N 7-isomer 15b (7 mg, 0.019 mmol) in satur-
ated methanolic ammonia (3 cm3) was stirred at RT for 16 h.
The mixture was evaporated under reduced pressure to give an
A solution of compound 11 (40 mg, 0.13 mmol) in saturated
methanolic ammonia (5 cm3) was stirred at RT for 2 h and the
mixture was evaporated under reduced pressure to give an oil,
which was purified by silica gel column chromatography using
methylene chloride and methanol (5.5 : 1) as the eluent to give
J. Chem. Soc., Perkin Trans. 1, 2002, 1800–1804
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oil, which was purified by silica gel column chromatography
using methylene chloride and methanol (12 : 1) as the eluent to
give the title compound 16b (2.1 mg, 45%) as a white solid;
λmax(MeOH)/nm 270; δH(400 MHz; MeOH-d4; Me4Si) 4.39
(1 H, s, HOCHH), 4.57 (1 H, s, HOCHH), 4.49–4.89 (1 H, m,
OCHH), 4.97–5.02 (1 H, m, OCHH ), 6.89 (1 H, m, anomeric
H), 8.22 (1 H, s, H-2), 8.25 (1 H, s, H-8); δF(376 MHz; MeOH-
d4) Ϫ149.00 (s).
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Acknowledgements
This work was supported by a grant from the Korea Health
R & D Project, Ministry of Health & Welfare, Korea (HMP-
01-PJ1-PG1–01CH13–0002).
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