Synthesis and biological activity of certain 4'-thio-D- arabinofuranosylpurine nucleosides

Article abstract of DOI:10.1021/jm980195+

A series of 4'-thio-D-arabinofuranosylpurine nucleosides was prepared and evaluated as potential anticancer agents. The details of a convenient and high-yielding synthesis of the carbohydrate precursor 1-O-acetyl-2,3,5-tri- O-benzyl-4-thio-D-arabinofurano

Full text of DOI:10.1021/jm980195+

J . Med. Chem. 1998, 41, 3865-3871
3865
Syn th esis a n d Biologica l Activity of Cer ta in 4′-Th io-D-a r a bin ofu r a n osylp u r in e
Nu cleosid es
J ohn A. Secrist III,* Kamal N. Tiwari, Anita T. Shortnacy-Fowler, Lea Messini, J ames M. Riordan, and
J ohn A. Montgomery*
Southern Research Institute, P.O. Box 55305, Birmingham, Alabama 35255-5305
Scott C. Meyers and Steven E. Ealick
Section of Biochemistry, Molecular and Cell Biology, Biotechnology Building, Cornell University, Ithaca, New York 14855
Received March 30, 1998
A series of 4′-thio-D-arabinofuranosylpurine nucleosides was prepared and evaluated as potential
anticancer agents. The details of a convenient and high-yielding synthesis of the carbohydrate
precursor 1-O-acetyl-2,3,5-tri-O-benzyl-4-thio-D-arabinofuranose (6) are presented. Proof of
structure and configuration at all chiral centers of the nucleosides was obtained through an
X-ray crystal structure of 9R as well as through NOE experiments on 9â and 9R. All six target
compounds were evaluated in a series of human cancer cell lines in culture. Two target
compounds, â anomers with diaminopurine (12) and guanine (16) as the bases, had significant
cytotoxicity. One of these compounds (12) was selected for animal studies but was found to
have no selectivity at the maximum tolerated dose in the murine colon 36 tumor model.
Interest in the synthesis and biological evaluation of
purine nucleosides and their analogues has continued
in recent years as new structures have been found to
have clinical activity as both anticancer1 and antiviral
agents.2 Fludarabine phosphate, which was developed
in our laboratory,3 has shown activity in a number of
human cancers4 and has been approved by the FDA for
the treatment of refractory lymphocytic leukemia. The
2-bromo-, 2-chloro-, and 2-fluoro-2′-deoxyadenosines all
have shown outstanding activity in murine leukemia
models,5 and the 2-chloro compound, known as cladrib-
ine,6 has received FDA approval for the treatment of
hairy cell leukemia. All of these 2-haloadenine nucleo-
sides are resistant to deamination by adenosine deami-
nase5 and are converted to the corresponding triphos-
phates. The 2-halo-2′-deoxyadenosines are readily
cleaved by Escherichia coli purine nucleoside phospho-
rylase (PNP) to the 2-haloadenines, which have no
selective cytotoxicity.7 2-Fluoroadenine has been de-
tected as a metabolite of fludarabine phosphate in
animals8 and humans,9 though the arabino nucleosides
are considerably more stable to enzymatic and hydro-
lytic degradation than the 2′-deoxy compounds. Some
years ago the resistance of 4′-thioinosine to cleavage by
PNP was reported,10 suggesting that this simple struc-
tural modification might impart resistance to phospho-
rolytic cleavage to nucleosides.
cal properties to certain members of the class, as either
the nucleoside or incorporated into oligonucleotide
chains.25 As a part of our research focused on the
development of new anticancer agents, we decided to
pursue the synthesis of certain 4′-thionucleosides with
the arabino configuration in the carbohydrate. Some
structures of this type were made over 20 years ago,18,20,22
and in particular our interest was prompted by the
significant cytotoxicity reported for 4′-thio-ara-C.22 As
noted above, a significant problem in obtaining these
compounds is the laborious synthetic routes,26 which
have been a major deterrent to obtaining sufficient
quantities to carry out both cell culture and animal
investigations. Our work in the area of 4′-thioarabino-
furanosyl nucleosides was initially disclosed several
years ago.15 Since then, another synthesis of 4′-thio-
arabinofuranosyl nucleosides has been reported, utiliz-
ing a very different and much longer synthetic approach
to the key carbohydrate intermediate.27
We herein report the details of a convenient synthesis
of a 4-thioarabinofuranose intermediate suitable for
conversion to nucleosides and its conversion to a series
of purine nucleoside analogues. These compounds have
been examined in anticancer screens, and both in vitro
and in vivo data are presented herein. To firmly
establish the identity of the carbohydrate as well as the
anomeric configuration of the nucleoside, the structure
of one compound (9R) has been determined by X-ray
crystallography, and that compound along with its
anomer (9â) have been examined in detail using NMR
spectroscopy.
On the basis of these considerations, we have under-
taken the synthesis and biological evaluation of a broad
series of 4′-thionucleosides with modifications in
both the nitrogen heterocyclic and the carbohydrate
moieties.11-16 A few 4′-thionucleosides were prepared
some years ago, though researchers were hampered by
laborious synthetic procedures.17-24 Interest by many
laboratories in the synthesis of various 4′-thionucleo-
sides has heightened recently as it has become clear that
this modification imparts desirable physical and biologi-
Ch em istr y
We have developed a five-step sequence to the ver-
satile carbohydrate precursor 6 using a strategy similar
to that previously used in our laboratory13 to prepare
2′-deoxy-4′-thionucleosides. The attractive features of
intermediate 6 include its ready accessibility as well as
S0022-2623(98)00195-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/01/1998

3866 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 20
Secrist et al.
Sch em e 1
the availability of both R and â anomers for biological
evaluation. Conversion of L-xylose to methyl 2,3,5-tri-
O-benzyl-L-xylofuranoside (3) was accomplished in two
steps by the usual method (Scheme 1). Conversion to
dibenzyl dithioacetal 4 employing benzyl mercaptan
and stannic chloride proceeded in 57% yield after
chromatographic purification. Cyclization at C-4 in-
volving a single inversion, thus converting the L-xylo to
the D-arabino configuration, was accomplished with
triphenylphosphine, iodine, and imidazole as previously
described.13 The final step, replacement of the ben-
zylthio group at C-1 by an acetoxy group, involved
treatment of 5 with mercuric acetate in acetic acid at
room temperature. The overall yield of 6 from 1,
including four column purifications, was 30%, and
afforded a ca. 1:1 mixture of R and â anomers. The
other recently reported synthesis of 6 requires 13 steps
with an overall yield of <10%.27
purification/separation. After treatment with ethanolic
ammonia to produce the respective blocked 2-chloroad-
enine nucleosides 8â and 8R, removal of the O-benzyl
groups was accomplished with BBr3 in CH2Cl2 at -78
°C to yield the final nucleoside targets 9â and 9R.
Treatment of 7â and 7R with sodium azide in aqueous
ethanol at reflux produced the corresponding 2,6-diazido
intermediates 10, which were subjected to reduction
with SnCl2 in CH2Cl2 to afford the blocked diaminopu-
rine nucleosides 11â and 11R in good yields. Deblocking
11â with BCl3 in CH2Cl2 produced the target diamino
nucleoside 12. Conversion of 12 to the corresponding
guanine nucleoside 16 was accomplished by treatment
with adenosine deaminase. Though the deamination
was slow, it went to completion at room temperature
in 15-20 h. The 2-fluoroadenine nucleosides 14â and
14R were also prepared starting from the separated
diaminopurine nucleoside anomers 11â and 11R. These
compounds were treated with HF-pyridine and tert-
butyl nitrite to produce the blocked 2-fluoroadenine
nucleosides 13â and 13R, which were deblocked with
BCl3 to the final target nucleosides. An acetylation/
deacetylation sequence via 15R was used to facilitate
the purification of the intractable solid 13R.
A series of purine nucleoside analogues were prepared
through the coupling of 6 and 2,6-dichloropurine. A
Lewis acid-catalyzed reaction utilizing SnCl4 in aceto-
nitrile was found to be an efficient method to achieve
this coupling, and 40% and 35% yields of â and R
anomers of 7 were obtained after chromatographic

4′-Thio-D-arabinofuranosylpurine Nucleosides
Ta ble 1. NOE Data (Hz)a
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 20 3867
Ta ble 2. Cytotoxicity Data: IC50 (µM)a,b
CCRF-CEM CAKI-1 DLD-1 NCI-H23 SK-MEL-28 SNB-7
compd
atom irradiated
H-8
H-1′
H-2′
H-3′
H-4′
compd (leukemia) (renal) (colon) (lung) (melanoma) (CNS)
9R
H-8
2.1
3.8
2.0
12
0.34 (>134)c
20
10
20
14
>25
>90
>100
>20
>25
>90
>100
>20
0.34
>90
>100
1.1
1.0
>90
>100
1.1
H-1′
H-2′
H-3′
H-4′
H-8
H-1′
H-2′
H-3′
H-4′
2.0
3.7
1.2
1.7
14â 30
2.7
1.3
1.9
14R >130
1.0
1.9
16
0.57
a
9â
1.0
9.7
5.4
7.3
1.7
Experimental details for the cell culture experiments on
1.0
7.8
8.7
CCRF-CEM cells are in ref 32; experimental details for the other
b
3.8
1.5
cell lines are in refs 33-35. No cytotoxicity was seen for 9â or
9R at the highest concentration used: 9â, 100 µM; 9R, 200 µM.
c In the presence of 2′-deoxycoformycin.
a
See Experimental Section for details.
glycosidic torsion angle C8-N9-C1′-S4′ has a value
of -57.71°. Crystallographic analysis show that the
O5′-hydroxyl of 9R is gauche-gauche with a torsion
angle S4′-C4′-C5′-O5′ equal to -59.15°. The C1′
atom deviates from the mean plane through the purine
base atoms by -0.14 Å, while the C3′ atom deviates by
0.64 Å from the mean plane through the four remaining
sugar atoms and is in agreement with standard val-
ues.28 Intermolecular hydrogen bonds stabilize the
crystal packing of the compound. Hydrogen bonds form
between O3′ and N1 atoms on two separate molecules
(3.24 and 3.18 Å). The O5′ position hydrogen bonds to
both N1 and O3′ (2.81 and 2.75 Å) and a final hydrogen
bond joins O2′ and N7 (2.67 Å).
F igu r e 1. ORTEP drawing of 9r.
Biologica l Da ta
To provide confirmatory evidence that the carbohy-
drate configuration and the anomeric configurations of
our target compounds had been properly assigned, the
NMR spectra of several compounds were examined by
NOE difference spectroscopy (see Table 1). Specifically,
NOE experiments were conducted on 9R in Me2SO-d6
with 1 drop of D2O, while those of 9â were conducted
in D2O solution because of the severe overlap of the H-2′
and H-3′ resonances in Me2SO-d6. In both compounds,
contacts between H-2′ and H-4′ demonstrated that the
single inversion desired in converting 4 to 5 had indeed
occurred. The NOE contacts between H-1′ and H-3′
confirm that 9R is the R isomer, while irradiation of the
H-8 signal of 9â, causing enhancement of the H-3′
signal, confirms it as the â anomer. Both 9â and 9R
appear to adopt predominantly the N conformation in
solution. In 9â, the large NOE between H-2′ and H-4′
and that between H-1′ and H-8 as well as the large J 2′,3′
of 9.5 Hz support the N conformation. Similarly, the
moderate NOE between H-2′ and H-4′, the NOE be-
tween H-1′ and H-3′, and the J 2′,3′ of 7.7 Hz show that
9R is also in the N conformation.
As a final structural proof for the series, and in order
to corroborate the NMR assignments and to compare
the carbohydrate conformation in solution and the solid
state, the crystal structure of 9R was determined by
single-crystal X-ray diffraction analysis (Figure 1). The
N conformation found for 9R and shown in Figure 1 is
consistent with the NMR data reported above. The
X-ray analysis also confirms the R anomeric configura-
tion. The arabinosyl group adopts a C2′-exo-C3′-endo
pucker with a calculated pseudorotation of 8.22°.28 The
substitution of a sulfur for an oxygen in the sugar ring
does not significantly affect the ring’s geometry or
conformation, as has been noted previously.29 The
endocyclic torsion angles starting with S4′ and proceed-
ing around the S4′-C1′-C2′-C3′-C4′ ring are 7.6°,
-33.3°, 49.9°, -42.7°, and 20.4°, respectively. The
The cell culture cytotoxicity of all six target com-
pounds was determined against six different human
cancer cell lines, identified in Table 2. Neither of the
two 2-chloroadenine-substituted nucleosides 9â and 9R
was found to be cytotoxic in any of the cell lines at the
highest concentrations utilized (see Table 2 footnote).
Significant cytotoxicity was seen with both 12 and 16,
the diaminopurine and guanine analogues with the â
configuration. Yoshimura et al. also reported significant
cytotoxicity for these compounds in one cell line.27 To
determine whether 12 was cytotoxic as the diaminopu-
rine nucleoside, or whether it required deamination in
order to exert its cytotoxicity, it was incubated with
CEM cells in the presence of 2′-deoxycoformycin, a
potent inhibitor of adenosine deaminase. Under those
conditions, no cytotoxicity was seen for 12, leading to
the conclusion that 16 is the cytotoxic agent. Modest
cytotoxicity was seen for both 14â and 14R against the
CAKI-1 renal line, and 14â also had very modest activity
against CEM cells. On the basis of these results, we
prepared larger quantities of 12 for evaluation in an
animal model. With nucleoside antimetabolites, we
initiate animal evaluations using the murine colon 36
model in female CD2F1 mice, which has proven to be a
good indicator of selectivity in compounds of this type.
After subcutaneous tumor implantation, the drug was
given by intraperitoneal injection three times a day at
4-h intervals for 9 days. The drug proved to be surpris-
ingly toxic, and the maximum tolerated dose range was
0.004-0.016 mg/kg/dose. At these levels no selective
inhibition of tumor growth was observed.
Exp er im en ta l Section
Melting points were determined on a Mel-Temp apparatus
and are uncorrected. 1H NMR spectra were recorded on a
Nicolet NT-300 NB spectrometer operating at 300.635 MHz
(1H). Chemical shifts are expressed in parts per million

3868 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 20
Secrist et al.
downfield from tetramethylsilane. The NOE experiments were
conducted on a degassed solution of DMSO-d6. To minimize
the effects of magnetic perturbations with the sample non-
spinning, eight FIDs were acquired with the decoupler set to
a desired frequency and eight FIDs were recorded with the
decoupler off resonance. The process was repeated until 800
FIDs had been acquired. UV absorption spectra were deter-
mined on a Perkin-Elmer lambda 9 spectrometer by dissolving
each compound in methanol or water and diluting 10-fold with
0.1 N HCl, pH 7 buffer, or 0.1 N NaOH. Numbers in
temperature. After the addition of CH3OH (25 mL) the
solution was evaporated under reduced pressure, and the crude
product was purified by silica gel chromatography (cyclohex-
ane/EtOAc, 9:1) to afford pure methyl 2,3,5-tri-O-benzyl-L-
xylofuranoside (3; 23 g, 87% yield): MS 435 (M + H)+, 433 (M
1
- H)+, 403 (M - OCH3)+; H NMR (CDCl3) δ 7.38-7.25 (m,
30H, aromatic H’s), 4.94 (d, 1H, H-1R, J 1,2 ) 4.3 Hz), 4.87 (d,
1H, H-1â, J 1,2 ) 0.9 Hz), 4.64-4.45 (m, 10H, PhCH2’s), 4.37
(m, 1H, H-4R), 4.27 (dt, 1H, H-4â, J 4,5a ) 3.7 Hz, J 4,5b ) 6.5
Hz, J 3,4 ) 6.2 Hz), 4.17 (t, 1H, H-3R, J 3,4 ) 6.9 Hz, J 2,3 ) 5.6
Hz), 4.07 (dd, 1H, H-3â, J 3,4 ) 6.2 Hz, J 2,3 ) 2.5 Hz), 4.00 (dd,
1H, H-2R, J 2,3 ) 5.6 Hz), 3.95 (t, 1H, H-2â, J 2,3 )2.5 Hz), 3.70
(dd, 1H, H-5aR, J 4,5a ) 4.5 Hz, J 5a,5b ) 10.4 Hz), 3.66 (dd, 1H,
H-5aâ, J 4,5a ) 3.7 Hz, J 5a,5b )10.7 Hz), 3.54 (dd, 1H, H-5bR,
J 4,5b ) 7.5 Hz), 3.49 (dd, 1H, H-5bâ, J 4,5b ) 6.5 Hz).
To a solution of 3 (42 g, 97 mmol) in CH2Cl2 (1000 mL) were
added benzyl mercaptan (49.6 g, 400 mmol) and SnCl4 (4.93
g, 18.9 mmol), and the reaction mixture was stirred at room
temperature overnight. After neutralization with 5% aqueous
NaHCO3 (750 mL), the organic layer was separated and the
aqueous layer was extracted with CH2Cl2 (500 mL). The
combined organic layers were evaporated, and crude 4 was
purified by silica gel chromatography (cyclohexane/EtOAc, 99:
1) to afford 4 (8.53 g, 57%) of sufficient purity to carry
forward: MS 657 (M + Li)+; 1H NMR (CDCl3) δ 7.35-7.29 (m,
19H, aromatic H’s), 7.19-7.13 (m, 4H, aromatic H’s), 7.01-
6.96 (m, 2H aromatic H’s), 4.86 (d, 1H, PhCHH, J ) 11.1 Hz),
4.70 (two overlapping d’s, 2H, PhCHH, PhCHH, J ) 11.1 Hz,
J ) 11.2 Hz), 4.43 (d, 1H, PhCHH, 11.2 Hz), 4.40 (d, 1H,
PhCHH, J ) 11.9 Hz), 4.36 (d, 1H, PhCHH, J ) 11.9 Hz), 4.07
(dd, 1H, H-2, J 1,2 ) 3.0 Hz, J 2,3 ) 7.5 Hz), 3.75-3.67 (m, 4H,
two PhCH2’s), 3.68 (d, 1H, H-1, J 1,2 ) 3.0 Hz), 3.36-3.25 (m,
2H, H-4, H-5a), 3.15-3.12 (m, 1H, H-5b), 2.22 (d, 1H, 4-OH, J
) 6.2 Hz).
2,3,5-Tr i-O-b e n zyl-1-O-a ce t yl-4-t h io-D-a r a b in ofu r a -
n ose (6). To a solution of 4 (13.0 g, 20 mmol) in dry 2:1
toluene/acetonitrile (200 mL) were added triphenylphosphine
(15.7 g, 60 mmol), iodine (12.7 g, 50 mmol), and imidazole (5.44
g, 80 mmol). The reaction mixture was stirred at 90 °C for 24
h after which time the solution was evaporated to dryness.
The crude product was purified by silica gel chromatography
(cyclohexane/EtOAc, 4:1) to afford benzyl 2,3,5-tri-O-benzyl-
1,4-dithio-D-arabinofuranoside as a syrup (5; 9.0 g, 83%): MS
543 (M + H)+; 1H NMR (CDCl3) δ 7.40-7.20 (m, 20H, aromatic
H’s), 4.69-4.42 (m, 6H, three PhCH2O’s), 4.37 (m, 1H, H-1),
4.20 (m, 2H, H-2, H-3), 3.87 (s, 2H, PhCH2S-), 3.80 (dd, 1H,
H-5a, J 4,5a ) 7.4 Hz, J 5a,5b ) 9.3 Hz), 3.55 (dd, 1H, H-5b, J 4,5b
) 7.1 Hz), 3.47 (m, 1H, H-4). Anal. (C33H34O3S2‚0.25H2O) C,
H.
parentheses are extinction coefficients (ꢀ × 10-3), sh
)
shoulder. Microanalyses were performed by Atlantic Microlab,
Inc. (Atlanta, GA) or the Molecular Spectroscopy Section of
Southern Research Institute. Analytical results indicated by
elemental symbols were within (0.4% of the theoretical values.
Mass spectra were recorded on a Varian/MAT 311A double-
focusing mass spectrometer in the fast atom bombardment
(FAB) mode. HPLC analyses were carried out on a Hewlett-
Packard HP1084B liquid chromatograph with a Waters As-
sociates µBondapak C18 column (3.9 mm × 30 cm) and UV
monitoring (254 nm). All chromatographic separations were
carried out by flash chromatography using 230-400 mesh
silica gel from E. Merck. TLC was carried out on Analtech
precoated (250 µm) silica gel (GF) plates.
Cr ysta llogr a p h y. Crystals of 9R suitable for X-ray dif-
fraction studies were obtained by recrystallization from a 50%
EtOH/H2O solution. The crystal chosen for data collection was
thin and platelike with approximate dimensions of 0.30 × 0.08
× 0.01 mm. The crystal belongs to the orthorhombic space
group P212121 with a ) 5.1470(10) Å, b ) 10.826(2) Å, c )
23.187(3) Å, V ) 1292.0(4) Å3, Z ) 4, and Dcalc ) 1.634 g/cm3.
Intensities were measured on a Nicolet P3 single-crystal X-ray
diffractometer using graphite monochromatized Cu KR radia-
tion (λ ) 1.5418 Å) and ω-2θ scans. Corrections were made
for Lorentz and polarization effects but not for absorption (µ
) 4.301 mm-1). All crystallographic data collection was carried
out using the Nicolet P3/V data collection system. A total of
1055 intensities were measured with 2θ < 110.04°. Of these
reflections, 16 had a net intensity less than zero and were
omitted from further calculations.
The structure was determined by direct methods using the
computer program SHELXS-8630 and refined using the com-
puter program SHELXL-93.31 All computations were per-
formed using a Digital Equipment Corp. Alpha computer
station. All non-hydrogen atoms were located from an E-map
and their positions partially refined. All hydrogen atom
positions were located using difference Fourier maps. The
structure was refined using full-matrix least-squares analysis
on F2 in which all non-hydrogen atoms were given anisotropic
thermal parameters. Hydrogen atoms were constrained to
have idealized geometry with tetrahedral angles. The hydro-
gen atom coordinates were reidealized before each cycle and
were tethered to the atoms to which they were attached. The
final R factor for 1039 independent reflections and 181
variables was 0.0704, and the goodness-of-fit was 1.102.
Figure 1 shows a computer-generated model of 9R. Positional
parameters and thermal parameters have been deposited as
Supporting Information.
2,3,5-Tr i-O-ben zyl-L-xylose Diben zyl Dith ioa ceta l (4).
L-Xylose (1; 25 g, 167 mmol) was stirred for 5 h in 0.5% HCl
in MeOH (675 mL) at room temperature and then neutralized
with Amberlite IRA-400 OH anion-exchange resin. The
filtrate and washings were combined and evaporated to
dryness, and the crude product was purified by silica gel
chromatography (CHCl3/MeOH, 92:8) to afford 26.2 g of methyl
L-xylofuranoside (2; 95% yield) as an R and â (1:1) mixture:
MS 164 (M)+, 165 (M + H)+, 133 (M - OCH3)+.
To an ice-cold solution of 2 (10 g, 60.9 mmol) in dry THF
(350 mL) was added sodium hydride (60% dispersion in
mineral oil, 14.8 g, 370 mmol), and the reaction mixture was
stirred for 15 min under N2. To this reaction mixture was
added solid tetrabutylammonium iodide (0.36 g, 0.96 mmol)
followed by a dropwise addition of benzyl bromide (36.6 g, 214
mmol). The reaction mixture was stirred for 3 days at room
To a suspension of mercuric acetate (7.29 g, 22.9 mmol) in
AcOH (96 g) was added 5 (5.42 g, 10 mmol), and the resulting
mixture was stirred at room temperature for 2 h. The reaction
mixture was diluted with CH2Cl2 (200 mL) and washed
successively with water, saturated aqueous NaHCO3, and 5%
aqueous KCN solution. The organic layer was dried over Na2-
SO4 and concentrated. Chromatography of the crude product
using cyclohexane/EtOAc (98:2) as eluent gave a mixture of R
and â (1:1) anomers of 6 (3.73 g, 78%) as a colorless syrup:
1
MS 479 (M + H)+; H NMR (CDCl3) δ 7.35-7.23 (m, 15H,
aromatic H’s), 6.07 (d, 0.25H, H-1â, J 1,2 ) 4.0 Hz), 5.98 (d,
0.75H, H-1R, J 1,2 ) 2.8 Hz), 4.83-4.45 (m, 6H, PhCH2’s), 4.26
(dd, 0.75H, H-2R, J 2,3 ) 5.4 Hz), 4.17-4.11 (m, 0.5H, H-2â,
H-3â), 4.03 (t, 0.75H, H-3R, J 3,4 ) 6 Hz), 3.80-3.67 (m, 1.25H,
H-4R, H-5aR, H-5aâ), 3.53-3.39 (m, 1.75H, H-5bR, H-4â,
H-5bâ), 2.06 (s, 3H, CH3-R and CH3-â). Anal. (C28H30O5S‚
0.75H2O) C, H.
9-(2,3,5-Tr i-O-ben zyl-4-th io-â- a n d -r-D-a r a bin ofu r a n o-
syl)-2,6-d ich lor op u r in e (7â a n d 7r). To a stirred mixture
of 6 (0.956 g, 2 mmol) and 2,6-dichloropurine (0.568 g, 3 mmol)
in acetonitrile (50 mL) at room temperature was added a
solution of SnCl4 in CH2Cl2 (3 mL of 1.0 M) over 1 min, and
stirring was continued for 2 h. The reaction was quenched
by pouring it into a mixture of 50 mL of CH2Cl2 and 25 mL of
saturated NaHCO3. The organic phase was dried (MgSO4) and

4′-Thio-D-arabinofuranosylpurine Nucleosides
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 20 3869
concentrated. The residue was purified by silica gel chroma-
tography (cyclohexane/EtOAc, 9:1) to afford 7â (485 mg, 40%)
eluting first followed by 7R (425 mg, 35%).
gel chromatography (CHCl3/MeOH, 97:3) to afford 11â (225
mg, 79%), which was suitable for deblocking: MS 569 (M +
H)+; 1H NMR (CDCl3) δ 8.19 (s, 1H, H-8), 7.37-7.20 (m, 13H,
aromatic H’s), 7.01 (m, 2H, aromatic H’s), 6.15 (d, 1H, H-1′,
J 1′,2′ ) 5.3 Hz), 5.36 (bs, 2H, NH2), 4.68 (d, 1H, PhCHH, J )
11.7 Hz), 4.67 (bs, 2H, NH2), 4.58-4.50 (m, 4H, two PhCH2’s),
Com p ou n d 7â: MS 608 (M + H)+; 1H NMR (CDCl3) δ 8.91
(s, 1H, H-8), 7.36-7.17 (m, 13H, aromatic H’s), 6.94 (m, 2H,
aromatic H’s), 6.22 (d, 1H, H-1′, J 1′,2′ ) 4.9 Hz), 4.68 (d, 1H,
PhCHH, J ) 11.6 Hz), 4.54 (s, 2H, PhCH2-), 4.52 (s, 2H,
PhCH2-), 4.50 (d, 1H, PhCHH-, J ) 11.6 Hz), 4.35-4.26 (m,
4.32 (dd, 1H, H-3′, J 3′,4′ ) 6.3 Hz), 4.22 (dd, 1H, H-2′, J 2′,3′
)
7.0 Hz), 3.72-3.62 (m, 2H, H-5′a, H-5′b), 3.53 (m, 1H, H-4′).
2H, H-2′, H-3′), 3.68 (dd, 1H, H-5′a, J 4′,5′a ) 4.6 Hz, J 5′a,5′b
)
9-(2,3,5-Tr i-O-ben zyl-4-th io-r-D-a r a bin ofu r a n osyl)-9H-
p u r in e-2,6-d ia m in e (11r). This compound was prepared in
75% yield by the same procedure as reported above for 11â
but starting from 7R, affording material suitable for deblock-
10.0 Hz), 3.65 (dd, 1H, H-5′b, J 4′,5′b ) 4.8 Hz), 3.54 (m, 1H,
H-4′, J 3′,4′ ) 5.0 Hz); 13C NMR (CDCl3) δ 153.3 (C-2), 152.5
(C-4), 151.3 (C-6), 146.8 (C-8), 137.4, 137.2, 136.1 (ipso C’s),
130.7 (C-5), 128.6, 128.5, 128.3, 128.21, 127.9, 127.6 (aromatic
C’s), 84.6 (C-3′), 80.7 (C-2′), 73.4, 73.3, 73.2 (three PhCH2-’s),
68.3 (C-5′), 57.4 (C-1′, J ) 162.0 Hz), 47.0 (C-4′).
1
ing: MS 569 (M + H)+; H NMR (CDCl3) δ 7.89 (s, 1H, H-8),
7.35-7.24 (m, 13H, aromatic CH’s), 7.13-7.18 (m, 2H, aro-
matic CH’s), 6.00 (d, 1H, H-1′, J 1′,2′ ) 4.0 Hz), 5.44 (bs, 2H,
NH2), 4.74 (bs, 1H, NH2), 4.64 (d, 1H, PhCHH-, J ) 12.1 Hz),
4.58 (d, 1H, PhCHH-, J ) 12.1 Hz), 4.52-4.49 (m, 4H,
PhCH2’s), 4.41 (t, 1H, H-2′, J 2′,3′ ) 3.2 Hz), 4.19 (t, 1H, H-3′,
J 3′,4′ ) 4.0 Hz), 4.01 (ddd, 1H, H-4′), 3.76 (dd, 1H, H-5′b, J 4′,5′b
) 7.4 Hz, J 5′a,5′b ) 9.6 Hz), 3.54 (dd, 1H, H-5′a, J 4′,5′a ) 6.7
Hz).
Com p ou n d 7r: MS 608 (M + H)+; 1H NMR (CDCl3) δ 8.49
(s, 1H, H-8), 7.36-7.21 (m, 13H, aromatic H’s), 7.01 (m, 2H,
aromatic H’s), 6.09 (d, 1H, H-1′, J 1′,2′ ) 2.1 Hz), 4.69 (s, 2H,
PhCH2-), 4.57 (d, 1H, PhCHH-, J ) 12.0 Hz), 4.51 (d, 1H,
PhCHH-, J ) 12.0 Hz), 4.48 (d, 1H, PhCHH-, J ) 11.9 Hz),
4.33 (d, 1H, PhCHH-, J ) 11.9 Hz), 4.26 (t, 1H, H-2′, J 1′,2′
)
2.1 Hz, J 2′,3′ ) 2.5 Hz), 4.23 (t, 1H, H-3′, J 3′,4′ ) 2.5 Hz), 4.07
(m, 1H, H-4′), 3.80 (dd, 1H, H-5′a, J 4′,5′a ) 8.2 Hz, J 5′a,5′b ) 9.5
Hz), 3.56 (dd, 1H, H-5′b, J 4′,5′b ) 6.7 Hz); 13C NMR (CDCl3) δ
152.5 (C-2), 152.4 (C-4), 151.3 (C-6), 146.2 (C-8), 137.7, 136.7
136.5 (ipso C’s), 131.2 (C-5), 128.4, 128.1, 127.9, 127.8, 127.7,
127.6 (aromatic C’s), 88.3 (C-3′), 85.2 (C-2′), 73.2, 72.7, 72.4
(three PhCH2-’s), 71.5 (C-5′), 64.5 (C-1′, J ) 160.0 Hz), 53.7
(C-4′).
9-(4-T h io -â-D -a r a b in ofu r a n osyl)-9H -p u r in e -2,6-d i-
a m in e (12). An ice-cold solution of 11â (654 mg, 1.15 mmol)
in CH2Cl2 (2.6 mL) was added dropwise to a solution of 1 M
BCl3 in CH2Cl2 (100 mL) at -50 °C. Solid precipitated from
the solution near the end of addition. The reaction in a tightly
sealed flask was stored at -20 °C for 16 h. The resulting clear
solution was evaporated to dryness at -20 °C to give a dark
residue. A solution of this material in ice-cold CH2Cl2 (25 mL)
was evaporated to dryness four times to provide a foam. Ice-
cold saturated aqueous NaHCO3 (20 mL) was added to the
foam, and the mixture was stirred vigorously until the pH
remained stable (pH 7-8). Water (150 mL) was added to form
a clear solution that was extracted with two portions of CH2-
Cl2 (50 mL, 25 mL) to remove color and impurities. The
colorless aqueous layer was held briefly under vacuum to
remove residual CH2Cl2 before being applied to a column (13
× 190 mm) of Bio Beads SM-4 (100-200 mesh; Bio-Rad
Laboratories) equilibrated in water. Water elution with
fractions monitored at 254 nm provided pure 12 that was
crystallized from hot H2O (233 mg, 68%). More 12 was
obtained from the column with a MeOH wash (33 mg, 10%):
mp 285 °C dec (lit.27 mp 292-295 °C); TLC 3:1:0.1 CHCl3-
MeOH-NH4OH, Rf 0.30; HPLC 100%, 3:1 NH4H2PO4 (0.01 M,
pH 5.1)-MeOH; MS 299 (M + H)+; UV λmax pH 1, 255 (11.1),
291 (10.9), pH 7, 257 (9.72), 280 (11.6), pH 13, 258 (9.67), 280
(11.8); 1H NMR and microanalytical data have been previously
reported.27
2-Ch lor o-9-(4-th io-â-D-a r a bin ofu r a n osyl)a d en in e (9â).
A mixture of compound 7â (608 mg, 1 mmol) and saturated
ethanolic ammonia (100 mL) was heated at 50 °C in a glass-
lined stainless steel pressure vessel for 48 h. The reaction
mixture was evaporated to dryness to afford a solid (8â) that
was dissolved in CH2Cl2 (50 mL) and was treated at -78 °C
under argon with a solution of 1 M BBr3 in CH2Cl2 (12 mL).
After the mixture stirred for 0.5 h at -78 °C, CH3OH (10 mL)
was added, followed by pyridine (10 mL), and the solution was
evaporated to dryness. The brown-colored crude product was
purified by silica gel chromatography (CHCl3/MeOH, 7:1) to
afford compound 9â as a white powder that was crystallized
from EtOH (257 mg, 81%): mp 207-209 °C; MS 318 (M +
1
H)+; H NMR (DMSO-d6) δ 8.39 (s, 1H, H-8), 7.78 (br s, 2H,
NH2), 5.90 (d, 1H, H-1′, J 1′,2′ ) 5.2 Hz), 5.74 (d, 1H, 2′-OH, J
) 4.3 Hz), 5.51 (d, 1H, 3′-OH, J ) 4.6 Hz), 5.18 (t, 1H, 5′-OH,
J ) 5.1 Hz), 4.12-4.08 (m, 2H, H-3′, H-2′), 3.80 (dd, 1H, H-5′a,
J 4′,5′a ) 4.3 Hz, J 5′a,5′b ) 11.2 Hz), 3.77 (dd, 1H, H-5′b, J 4′,5′b
)
6.5 Hz), 3.22 (mm, 1H, H-4′, J 3′,4′ ) 6.4 Hz). Anal. (C10H12
-
ClN5O3S) C, H, N.
2-F lu or o-9-(2,3,5-t r i-O-b en zyl-4-t h io-â-D-a r a b in ofu r a -
n osyl)a d en in e (13â). Diamino compound 11â (91 mg, 0.16
mmol) was dissolved in 1:1 HF-pyridine at 0-5 °C by vigorous
stirring and sonication. To this cloudy solution at -20 °C was
added tert-butyl nitrite (30 µL, 0.24 mmol). After 2.75 h, more
tert-butyl nitrite (8 µL, 0.065 mmol) was added, and the
reaction was held at -15 °C for an additional 1 h. The cold
reaction solution was added dropwise over 0.5 h to a vigorously
stirred mixture of saturated aqueous NaHCO3 and ice (400
mL). The mixture was stirred until most of the ice had melted.
Small portions of solid NaHCO3 were added to stabilize the
pH at 7-8 (monitor with pH paper). CHCl3 (50 mL) was
added, the layers were separated, and the aqueous layer was
extracted with more CHCl3 (2 × 50 mL). The combined CHCl3
layers were washed with H2O (2 × 50 mL), dried (MgSO4),
and evaporated to dryness. The resulting residue was taken
up in CHCl3 and applied to two Analtech GF plates (20 × 20
cm, 1000 µm) that were developed in 95:5 CHCl3/MeOH.
Extraction of the desired band with 1:1 CHCl3/MeOH yielded
upon evaporation essentially pure 13â (70 mg, 76%). This
residue was used directly in the deprotection step described
below. Crystallization of a small sample from MeOH gave
pure 13â: mp 196-197 °C; TLC 98:2 CHCl3-MeOH, Rf 0.50;
HPLC 100%, 9:1 MeCN/H2O; MS 572 (M + H)+; UV (EtOH)
λmax 263 (16.8), 271 (sh); 1H NMR (CDCl3) δ 8.48 (s, 1H, H-8),
7.36-7.18 (m, 13H, aromatic CH’s), 6.99 (m, 2H, aromatic
2-Ch lor o-9-(4-th io-r-D-a r a bin ofu r a n osyl)a d en in e (9r).
This compound was prepared from 7R by the same procedure
as reported for 9â in 56% yield after two crystallizations from
EtOH: mp 237 °C dec; TLC 3:1:0.1 CHCl3-MeOH-NH4OH,
Rf 0.55; MS 318 (M + H)+; UV λmax pH 1, 266 (14.7), pH 7, 265
1
(15.6), pH 13, 266 (15.3); H NMR (DMSO-d6) δ 8.47 (s, 1H,
H-8), 7.82 (br s, 2H, NH2), 5.83 (d, 1H, 2′-OH, J ) 5.5 Hz),
5.66 (d, 1H, 3′-OH, J ) 5.0 Hz), 5.65 (d, 1H, H-1′, J 1′,2′ ) 7.1
Hz), 4.98 (dd, 1H, 5′-OH, J 5′a,OH ) 4.6 Hz, J 5′b,OH ) 6.0 Hz),
4.48 (m, 1H, H-2′, J 2′,3′ ) 7.7 Hz), 3.90 (m, 1H, H-5′a, J 4′,5′a
)
3.8 Hz, J 5′a,5′b ) 10.9 Hz), 3.75 (m, 1H, H-3′, J 3′,4′ ) 8.2 Hz),
3.64 (m, 1H, H-4′), 3.44 (m, 1H, H-5′b, J 4′,5′b ) 8.3 Hz). Anal.
(C10H12ClN5O3S) C, H, N.
9-(2,3,5-Tr i-O-ben zyl-4-th io-â-D-a r a bin ofu r a n osyl)-9H-
p u r in e-2,6-d ia m in e (11â). A solution of 7â (303 mg, 0.5
mmol) and sodium azide (162.5 mg, 2.5 mmol) in 20 mL of
95% EtOH was heated at reflux for 2 h. The solvent was
removed in vacuo, and the residue was partitioned between
CH2Cl2 and H2O. The organic phase was dried (MgSO4) and
concentrated in vacuo to yield 290 mg of a yellowish solid (10â)
[TLC CHCl3/MeOH, 97:3; Rf 0.45; MS m/z 621 (M + H)+],
which was redissolved in 20 mL of CH2Cl2 and 2 mL of CH3-
OH. This solution was treated with SnCl2 (190 mg, 1 mmol),
and the resulting suspension was stirred for 30 min. After
evaporation of solvent, purification was accomplished by silica

3870 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 20
Secrist et al.
CH’s), 6.16 (d, 1H, H-1′, J 1′,2′ ) 5.3 Hz), 5.76 (bs, 2H, NH2),
4.69 (d, 1H, PhCHH-, J ) 11.7 Hz), 4.55 (dd, 1H, PhCHH, J
) 11.3 Hz), 4.53 (s, 2H, PhCHH), 4.47 (d, 1H, PhCHH, J )
11.7 Hz), 4.44 (d, 1H, PhCHH, J ) 11.3 Hz), 4.33 (dd, 1H,
H-3′, J 3′,4′ ) 6.3 Hz), 4.20 (dd, 1H, H-2′, J 2′,3′ ) 7.4 Hz), 3.70
(m, 1H, H-5′b, J 4′,5′b ) 4.7 Hz), 3.68 (m, 1H, H-5′a, J 4′,5′a ) 4.6
Hz), 3.53 (m, 1H, H-4′). Anal. (C31H30FN5O3S‚0.25H2O) C, H,
N.
2-F lu or o-9-(2,3,5-t r i-O-b en zyl-4-t h io-2-D-a r a b in ofu r a -
n osyl)a d en in e (13r). Conversion of 11R to 13R was ac-
complished in 62% yield by the procedure reported above for
13â: mp 135-136 °C; TLC 98:2 CHCl3-MeOH, Rf 0.40; HPLC
100%, 9:1 MeCN-H2O; MS 572 (M + H)+; UV (EtOH) λmax
263 (16.7), 270 (sh); 1H NMR (CDCl3) δ 8.14 (s, 1H, H-8), 7.34-
7.19 (m, 13H, aromatic CH’s), 7.06-7.09 (m, 2H, aromatic
CH’s), 6.04 (d, 1H, H-1′, J 1′,2′ ) 2.5 Hz), 5.95 (bd, 1H, NH2),
4.70 (d, 1H, PhCHH, J ) 12.3 Hz), 4.64 (d, 1H, PhCHH, J )
12.3 Hz), 4.55 (d, 1H, PhCHH, J ) 12.0 Hz), 4.50 (d, 1H,
PhCHH, J ) 12.0 Hz), 4.47 (d, 1H, PhCHH, J ) 12.1 Hz), 4.40
(d, 1H, PhCHH, J ) 12.1 Hz), 4.33 (t, 1H, H-2′, J 2′,3′ ) 2.9
Hz), 4.22 (t, H, H-3′, J 3′,4′ ) 3.1 Hz), 4.05 (ddd, 1H, H-4′), 3.78
(dd, 1H, H-5′b, J 4′,5′b ) 8.0 Hz, J 4′,5′b ) 9.6 Hz), 3.56 (dd, 1H,
H-5′a, J 4′,5′a ) 6.7 Hz). Anal. (C31H30FN5O3S) C, H, N.
mixture was refrigerated for 5 days and then evaporated. The
white solid residue was crystallized from boiling EtOH (10 mL)
to give pure 14R (72 mg, 38% from 13R): mp 290 °C dec; TLC
3:1:0.1 CHCl3-MeOH-NH4OH, Rf 0.60; HPLC 99%, 7:3
NH4H2PO4 (0.01 M, pH 5.1)-MeOH; MS 302 (M + H)+; UV
λmax pH 1, 262 (14.8), 270 (sh), pH 7, 262 (15.6), 270 (sh), pH
13, 262 (15.7), 270 (sh); 1H NMR (DMSO-d6) δ 8.39 (s, 1H, H-8),
7.83 (bs, 2H, NH2), 5.81 (d, 1H, 2′-OH, J ) 6.0 Hz), 5.63 (d,
1H, 3′-OH, J ) 5.0 Hz), 5.61 (d, 1H, H-1′, J 1′,2′ ) 7.1 Hz), 4.96
(t, 1H, 5′-OH, J ) 4.7, 6.0 Hz), 4.48 (dd, 1H, H-2′, J 2′,3′ ) 7.7
Hz), 3.89 (dd, 1H, H-5′b, J 4′,5′b ) 3.7 Hz, J 5′a,5′b ) 10.8 Hz),
3.73 (t, 1H, H-3′, J 3′,4′ ) 7.1 Hz), 3.64 (dt, 1H, H-4′), 3.42 (dd,
1H, H-5′a, J 4′,5′a ) 8.1 Hz). Anal. (C10H12FN5O3S‚0.15C2H5-
OH) C, H, N.
9-(4-Th io-â-D-a r a bin ofu r a n osyl)gu a n in e (16). To a so-
lution of 12 (51 mg, 0.17 mmol) in 20 mL of water was added
100 units of calf intestine adenosine deaminase type VIII (40
µL; Boehringer Mannheim GmbH). The reaction was stirred
for 17 h, the solution was boiled for 3 min to deactivate the
enzyme, and the suspension was treated with charcoal and
filtered through Celite. The filtrate was concentrated to give
gelatinous 16 which was dissolved in hot H2O (4 mL) and
filtered through a 0.45-µm filter (25 mm; Gelman Acrodisc
GHP-GF). The clear filtrate was lyophilized to provide 16 as
a fluffy white solid (44 mg, 73%): mp >250 °C dec (lit.27 mp
260-264 °C); TLC 4:1 MeCN/1 N NH4OH, Rf 0.40; HPLC
99.6%, 9:1 NH4H2PO4 (0.01 M, pH 5.1)-MeOH; MS 300 (M +
H)+; UV λmax pH 1, 257 (12.5), 282 (sh), pH 7, 255 (14.8), 273
(sh), pH 13, 257 (sh), 268 (12.3); 1H NMR and microanalytical
data have been reported.27
2-F lu or o-9-(4-th io-â-D-a r a bin ofu r a n osyl)a d en in e (14â).
An ice-cold solution of 13â (69 mg, 0.12 mmol) in CH2Cl2 (1.5
mL) was added dropwise under argon to 5 mL of 1.0 M BCl3
in CH2Cl2 chilled to -40 °C. The mixture, which contained a
small amount of undissolved solid, was stirred at -30 °C for
30 min and then allowed to stand at -20 °C for 23 h. The
resulting clear solution was evaporated to dryness beginning
at -20 °C. The residue was coevaporated with cold CH2Cl2
(4 × 3 mL) producing a solid that was suspended in cold
aqueous saturated NaHCO3 (5 mL). After addition of EtOH
(5 mL) the mixture was heated to boiling, treated with
charcoal, filtered (Celite), and concentrated to provide crude
14â. This material was purified by preparative TLC (Analtech
GF taper plates, 20 × 20 cm, 1000 µm) with development in
3:1:0.1 CHCl3/MeOH/NH4OH. The isolated material was
crystallized from EtOH to give pure 14â (19 mg, 53%): mp
235 °C; TLC 3:1:0.1 CHCl3-MeOH-NH4OH, Rf 0.60; HPLC
99%, 7:3 NH4H2PO4 (0.01 M, pH 5.1)-MeOH; MS 302 (M +
H)+; UV λmax pH 1, 263 (15.4), 270 (sh), pH 7, 262 (16.5), 270
Ack n ow led gm en t . This investigation was sup-
ported by NIH Grant No. CA34200. We gratefully
acknowledge the data received from the following
laboratories at Southern Research Institute: Drs. Steven
M. Schmid, L. Lee Bennett, and William B. Parker (cell
culture data); Dr. William J . Waud (animal data); Ms.
Sheila Campbell (HPLC analyses). Spectral data were
gathered in the Molecular Spectroscopy Laboratory at
Southern Research.
1
(sh), pH 13, 263 (16.8), 270 (sh); H NMR (DMSO-d6) δ 8.35
Su p p or tin g In for m a tion Ava ila ble: Listings of atomic
coordinates, bond lengths, bond angles, anisotropic displace-
ment parameters, hydrogen coordinates, and isotropic dis-
placement parameters (6 pages). Ordering information is
given on any current masthead page.
(s, 1H, H-8), 7.77 (bs, 2H, NH2), 5.87 (d, 1H, H-1′, J 1′,2′ ) 5.0
Hz), 5.72, (bd, 1H, 2′-OH, J ) 4.1 Hz), 5.49 (d, 1H, 3′-OH, J )
4.8 Hz), 5.17 (bt, 1H, 5′-OH, J ) 4.8 Hz), 4.12-4.05 (m, 2H,
H-2′, H-3′), 3.82 (m, 1H, H-5′a, J 4′,5′a ) 4.2 Hz, J 5′a,5′b ) 11.2
Hz), 3.76 (m, 1H, H-5′b, J 4′,5′b ) 6.9 Hz), 3.22 (m, 1H, H-4′).
Anal. (C10H12FN5O3S‚0.3C2H5OH‚0.6H2O) C, H, N.
Refer en ces
2-F lu or o-9-(4-th io-r-D-a r a bin ofu r a n osyl)a d en in e (14r).
Treatment of 13R (357 mg, 0.62 mmol) with BCl3 as reported
above for 13â provided crude 14R (222 mg) as an intractable
solid containing 10% of an unknown impurity. This material
was dissolved in pyridine (10 mL) at 5 °C and treated with
acetic anhydride (0.63 mL, 6.5 mmol). This solution was
stirred at room temperature for 20 h and then poured into ice
water (300 mL). CHCl3 (50 mL) was added, the layers were
separated, and the aqueous layer was extracted with ad-
ditional CHCl3 (2 × 50 mL). The combined CHCl3 layers were
washed with H2O (2 × 25 mL), dried (MgSO4), and evaporated
to give 196 mg of crude acetylated nucleoside 15R. Purification
of 15R was accomplished by preparative TLC (Analtech GF,
20 × 20 cm, 2000 µm) developed twice in 4:1 EtOAc/cyclohex-
ane. The EtOAc extract of the plate bands was evaporated
and then crystallized from hot 2-propanol to yield a white solid
(116 mg): mp 175-176 °C; TLC 4:1 EtOAc/cyclohexane, Rf
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1
0.50; MS 428 (M + H)+; H NMR (CDCl3) δ 8.13 (s, 1H, H-8),
6.07 (d, 1H, H-1′, J 1′,2′ ) 4.1 Hz), 6.02 (bs, 2H, NH2), 5.73 (t,
1H, H-2′, J 2′,3′ ) 5.2 Hz), 5.48 (t, 1H, H-3′, J 3′,4′ ) 4.8 Hz), 4.39
(dd, 1H, H-5′a, J 4′,5′a ) 7.0 Hz, J 5′a,5′b ) 11.2 Hz), 4.21 (m, 1H,
H-5′b, J 4′,5′b ) 6.5 Hz), 4.13 (m, 1H, H-4′), 2.12 (s, 3H, CH3),
2.10 (s, 3H, CH3), 2.07 (s, 3H, CH3).
Acetylated nucleoside 15R (109 mg, 0.25 mmol) was treated
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4′-Thio-D-arabinofuranosylpurine Nucleosides
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