Nucleosides with furanyl scaffolds

Article abstract of DOI:10.1016/S0040-4020(02)00430-1

Synthesis of purine and pyrimidine nucleosides with furanyl scaffolds is described. The 2-functionalized tetrahydrofuranol derivatives 12 and 15 were coupled with nucleobases through the Mitsunobu reaction. The methodology developed is general and can als

Full text of DOI:10.1016/S0040-4020(02)00430-1

TETRAHEDRON
Pergamon
Tetrahedron 58 52002) 4865±4871
Nucleosides with furanyl scaffolds
Sanjib Bera and Vasu Nairp
Department of Chemistry, The University of Iowa, Iowa City, IA 52242, USA
Received 28 January 2002; accepted 18 April 2002
AbstractÐSynthesis of purine and pyrimidine nucleosides with furanyl scaffolds is described. The 2-functionalized tetrahydrofuranol
derivatives 12 and 15 were coupled with nucleobases through the Mitsunobu reaction. The methodology developed is general and can
also be applied for an ef®cient synthesis of apionucleosides. In addition, the methodology was used for the synthesis of the unsaturated purine
nucleoside 22. However, when the elimination reaction used to produce 22 was applied to the pyrimidine case, the stable anhydro compound
24 was produced. The structures of 18 and 22 were con®rmed by single-crystal X-ray data. Antiviral evaluation was performed. q 2002
Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The anti-HIV activity ofunusual dideoxynucleosides, where
the base or the 50-CH2OH are transposed from their normal
10 or 40 position to non-natural or isomeric positions, has
generated much interest in the synthesis ofother related
non-natural nucleosides. 20-Isomeric dideoxynucleosides
51) synthesized in our laboratory,1 have anti-HIV activity
against HIV-1 and HIV-2. Dideoxynucleosides ofthe apiose
family 52)2 show anti-HIV activity in MT-4 cells. 1,2-
Disubstituted carba- and iso-nucleosides 53) also show
some antiviral activity.3 Based on these ®ndings, we
designed and synthesized novel dideoxynucleosides with
furanyl scaffolds 54±6) as potential antiviral agents. In the
process ofthis work, we also discovered an excellent
synthesis ofan isomer of5 ^)-apioadenosine4 that can be
applied to the synthesis ofapioadenosine itself.
Commercially available meso-1,4-anhydroerythritol 7 was
chosen as a starting material for the synthesis of the
hydroxymethyl nucleosides. Protection ofone ofthe
hydroxyl groups of 7 by treatment with one equivalent of
TBDPSCl in DMF5 gave the racemic monosilyl protected
derivative 8. The free hydroxyl group of 8 was oxidized6 to
the keto derivative 9. Wittig reaction7 of 9 with Ph3PCH3I
and ButOK in dry benzene afforded the ole®n 10 in 60%
overall yield from 8. Hydroboration8 ofthe protected allyl
alcohol 10 with 9-BBN in THF produced the 5^)-cis-
hydroxymethyl derivative 11 as the major product in
70% yield. The 5^)-cis-derivatives could easily be sepa-
rated from the 5^)-trans derivatives by silica gel column
chromatography. Protection ofthe primary hydroxyl
group with benzoyl chloride in pyridine followed by depro-
tection ofthe silyl protecting group oafrfded 5
5Scheme 1).
^)-12
Compound 12, on treatment with adenine under Mitsunobu
conditions,9a±c afforded the trans 1,2-disubstituted adenine
derivative, 5^)-13a. Similar treatment of 12 with N-3
protected pyrimidine bases afforded coupling products that
were partially deprotected 5N-3 benzoyl deprotection) by
treatment with aqueous ammonia to give 13b,d. The uracil
derivatives 13b and d were converted to their corresponding
cytidine derivatives 13c and e. Compounds 13 on treatment
with CH3ONa in MeOH produced racemic 1,2-disubstituted
trans-hydroxymethyl nucleosides 14. The stereochemistry
of 14c was con®rmed by difference NOE spectroscopy.
For example, the a con®guration ofthe hydroxymethyl
group at C-40 was con®rmed by the NOE observed for
H-6 and H-20 when H-40 was irradiated. Similarly, a strong
NOE was observed for H-40 when H-6 was irradiated. The
Keywords: nucleosides; furanyl scaffolds; pyrimidine.
Corresponding author. Tel.: 11-319-335-1364; fax: 11-319-353-2621;
e-mail: vasu-nair@uiowa.edu
p
0
absence ofan NOE correlation between H-3 and H-40
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020502)00430-1

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S. Bera, V. Nair / Tetrahedron 58 $2002) 4865±4871
Scheme 1. Reagents and conditions: 5i) TBDPSCl, imidazole, DMF; 5ii) CrO3, Ac2O, pyridine, CH2Cl2; 5iii) CH3PPh3I, ButOK, benzene; 5iv) 5a) 9-BBN, THF,
room temperature; 5b) H2O2, NaOH; 5v) BzCl, pyridine; 5vi) NH4F, MeOH; 5vii) Ph3P, DEAD, dioxane; 5viii) aqueous NH3 and MeOH; 5ix) 5a) TIPSCl,
DMAP, TEA, CH3CN, 5b) aqueous NH3; 5x) CH3ONa, MeOH.
indicates that hydroxymethyl group and nucleobase are in a
trans con®guration in the target molecules 5Fig. 1).
of 10. Reaction of 15 with adenine under Mitsunobu
conditions9d,e gave poor yields. However, the Mitsunobu
condensation of 15 with 6-chloropurine proceeded
smoothly to give nucleoside 16a bearing the exocyclic
methylene group. Similarly, the Mitsunobu reaction of 15
For compounds ofthe cis-series, the starting material was
the unsaturated alcohol, 5^)-15, derived from deprotection
Scheme 2. Reagents and conditions: 5i) NH4F, MeOH; 5ii) 6-chloropurine or N-3 benzoyluracil, Ph3P, DEAD; 5iii) OsO4, acetone; 5iv) aqueous NH3 in MeOH;
5v) BzCl, pyridine, 2108C; 5vi) MsCl, CH2Cl2, TEA, 08C; 5vii) NH4F, THF; 5viii) NH3/MeOH, 808C; 5ix) H2/Pd±C.

S. Bera, V. Nair / Tetrahedron 58 $2002) 4865±4871
4867
benzoyl chloride in pyridine to produce 19a 584%). The tert-
hydroxy group of 19a was then mesylated by treatment with
mesyl chloride in the presence oftriethylamine to give 20a.
cis-Elimination11 of 20a with tetrabutylammonium ¯uoride
at 08C afforded the unsaturated derivative 21, which on
treatment with methanolic ammonia in a steel bomb at
808C, afforded the 1,2-disubstituted unsaturated adenine
derivative 22 523% yield from 19a). The structure of 22
was con®rmed by single crystal X-ray data 5Fig. 3).
Figure 1. NOE NMR correlations ofcompound 14c.
Interestingly, the X-ray data also showed that the compound
crystallized out in the dimeric form depicted in Fig. 2 with
hydrogen bonding between N-7 5ofmolecule 1) and NH 5of
NH2 ofmolecule 2), and NH 5ofNH ofmolecule 1) and
2
N-1 ofmolecule 2. Catalytic hydrogenation of 22 produced
the racemic saturated derivative 23. Unlike 20a, treatment
of 20b with Bu4NF did not produce the unsaturated elimina-
tion product, but the 2,30-O-anhydro compound 24. Forma-
tion of 24 is unlikely through an SN2 mechanism because of
the b-stereochemistry ofthe benzyloxymethyl group. Thus,
it is likely that compound 24 arises from an SN1 pathway in
which a carbocation formed at C-30 is attacked by O-2 of
uracil. This type ofanhydro compound has not been
reported previously in nucleoside chemistry. Various
attempts to convert the anhydro compound to the unsatu-
rated derivative failed.
In summary, new furanyl nucleosides in which the base and
±CH2OH have a 1,2-relationship have been synthesized and
their structures con®rmed by HRMS, NMR and X-ray crys-
tal structure data. The methodology developed is general
and can be applied to the synthesis ofapio- as well as
normal nucleoside analogs. Antiviral studies 5HIV-1,
HSV, VZV, CMV) revealed that the compounds were
marginally active or inactive.
Figure 2. ORTEP plot ofcrystal structure of 18.
with N-3 benzoyluracil produced 16b in good yields
5Scheme 2).
Dihydroxylation10 ofcompound 16a through treatment with
OsO4 in the presence of N-methylmorpholine-N-oxide gave
17a in 41% overall yield from 15. Similarly, deprotection
ofthe N-3 benzoyl group of 16b, followed by dihydroxyl-
ation ofthe deprotected compoundorfdafed
17b.
3. Experimental
3.1. General
Compound 17a, on treatment with saturated methanolic
ammonia in a steel bomb, afforded 5^)-5isoapiofuranosyl)-
adenine 18 in 75% yield. The structure, regiochemistry and
stereochemistry of 18 was con®rmed by single crystal X-ray
data 5Fig. 2).
Melting points reported were uncorrected and were deter-
mined on an Electrothermal Engineering Ltd. Melting point
apparatus. Ultraviolet 5UV) spectra were recorded on a Cary
3 UV±Vis spectrophotometer. 1H and 13C NMR were
recorded on a AC-300 and WM-360 instruments. Chemical
For the synthesis ofunsaturated nucleoside 22, the primary
hydroxyl group of 17a was benzoylated by treatment with
Figure 3. ORTEP plot ofcrystal structure of 22 showing dimeric form and intermolecular hydrogen bonding.

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S. Bera, V. Nair / Tetrahedron 58 $2002) 4865±4871
1
shifts are referenced to an internal TMS standard for H
NMR spectra and to solvent 5CDCl3, d6-DMSO, d6-Acetone
or CD3OD) for 13C NMR spectra. Column chromatographic
separations were carried out using 230±400 mesh silica gel.
High resolution FAB mass spectral data were obtained on a
VG ZAB-HF high resolution mass spectrometer.
510 mL) was added to destroy excess ofperoxide. Extracted
with EtOAc 53£30 mL), the combined EtOAc part was
dried over Na2SO4 and evaporated to dryness. The residue
was puri®ed over silica gel to give the hydroxymethyl
1
derivative 11 50.65 g, 61%) as gum. H NMR 5CDCl3) d
7.67±7.35 5m, 10H, phenyl), 4.52 5m, 1H, H-3), 3.86 5m,
4H, H-2, H-5), 3.53 5ddd, Jˆ3.8, 4.8, 9.6 Hz, 2H), 2.31 5m,
1H, H-4), 1.08 5s, 9H, t-butyl). 13C NMR 5CDCl3) d 135.7,
135.6, 133.3, 132.7, 130.0, 127.9, 127.8 5phenyl), 74.8
5C-3), 74.6 5C-2), 69.2 5C-5), 60.5 5CH2OH), 45.6 5C-4),
26.9 5t-butyl), 19.1 5t-butyl); HRMS 5FAB): 5M1H)1
calcd for C21H29O3Si: 357.1886, found 357.1889.
3.1.1.
)^)-4-)tert-Butyldiphenylsilyloxy)-tetrahydro-
furan-3-ol 8. To a solution of 7 51.04 g, 10 mmol) and
imidazole 51.02 g, 15 mmol) in DMF 550 mL), TBDPSCl
52.6 mL, 11 mmol) was added. The reaction mixture was
then heated at 858C overnight. DMF was removed under
reduced pressure and the residue was taken in EtOAc
5100 mL) and washed with water 52£100 mL). The EtOAc
part was dried over Na2SO4 and evaporated to dryness. The
residue was puri®ed over silica gel column to give the silyl
3.1.4. )^)-4-)Benzoyloxymethyl)-tetrahydrofuran-3-ol
12. To a solution of 11 51.0 g, 2.8 mmol) in pyridine
530 mL), benzoyl chloride 51.64 mL, 14 mmol) was added
dropwise at 08C. After the addition the reaction mixture was
stirred at 08C for 4 h. The reaction was quenched with water
55 mL) and evaporated to dryness and coevaporated with
toluene. The residue was taken in EtOAc 5100 mL) and
washed with water 52£100 mL). The EtOAc part was
dried over Na2SO4, evaporated to dryness and puri®ed
over silica gel to give the benzoyl derivative 51.08 g,
2.35 mmol). The benzoyl derivative was dissolved in
MeOH 560 mL) and to the solution NH4F 50.8 g) was
added. The solution was heated under re¯ux for 40 h and
cooled down to room temperature. It was adsorbed directly
on silica gel and puri®ed on silica gel column to give 12
50.49 g, 79%). 1H NMR 5CDCl3) d 8.00±7.37 5m, 5H,
phenyl), 4.67 5dd, Jˆ8.3 Hz, 1H), 4.36 5bs, 1H), 4.28 5dd,
Jˆ6.2, 11.3 Hz, 1H), 4.00±3.82 5m, 3H), 3.69 5m, 1H), 2.58
5m, 1H). 13C NMR 5CDCl3) d 166.9 5ester CO), 133.1,
129.6, 128.5, 128.3 5phenyl), 75.7 5C-2), 71.2 5C-3), 68.4
5C-5), 61.6 5CH2OBz), 44.5 5C-4). HRMS 5FAB): 5M1H)1
calcd for C12H15O4: 223.0970, found 223.0970
1
derivative 8 53.3 g, 83%) as a colourless gum. H NMR
5CDCl3)
d
7.69±7.38 5m, 10H, phenyl), 4.30 5q,
Jˆ5.8 Hz, 1H, H-3), 4.08 5m, 1H, H-4), 3.82 5ddd, Jˆ3.4,
4.7, 9.8 Hz, 2H, H-5), 3.60 5d, Jˆ6.2 Hz, 2H, H-2), 1.12 5s,
9H, t-butyl); 13C NMR 5CDCl3) d 135.4, 135.3, 132.6,
132.3, 130.1, 130.0, 127.8, 127.7 5phenyl), 73.2 5C-2),
73.0 5C-3), 71.3 5C-5), 70.8 5C-4), 26.7 5t-butyl), 19.0 5t-
butyl); HRMS 5FAB): 5M1H)1 calcd for C20H27O3Si:
343.1729, found 343.1728.
3.1.2. )^)-3-)tert-Butyldiphenylsilyloxy)-tetrahydro-4-
methylidene furan 10. To a stirred suspension ofCrO
3
58.25 g), pyridine 513.7 mL) and Ac2O 58.25 mL) in
CH2Cl2 575 mL) was added the solution of 8 59 g,
26 mmol) in CH2Cl2 575 mL). After the addition the
reaction mixture was stirred at room temperature for 1 h.
Poured into EtOAc 5300 mL) and ®ltered through a
silica gel column. The eluent was evaporated to dryness,
coevaporated with toluene to give the keto product which
after drying was used for Wittig reaction.
3.2. General methods for the synthesis of 13b,d
t
A suspension ofBu OK 54.68 g) and CH3PPh3I 517.1 g) in
benzene 5150 mL) was heated under re¯ux for 1 h. The
yellow turbid solution was evaporated to dryness and the
solution ofthe keto derivative in benzene 5150 mL) was
added to the residue. The reaction mixture was then heated
at 658C for 2.5 h. Water 5150 mL) was added and extracted
with EtOAc 53£80 mL). The organic part was dried over
Na2SO4 and evaporated to dryness. The residue was puri®ed
over silica gel to afford the methylene derivative 10 560%
To a suspension of 12 50.18 g, 0.81 mmol), PPh3 50.425 g,
1.62 mmol) and N-3 benzoyl pyrimidine base 51.6 mmol) in
dioxane 525 mL) was added DEAD 50.26 mL, 1.62 mmol)
dropwise. After the addition the reaction mixture was stirred
at room temperature for 3 days. The solution was directly
adsorbed on silica gel and puri®ed over silica gel column to
give the protected nucleosides which were characterized
after N-3 benzoyl deprotection. The protected nucleosides
were dissolved in MeOH 520 mL) and to this was added
aqueous ammonia 54 mL, 28%). The solution was stirred
at room temperature for 2±3 h and evaporated to dryness
under reduced pressure. The residue was puri®ed over silica
gel to give 13b 543%), d 540%). The uracil derivatives 13b
and d were converted to the corresponding cytidine
derivatives 13c and e, respectively, following the literature
procedure.12 These cytidine derivatives 13c and e were
characterized as their deprotected form 14c and e.
1
yield in two steps) as viscous liquid. H NMR 5CDCl3) d
7.74±7.40 5m, 10H, phenyl), 5.10 5d, Jˆ1.1 Hz, vinyl), 5.02
5s, 1H, vinyl), 4.66 5bs, 1H, H-3), 4.46 5d, Jˆ13.2 Hz, 1H,
H-2a), 4.28 5d, Jˆ13.1 Hz, 1H, H-2b), 3.71±3.60 5m, 2H,
H-5). 13C NMR 5CDCl3) d 149.5 5C-4), 135.8, 133.7, 133.4
5phenyl), 106.7 5vinyl), 74.1 5C-2), 73.6 5C-3), 69.9 5C-5),
26.8 5t-butyl), 19.2 5t-butyl). HRMS 5FAB): 5M1Na)1
calcd for C21H26O2NaSi: 361.1599, found 361.1614.
3.1.3.
)^)-3-)tert-Butyldiphenylsilyloxy)-4-)hydroxy-
1
3.2.1. Compound 13b. H NMR 5CDCl3) d 10.01 5s, 1H,
methyl)-tetrahydrofuran 11. To a solution of 10 51.01 g,
3 mmol) in THF 530 mL) was added 9-BBN 50.5 M, 8 mL)
and the reaction mixture was stirred at room temperature for
24 h. Another 8 ml of9-BBN was added and stirred ofr
another 48 h. NaOH 52 N, 10 mL) was added followed by
30% H2O2 51.5 mL) at 08C. The turbid solution was then
stirred at room temperature for 2 h. Saturated Na2S2O3
NH), 7.96±7.35 5m, 6H, H-6, phenyl), 5.72 5d, Jˆ8.1 Hz,
1H, H-5), 5.14 5m, 1H, H-30), 4.40 5d, Jˆ6.5 Hz, 2H,
CH2OBz), 4.28 5dd, Jˆ8.3, 9.4 Hz, 1H, H-20a), 3.95 5d,
Jˆ4.6 Hz, 2H, H-50), 3.61 5dd, Jˆ7.4, 9.5 Hz, 1H, H-20b),
2.73 5m, 1H, H-40). 13C NMR 5CDCl3) d 166.1 5ester CO),
163.3 5C-4), 150.8 5C-2), 140.8 5C-6), 133.1, 129.4, 129.3,

S. Bera, V. Nair / Tetrahedron 58 $2002) 4865±4871
4869
128.3 5phenyl), 103.3 5C-5), 71.6 5C-20), 70.1 5C-50), 64.1
5CH2OBz), 58.4 5C-30), 46.1 5C-40); HRMS 5FAB):
5M1H)1 calcd for C16H17N2O5: 317.1137, found 317.1153.
1H, H-40); 13C NMR 5d4-MeOH1D2O) d 159.1 5d,
Jˆ13.8 Hz, C-4), 157.2 5C-2), 136.5 5d, C-5), 128.2 5d,
Jˆ32.0 Hz, C-6), 72.7 5C-20), 71.4 5C-50), 63.1 5CH2OH),
61.8 5C-30), 50.3 5C-40) HRMS 5FAB): 5M1H)1 calcd for
C10H13FN3O3: 230.0940, found 230.0944.
3.2.2. Compound 13d. 1H NMR 5CDCl3) d 7.99±7.39 5m,
6H, H-6, phenyl), 5.18 5m, 1H, H-30), 4.44 5d, Jˆ6.5 Hz,
2H, CH2OBz), 4.35 5dd, Jˆ8.5, 9.4 Hz, 1H, H-20a), 3.99 5m,
2H, H-50), 3.62 5dd, Jˆ7.6, 9.5 Hz, 1H, H-20b), 2.75 5m, 1H,
H-40). 13C NMR 5CDCl3) d 166.2 5ester CO), 156.7 5d,
Jˆ26.9 Hz, C-4), 149.4 5C-2), 141.2 5d, Jˆ239 Hz, C-5),
133.3, 129.6, 129.3, 128.5 5phenyl), 125.1 5d, Jˆ33.4 Hz,
C-6), 71.7 5C-20), 70.1 5C-50), 63.9 5CH2OBz), 58.8 5C-30),
46.4 5C-40).
3.3.4. )^)-Tetrahydrofuran-4-methylidene-3-ol 15. To a
solution of 10 51.69 g, 5 mmol) in methanol 5100 mL) was
added NH4F 51 g) and the reaction mixture was heated under
re¯ux for 4 h. The solution was adsorbed directly on silica
gel and puri®ed over silica gel to produce the allyl alcohol
1
derivative 15 50.43 g, 86%) as an oil. H NMR 5CDCl3) d
5.24 5m, 1H, vinyl), 5.05 5m, 1H, vinyl), 4.47 5bs, 1H, H-3),
4.39 5m, 1H, H-2a), 4.19 5m, 1H, H-2b), 3.83 5dd, Jˆ5.2,
9.6 Hz, 1H, H-5a), 3.65 5dd, Jˆ3.9, 9.6, 1H, H-5b). 13C
NMR 5CDCl3) d 150.2 5C-4), 107.7 5vinyl), 74.9 5C-2),
72.5 5C-3), 69.8 5C-5).
3.3. General method for the synthesis of 14 from 13
To a solution of 13 51 mmol) in anhydrous MeOH 510 ml)
was added NaOMe 50.15 g) and the reaction mixture was
stirred at room temperature for 3 h. The solution was neutra-
lized with 10% aqueous acetic acid and evaporated to
dryness under reduced pressure. The residue was puri®ed
over silica gel to give 14.
3.3.5.
)^)-4-)6-Chloro-9H-purin-9-yl)-3-)hydroxy-
methyl)-tetrahydrofuran-3-ol 17a. To a suspension of 15
50.45 g, 4.5 mmol), PPh3 51.8 g) and 6-chloro purine
50.77 g) in THF 570 mL) was added DEAD 51.5 mL) drop-
wise at 08C. After the addition the reaction mixture was
stirred at 08C for 5 h. The solution was directly adsorbed
on silica gel and puri®ed over silica gel column to give 16a.
Compound 16a was dissolved in acetone±water 550 mL,
4:1) and to the solution N-methylmorpholine-N-oxide
50.6 g) and OsO4 50.05 g) were added. The reaction mixture
was then stirred at room temperature for 24 h. Solvent was
evaporated to dryness under reduced pressure and the
residue was puri®ed over silica gel to produce the
dihydroxylated derivative 17a 50.5 g, 41% from 15) as
white solid. Mp: 2028C; UV 5MeOH) lmax 265 5e
3.3.1. )^)-trans-6-Amino-9-[4-)hydroxymethyl)-tetra-
hydrofuran-3-yl]-9H-purin 14a. To a suspension of 12
50.16 g, 0.72 mmol), PPh3 50.38 g, 1.4 mmol) and adenine
50.15 g) in dioxane 515 mL) was added DEAD 50.23 mL,
1.4 mmol) dropwise. After the addition the reaction mixture
was stirred at room temperature for 5 days. The solution was
directly adsorbed on silica gel and puri®ed over silica gel
column to give 13a 50.06 g, 24%) as white solid. Compound
13a 50.05 g) was dissolved in MeOH 510 mL) and to the
solution sodium methoxide 50.02 g) was added. The reac-
tion mixture was stirred at room temperature for 3 h. The
solution was neutralized with 10% aqueous acetic acid and
evaporated to dryness. The residue was puri®ed over silica
gel column to give 14a 50.03 g, 86%) as white powder. Mp:
1
11,500); H NMR 5d6-DMSO) d 8.76 5s, 1H, H-2), 8.48
5s, 1H, H-8), 5.59 5s, 1H, ±OH), 5.07 5m, 1H, H-40), 4.50
5t, Jˆ5.0 Hz, 1H, ±OH), 4.36 5dd, Jˆ5.5, 9.9 Hz, 1H), 4.24
5dd, Jˆ1.5, 9.9 Hz, 1H), 4.12 5d, Jˆ9.7 Hz, 1H), 3.71 5d,
Jˆ9.8 Hz, 1H) 3.17 5m, 2H); 13C NMR 5d6-DMSO) d 152.4
5C-6), 151.4 5C-2), 148.9 5C-4), 145.9 5C-8), 130.4 5C-5),
82.2 5C-30), 74.9 5C-20), 71.2 5C-50), 62.8 5CH2OH), 62.2
5C-40); HRMS 5FAB): 5M1H)1 calcd for C10H12ClN4O3:
271.0597, found 271.0598.
1
1948C; UV 5MeOH) lmax 261 5e 14,500); H NMR 5d4-
MeOH) d 8.20 5s, 1H, H-2), 8.19 5s, 1H, H-8), 5.06 5m,
1H, H-30), 4.34 5t, Jˆ8.5 Hz, 1H), 4.09 5m, 2H), 3.71 5m,
3H), 2.82 5m, 1H); 13C NMR 5d4-MeOH) d 157.0 5C-6),
153.6 5C-2), 150.1 5C-4), 141.0 5C-8), 119.8 5C-5), 73.1
5C-20), 71.2 5C-50), 62.5 5CH2OH), 58.8 5C-30), 49.6
5C-40). HRMS 5FAB): 5M1H)1 calcd for C10H14N5O2:
236.1147, found 236.1147;
3.3.6. )^)-4-[Pyrimidine-2,4)1H,3H)-dione-1-yl]-3-)hy-
droxy-methyl)-tetrahydrofuran-3-ol 17b. To a suspension
of 15 50.2 g, 2 mmol), PPh3 51.05 g, 4 mmol) N-3 benzoyl
uracil 50.8 g, 3.7 mmol) in THF 550 mL) was added DEAD
50.66 mL, 4 mmol) dropwise at 2608C. After the addition
the reaction mixture was stirred at 2458C for 24 h. The
solution was directly adsorbed on silica gel and puri®ed
over silica gel column to give 16b. Compound 16b was
dissolved in MeOH 575 mL) and NaOMe 50.9 g) was
added into it. The reaction mixture was stirred at room
temperature for 20 h. Neutralized with 10% acetic acid
and evaporated to dryness. The residue was puri®ed over
silica gel. The deprotected nucleoside was dissolved in
acetone acetone±water 575 mL, 4:1) and to the solution
3.3.2. )^)-trans-4-Amino-1-[4-)hydroxymethyl)-tetra-
hydrofuran-3-yl]-pyrimidine-2)1H)-one 14c. Mp: 2008C;
UV 5MeOH) lmax 276 5e 9300); H NMR 5d4-MeOH) d
1
7.62 5d, Jˆ7.4 Hz, 1H, H-6), 5.90 5d, Jˆ7.4 Hz, 1H, H-5),
4.94 5m, 1H, H-30), 4.22 5t, Jˆ8.0 Hz, 1H, H-20a), 3.91 5m,
2H, H-50), 3.67±3.56 5m, 3H, H-20b, CH2OH), 2.48 5m, 1H,
H-40); 13C NMR 5d4-MeOH1D2O 4:1) d 167.1 5C-4), 158.8
5C-2), 144.1 5C-6), 96.9 5C-5), 72.7/71.5, C-20/C-50, 63.0,
CH2OH, 61.1, C-30, 49.0, C-40; HRMS 5FAB): 5M1H)1
calcd for C9H14N3O3: 212.1035, found 212.1038.
were
added
N-methylmorpholine-N-oxide
50.35 g,
3.3.3. )^)-trans-4-Amino-1-[4-)hydroxymethyl)-tetra-
hydrofuran-3-yl]-5-¯uoro-pyrimidine-2)1H)-one
UV 5MeOH) lmax 286 5e 6,700); 241 nm; H NMR 5d4-
MeOH1D2O) d 7.75 5m, 1H, H-6), 4.92 5bs, 1H, H-30),
4.23 5t, Jˆ7.8 Hz, 1H, H-20a), 3.91 5m, 2H, H-50), 3.65
5m, 2H, CH2OH), 3.58 5t, Jˆ7.8 Hz, 1H, H-20b), 2.48 5m,
3 mmol) and OsO4 50.03 g). The reaction mixture was
then stirred at room temperature for 24 h. Solvent was
evaporated to dryness under reduced pressure and the
residue was puri®ed over silica gel to produce the
dihydroxylated derivative 17b 50.28 g, 68% overall yield
14e.
1

4870
S. Bera, V. Nair / Tetrahedron 58 $2002) 4865±4871
from 15) as hygroscopic solid. UV 5MeOH) lmax 267 5e
9700); H NMR 5d6-DMSO) d 11.23 5s, 1H, NH), 7.38 5d,
3.3.10. )^)-6-Amino-9-)4-hydroxymethyl-2,5-dihydro-
furan-3-yl)-purine 22. To a solution of 19a 50.3 g,
0.85 mmol) in CH2Cl2 530 mL) were added Et3N
50.83 mL, 6 mmol) and mesyl chloride 50.33 mL,
4.2 mmol) at 08C. The reaction mixture was then stirred at
08C for 2 h. The reaction was quenched with water 52 mL).
Organic part was washed with saturated aqueous NaHCO3
530 mL) and water 530 mL), dried over Na2SO4 and evapo-
rated to dryness to give the mesyl derivative 20a. Crude
mesyl product 50.4 g) was dissolved in THF 540 mL) and
to this was added Bu4NF 51 M, 15 ml) at 08C and the solu-
tion was stirred at 08C for 1.5 h. The reaction mixture was
diluted with ethyl acetate 5100 mL). The organic part was
washed with NaHCO3 525 mL) and brine 530 mL), dried
over Na2SO4 and puri®ed over silica gel column to give
the elimination product 21. Compound 21 was always
contaminated with unidenti®ed impurities, so it was char-
acterized after converting it to amino derivative 22. A
solution of 21 in methanolic ammonia 512 mL) was heated
in a steel bomb for 20 h. Solvent was evaporated and the
residue was puri®ed over silica gel to give 22 50.045 g, 23%
from 19) as a pale yellow coloured solid powder. Mp:
1
Jˆ8.0 Hz, 1H, H-6), 5.57 5d, Jˆ8.0 Hz, 1H, H-5), 4.75 5d,
Jˆ5.0 Hz, 1H, H-40), 4.73 5t, Jˆ5.4 Hz, 1H, OH), 4.18 5dd,
Jˆ5.6, 10.4 Hz, 1H, H-20a), 3.96 5d, Jˆ10.4 Hz, 1H,
H-20b), 3.90 5d, Jˆ9.9 Hz, 1H, H-50a), 3.61 5d, Jˆ9.8 Hz,
1H, H-50b), 3.27 5m, 2H, CH2OH); 13C NMR 5d4-MeOH) d
166.2 5C-4), 153.4 5C-2), 144.0 5C-6), 103.3 5C-5), 84.2
5C-30), 76.4 5C-20), 71.9 5C-50), 64.9 5C-40), 63.8
5CH2OH); HRMS 5FAB): 5M1H)1 calcd for C9H13N2O5:
229.0824, found 229.0828.
3.3.7. )^)-4-)6-Amino-9H-purin-9-yl)-3-)hydroxymethyl)-
tetrahydrofuran-3-ol 18. A solution of 17a 50.1 g) in
saturated methanolic ammonia 515 mL) was heated at
808C for 20 h. Solvent was removed and the residue was
puri®ed over silica gel column to give 18 50.07 g, 75%) as
white powder. Mp: 2348C; UV 5MeOH) lmax 260.6 5e
1
15,500); H NMR 5d6-DMSO) d 8.14 5s, 1H, H-2), 7.97
5s, 1H, H-8), 7.26 5s, 2H, ±NH2), 4.89 5m, 1H, H-40), 4.61
5t, Jˆ6.0 Hz, 1H, ±OH), 4.34 5dd, Jˆ5.6, 9.8 Hz, 1H), 4.19
5dd, Jˆ2.1, 9.8 Hz, 1H), 4.03 5d, Jˆ9.7 Hz, 1H), 3.73 5d,
Jˆ9.7 Hz, 1H), 3.17 5dd, Jˆ4.9, 11.0 Hz, 1H), 2.98 5dd,
Jˆ6.1, 11.2, 1H). 13C NMR 5d6-DMSO) d 156.0 5C-6),
152.4 5C-2), 149.8 5C-4), 138.9 5C-8), 118.2 5C-5), 82.5
5C-30), 75.2 5C-20), 71.3 5C-50), 62.5 5CH2OH), 61.7
5C-40); HRMS 5FAB): 5M1H)1 calcd for C10H14N5O3:
252.1096, found 252.1100.
1
2468C; UV 5MeOH) lmax 259 5e 13,700); H NMR 5d6-
DMSO) d 8.23 5s, 1H, H-2), 8.15 5s, 1H, H-8), 7.39 5s,
2H, ±NH2), 5.12 5bs, 1H, ±OH), 5.00 5m, 2H, H-50), 4.82
5m, 2H, H-50), 4.15 5s, 2H, ±CH2OH); 13C NMR 5d6-
DMSO) d 156.2 5C-6), 153.0 5C-2), 149.3 5C-4), 139.9
5C-8), 130.7 5C-30), 124.7 5C-40), 118.4 5C-5); 75.6 5C-20),
73.3 5C-50), 54.2 5CH2OH); HRMS 5FAB): 5M1H)1 calcd
for C10H12N5O2: 234.0991, found 234.0989.
3.3.8.
)^)-4-)6-Chloro-9H-purin-9-yl)-3-)benzoyloxy-
methyl)-tetrahydrofuran-3-ol 19a. Benzoyl chloride
50.22 mL, 1.87 mmol) in pyridine 55 mL) was added drop-
wise at 08C to a solution of 17a 50.44 g, 1.63 mmol) in
pyridine 525 mL) for a period of 1 h. After the addition
the reaction mixture was stirred for another 2 h at 08C.
Saturated aqueous NaHCO3 525 mL) was added and the
solution was extracted with CH2Cl2 53£25 mL). The
combined organic part was evaporated under reduced pres-
sure, coevaporated with toluene. The residue was puri®ed
over silica gel column to give 19a 50.59 g. 84%) as solid
3.3.11. )^)-cis-6-Amino-9-)4-hydroxymethyl-tetrahydro-
furan-3-yl)-purine 23. A suspension of 22 50.03 g) and
Pd±C 510% Pd, 0.01 g) in MeOH±EtOAc 510 ml, 1:1) was
stirred under hydrogen pressure 525 PSI) for 16 h. The solu-
tion was ®lter and evaporated to dryness. The residue was
puri®ed over silica gel column to give 23 50.022 g, 73%) as
white powder. Mp: 2258C; UV 5MeOH) lmax 261 5e 14,700)
1H NMR 5CDCl31d4-MeOH, 1:1) d 8.01 5s, 1H, H-2), 7.80
5s, 1H, H-8), 5.02 5t, Jˆ4.9 Hz, 1H, H-30), 4.09 5d,
Jˆ10.5 Hz, 1H), 3.95 5m, 2H), 3.46 5t, Jˆ9.1 Hz, 1H), 3.00
5dd, Jˆ6.2, 11.4 Hz, 1H), 2.87 5dd, Jˆ7.8, 11.4 Hz, 1H), 2.77
1
white foam. Mp: 2028C; H NMR 5CDCl3) d 8.55 5s, 1H,
H-2), 8.41 5s, 1H, H-8), 7.69±7.27 5m, 5H, phenyl), 5.32 5d,
Jˆ4.2 Hz, 1H, H-40), 4.68 5bs, 1H, ±OH), 4.61 5dd, Jˆ4.8,
10.2 Hz, 1H), 4.32±4.06 5m, 5H). 13C NMR 5CDCl3) d
166.06 5carbonyl), 152.2 5C-2), 151.9/ 151.4 5C-4/C-6),
143.7 5C-8), 133.7 5phenyl), 131.1 5C-5), 129.6, 128.5
5phenyl), 82.5 5C-30), 75.7 5C-20), 72.1 5C-50), 64.9
5CH2OBz), 62.9 5C-40); HRMS 5FAB): 5M1H)1 calcd for
C17H16ClN4O4: 375.0860, found 375.0867.
1
5m, 1H). H NMR 5CDCl31d4-MeOH, 1:1) d 155.4 5C-6),
152.4 5C-2), 149.5 5C-4), 139.0 5C-8), 117.9 5C-5), 72.5
5C-20), 68.2 5C-50), 58.4 5CH2OH), 55.6 5C-30), 46.3 5C-40);
HRMS 5FAB): 5M1H)1 calcd for C10H14N5O2: 236.1147,
found 236.1152.
3.3.12. Compound 24. As described for 19a, compound
19b, 50.12 g, 0.36 mmol) on treatment with mesyl chloride
in CH2Cl2 gave the mesylated derivative 20b 50.1 g, 67%).
The mesylated derivative 20b 50.1 g, 0.24 mmol) was
dissolved in THF 515 mL) and to this solution was added
Bu4NF 55 mL, 1 M solution) at 08C. The reaction mixture
was stirred at 08C for 3 h. Saturated NaHCO3 550 mL) solu-
tion was added to the reaction mixture and the extracted
with EtOAc 53£20 mL). The combined EtOAc part was
dried over Na2SO4 and evaporated to dryness. The residue
was puri®ed over silica gel column to produce 24 50.05 g,
66%) as pale yellow solid. Mp: 2338C; UV 5MeOH) lmax
3.3.9.
)^)-4-[Pyrimidine-2,4)1H,3H)-dione-1-yl]-3-
)benzoyloxymethyl)-tetrahydrofuran-3-ol 19b. Com-
pound 19b was prepared following the same method as
described for 19a in 71% yield. Mp: 1828C; 1H NMR
5CDCl31d4-MeOH) d 7.99±7.41 5m, 6H, H-6, phenyl),
5.68 5d, Jˆ8.1 Hz, 1H, H-5), 5.07 5d, Jˆ5.3 Hz, 1H,
H-40), 4.41 5m, 3H), 4.12 52£d, Jˆ5.5, 4.6 Hz, 2H), 3.95
5d, Jˆ10.3 Hz, 1H); 13C NMR 5CDCl31d4-MeOH) d 165.9
5CO), 163.6 5C-4), 151.1 5C-2), 141.2 5C-6), 132.8, 129.1,
128.6, 127.8 5phenyl), 102.6 5C-5), 81.1 5C-30), 75.0 5C-20),
70.6 5C-50), 64.5 5CH2OBz), 63.1 5C-40); HRMS
5FAB): 5M1H)1 calcd for C16H17N2O6: 333.1087, found
229.0828.
1
253, 229 nm; H NMR 5CDCl31d4-MeOH) d 7.85±7.34
5m, 6H, H-6, phenyl), 6.02 5d, Jˆ7.4 Hz, 1H, H-5), 4.94

S. Bera, V. Nair / Tetrahedron 58 $2002) 4865±4871
4871
5d, Jˆ4.0 Hz, 1H, H-40), 4.34 5d, Jˆ11.4 Hz, 1H, CH2O),
4.17 5d, Jˆ11.4 Hz, 1H, CH2O), 3.81 5dd, Jˆ4.1, 11.3 Hz,
1H, H-50a), 3.73 5d, Jˆ11.2 Hz, 1H, H-50b); 13C NMR
5CDCl31d4-MeOH) d 172.6 5C-4), 165.6 5ester CO),
160.2 5C-2), 135.8 5C-6), 133.8, 129.5, 128.6, 128.2
5phenyl), 110.0 5C-5), 94.2 5C-30), 74.6 5C-50), 72.8
2. 5a) Sells, T. B.; Nair, V. Tetrahedron Lett. 1992, 33, 7639±
7642. 5b) Terao, Y.; Akamatsu, M.; Achiwa, K. Chem. Pharm.
Bull. 1991, 39, 823±825.
3. 5a) Santana, L.; Uriarte, E. T.; Balzarini, J.; Clercq, E. D.
Bioorg. Med. Chem. Lett. 1998, 8, 1349±1352. 5b) Nuesca,
M. Z.; Nair, V. Tetrahedron Lett. 1994, 35, 2485±2488.
4. 5a) Sells, T. B.; Nair, V. Tetrahedron 1994, 50, 117±138.
5b) Tronchet, J. M. J.; Tronchet, J. Helv. Chim. Acta. 1971,
54, 1466±1479. 5c) Parikh, D. K.; Watson, R. R. J. Med.
Chem. 1978, 21, 706±709. 5d) Tronchet, J. M. J.; Tronchet,
J.; Graf, R. J. Med. Chem. 1974, 17, 1055±1056.
5C-20),
65.5
5C-40),
63.0
5CH2OBz)
HRMS
5FAB): 5M1H)1 calcd for C16H15N2O5: 315.0980, found
315.0983.
3.4. X-Ray crystallographic data
5. Wenzel, T.; Nair, V. Biocongugate Chem. 1998, 9, 683±690.
6. Du, J.; Choi, Y.; Lee, K.; Chun, B. K.; Hong, J. H.; Chu, C. K.
Nucleosides Nucleotides 1999, 18, 187±195.
Crystallographic data for the structures in this paper have
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication numbers CCDC
178196 and 178197.
7. Chao, Q.; Zhang, J.; Pickering, L.; Jahnke, T. S.; Nair, V.
Tetrahedron 1998, 54, 3113±3124.
8. 5a) Action, E. M.; Goerner, R. N.; Uh, H. S.; Ryan, K. J.;
Henry, D. W. J. Med. Chem. 1979, 22, 518±525. 5b) Wengel,
J.; Schinazi, R. F.; Caruthers, M. V. Bioorg. Med. Chem. 1995,
3, 1223±1229.
Acknowledgements
This research work was supported by the NIH 5NIAID).
Single-crystal X-ray structure determinations were carried
out by Dr Dale Swenson. We thank Professors Erik De
Clercq and Jan Balzarini for antiviral evaluations.
9. 5a) Jenny, T. F.; Previsani, N.; Benner, S. A. Tetrahedron Lett.
1991, 32, 7029±7032. 5b) Bonnal, C.; Chavis, C.; Lucas, M.
J. Chem. Soc. Parkin Trans 1. 1994, 1401±1410. 5c) Jenny,
T. F.; Horlacher, J.; Previsani, N.; Benner, S. A. Helv. Chim.
Acta 1992, 75, 1944±1954. 5d) Jeong, L. S.; Yoo, S. J. Bioorg.
Med. Chem. Lett. 1998, 8, 847±852. 5e) Bera, S.; Nair, V.
Helv. Chim. Acta 2000, 83, 1398±1407.
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