Synthesis of 4'-thiopurine nucleosides using hypervalent iodine compounds

Article abstract of DOI:10.3987/COM-07-11250

The reaction of a silylated purine base with thiofuranoid using phenyl iodosyl bis(trifluoroacetate) gave 4'-thio purine nucleosides.

Full text of DOI:10.3987/COM-07-11250

HETEROCYCLES, Vol. 75, No. 3, 2008
619
HETEROCYCLES, Vol. 75, No. 3, 2008, pp. 619 - 634. © The Japan Institute of Heterocyclic Chemistry
Received, 22nd October, 2007, Accepted, 5th December, 2007, Published online, 11th December, 2007. COM-07-11250
SYNTHESIS
OF
4'-THIOPURINE
NUCLEOSIDES
USING
HYPERVALENT IODINE COMPOUNDS
Naozumi Nishizono,* Kayo Soma, Ryosuke Baba, Minoru Machida, and
Kazuaki Oda*
Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido,
Ishikari-Tobetsu, Hokkaido 061-0293, Japan
E-mail: nishizon@hoku-iryo-u.ac.jp
Abstract – The reaction of a silylated purine base with thiofuranoid using phenyl
iodosyl bis(trifluoroacetate) gave 4'-thio purine nucleosides.
INTRODUCTION
Nucleoside analogues are recognized as an important class of biologically active compounds, especially
as antiviral and antitumor agents. Therefore, many nucleoside derivatives have been synthesized and
their biological activities have been evaluated.
Among these, thionucleosides are attractive
compounds that contain sulfur either in the nucleobase or the sugar moiety.1 4'-Thionucleosides, in
which the furanose ring oxygen is replaced by a sulfur atom, have been studied extensively over the past
10 years because a number of 4'-thionucleoside analogs have emerged as potent antiviral agents.
Importantly, these analogs have good metabolic stability against phosphorylase enzymes2 that cleave the
glycosidic bond of nucleosides.
We recently reported a novel method for synthesizing 4'-thio pyrimidine nucleosides based on the
condensation of thiofuranoid and silylated nucleobases in the presence of a hypervalent iodine
compound.3 In this paper, the application of this approach to the synthesis of purine 4'-thionucleosides
1-2 is described (Figure 1). These thionucleosides 1 are expected to act as inhibitors of an
S-adenosyl-L-homocysteine hydrolase, which has emerged as a target enzyme for the molecular design of
antiviral agents.4
NH2
NH2
N
N
N
N
N
N
HO
N
N
X
S
S
1a: X = H
1b
HO
OH
: X = F
1c: X = Cl
HO
OH
2
Figure 1. Structures of target compounds

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HETEROCYCLES, Vol. 75, No. 3, 2008
RESULTS AND DISCUSSION
First, the coupling reaction of 3 with purine in the presence of a hypervalent iodine compound was
examined under various conditions (Table 1). When 6-chloropurine was treated with 3 under conditions
similar to those used for the synthesis of 4'-thio pyrimidine nucleosides,3 the desired 4a was not obtained;
instead, thiophene derivative 5 was produced due to the low nucleophilicity of the purine base. Using
phenyl iodosyl bis(trifluoroacetate) (PIFA) instead of iodosobenzene, the desired 4a was obtained in 35%
yield along with the N-7 stereoisomer (24%).
The nucleobases 2,6-dichloropurine and
2-fluoro-6-chloropurine similarly reacted with 3 to give products 4b and 4c, respectively. In the case of
2,6-dichloropurine, the product 4c was obtained in 72% yield.
Table 1. Coupling reaction of 3 with purine base.
Cl
N
N
N
N
X
S
S
S
+
CH2Cl2, 0 ºC
4a: X = H
4b: X = F
4c: X = Cl
BzO
OBz
BzO
OBz
BzO
5
3
yield of 4
ratio
(β:α)
entry
base
condition
(%)
6-chloropurine
6-chloropurine
PhI=O (1.5 eq), TMSOTf (10 eq), Et3N (10 eq)
PIFA (1.5 eq), TMSOTf (10 eq), Et3N (10 eq)
PIFA (1.5 eq), TMSOTf (10 eq), Et3N (10 eq)
PIFA (1.5 eq), TMSOTf (10 eq), Et3N (10 eq)
-
-
1
2
3
4
35
36
72
5:1
3:1
15:1
2-fluoro-6-chloropurine
2,6-dichloropurine
The target compounds 1a-c were obtained by treating 4a-c with methanolic ammonia in a steel container
at 100 °C (Scheme 1).
Cl
N
NH2
N
N
N
N
N
N
X
N
X
NH3 / MeOH
100 ºC
S
S
BzO
OBz
HO
OH
4a: X = H
4b: X = F
1a: X = H (quant.)
1b: X = F (81%)
1c: X = Cl (67%)
4c
: X = Cl
Scheme 1

HETEROCYCLES, Vol. 75, No. 3, 2008
621
Next, the synthesis of 4'-thioadenosine (2)5 was examined. Thiofuranoids 10a-d were prepared as
shown in Scheme 2. 1,4-Anhydro-2,3-isopropylidene-4-thio-D-ribitol (7), prepared from
D-glulono-γ-lactone (6) by a modification of the method of Jeong et al. 6, was treated with 80% acetic
acid under reflux to give 1,4-anhydro-4-thio-D-ribitol (8) in 81% yield. The 3- and 5-hydroxy groups of
8 were first protected with silyl groups, and the resulting silylated compounds 9 were then reacted with
acyl chloride to give 10.
HO
HO
O
S
S
i, ii
iii
O
HO
HO
81%
76%
O
O
HO OH
HO
OH
6
7
8
O
O
R1
S
S
iv or v
vi or vii
R1
O
OH
O
OR2
9a : R1 = TIPDS (70%)
9b : R1 = BTDS (76%)
10a : R1 = TIPDS, R2 = PMBz (98%)
10b : R1 = TIPDS, R2 = Bz (90%)
10c : R1 = BTDS, R2 = PMBz (67%)
10d : R1 = BTDS, R2 = Bz (88%)
Scheme 2. Reagents and conditions: i) Pb(OAc)2, EtOAc, 0 ºC; ii) NaBH4, MeOH;
iii) 80% AcOH, reflux; iv) TIPDSCl, pyridine; v) BTDSCl2, DMAP, DMF; vi) PMBzCl,
pyridine; vii) BzCl, pyridine.
Surprisingly, treatment of 10a with 6-chloropurine under the conditions used for the synthesis of 4
afforded regioisomer 12a in 54% yield, but the desired nucleoside 11a was not obtained (Scheme 3).
1
The structure of 12a was determined by H-NMR spectroscopy, an NOE experiment and FAB-HRMS.
In contrast to the case of the pyrimidine reported in a previous paper,3 this result indicates that the
reaction progresses via the more stable tertiary cation intermediate B which is generated by elimination of
a proton at the 4-position on the thiofuranose ring. The generated thionium cation B is attacked by a
nucleobase from the β-face to give only the β-anomer 12a.
The desired nucleoside was obtained using 10b, which possesses benzoyl instead of p-methoxybenzoyl
protecting groups on the 2-hydroxy groups. The acidity of the 1-position of 10b is increased, as benzoyl
is a more electron-withdrawing group than p-methoxybenzoyl. Consequently, the thionium cation A is
generated by elimination of a proton at the 1-position of 10b. The silylated 6-chloropurine then attacks
the generated A to afford 11b. This result suggests that the acidity of the α hydrogen adjacent to a
sulfur atom affects the regioselectivity of a reaction.
When the 1,4-hydroxyl groups were protected by DTBS (di-tert-butyl-silylene) instead of TIPDS
(tetraisopropyldisiloxanane-1,3-diyl), regardless of the protective group on the 2-hydroxyl group, the
desired nucleoside 11c-d was obtained regioselectively along with the N-7 stereoisomer. In a manner

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HETEROCYCLES, Vol. 75, No. 3, 2008
similar to the Pummerer reaction, regiochemistry is controlled by steric hindrance due to the bulkiness of
the protecting group, the DTBS group being more bulky than TIPDS. Therefore, elimination of a proton
will occur at the less hindered 1-position in preference to the 4-position on the thiofuranose ring to
generate thionium cation A. The generated A coupled with silylated 6-chloropurine to give 11c-d.
OCOCF3
OCOCF3
S
I
Ph
O
O
O
S
S
O
O
S
i
S
R1
R1
R1
R1
R1
OR2
O
OR2
O
O
OR2
OR2
O
OR2
O
A
10a : R1 = TIPDS, R2 = PMBz
10b : R1 = TIPDS, R2 = Bz
10c : R1 = BTDS, R2 = PMBz
10d : R1 = BTDS, R2 = Bz
Cl
N
N
N
N
O
S
R1
O
OR2
11a : R1 = TIPDS, R2 = PMBz (0%)
11b : R1 = TIPDS, R2 = Bz (16%, N-7 isomer 12%)
11c : R1 = BTDS, R2 = PMBz (11%, N-7 isomer 17%)
11d : R1 = BTDS, R2 = Bz (22%, N-7 isomer 17%)
Cl
N
N
S
S
N
N
S
O
O
OR2
O
OR2
O
R1
O
R1
O
OR2
R1
12a : R1 = TIPDS, R2 = PMBz (54%)
12b : R1 = TIPDS, R2 = Bz (5%)
12c : R1 = BTDS, R2 = PMBz
12d : R1 = BTDS, R2 = Bz
B
Scheme 3. Reagents and conditions: i) 6-chloropurine, TMSOTf, Et3N, PIFA, CH2Cl2.
Different protecting groups on the hydroxyl groups in the sugar moiety clearly affected regioselectivity;
therefore, the regioselectivity of the reaction was examined using the 2,3-O-acetonides 13a-b (Scheme 4).
When the 5-hydroxyl group was protected with a benzoyl group, a condensation reaction occurred at the
4-position of 13a to give 15a (44%) as the main product. In contrast, when the 5-hydroxyl group was
protected with TBS (tert-butyldimethylsilyl), a condensation reaction occurred at the 1-position of 13b to

HETEROCYCLES, Vol. 75, No. 3, 2008
623
give 14b (25%) along with the N-7 stereoisomer (10%). These results also indicate that the acidity of
the α hydrogen adjacent to the sulfur atom affects the regioselectivity of the reaction.
Cl
N
Cl
N
N
N
N
N
N
N
HO
RO
S
S
RO
iii
i or ii
S
S
+
RO
O
O
O
O
O
O
O
O
7
13a
13b
: R = Bz (quant.)
: R = TBS (97%)
14a
: R = Bz (14%, N-7 isomer 8%)
14b: R = TBS ( 28%, N-7 isomer 10%) 15b: R = TBS (<1%)
15a
: R = Bz (44%)
Scheme 4.
Reagents and conditions: i) TBSCl, imidazol, DMF; ii) BzCl, pyridine;
iii) 6-chloropurine, TMSOTf, Et3N, PIFA, CH2Cl2.
Finally, 4'-thioadenosine (2) was obtained in 59% yield by treatment of 14b with TFA and then with
methanolic ammonia in a steel container at 100 °C (Scheme 5).
Cl
N
NH2
N
Cl
N
N
N
N
N
N
N
N
N
N
TBSO
HO
HO
TFA, H2O
66%
NH3 / MeOH
S
S
S
100 ºC
90%
HO
OH
O
O
HO OH
16
2
14b
Scheme 5
As described, the 4'-thio purine nucleosides were synthesized by a condensation of thiofuranoid and
silylated nucleobase in the presence of a phenyl iodosyl bis(trifluoroacetate), and the regioselectivity of
this reaction was clarified. Increasing the acidity of the 1-position hydrogen or protecting the 3,
5-hydroxyl groups with bulky DTBS favored the condensate at the 1-position as the major product. This
method will provide a convenient tool for the synthesis of 4'-thio purine nucleosides. Further
investigations using this approach are in progress.
EXPERIMENTAL
All melting points were determined on a Yamato melting point apparatus (model MP-2) and are
uncorrected. NMR spectra were recorded on a JEOL JNM-LA-300 and JEOL JNM-ECA-500

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HETEROCYCLES, Vol. 75, No. 3, 2008
spectrometer. Chemical shifts are reported in ppm (δ) relative to TMS (0.0 ppm) as internal standard,
and signals are expressed as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), or br (broad).
Coupling constants, J, are given in Hz. MS spectra were obtained on a JEOL JMS-HX110 and JEOL
JMS-700TZ. TLC was done on Merck Silica gel 60 F254 plates. Column chromatography was
conducted using silica gel (Merck, Silica gel 60, 70-230 mesh).
(2R*, 3R*, 4S*)-6-Chloro-9-(3,4-di-O-benzoylthiolan-3,4-diol-2-yl)-9H-purine (4a). To a suspension of
6-chrolopurine (94 mg, 0.60 mmol) in dry CH2Cl2 (2 mL) were added Et3N (84 µL, 0.60 mmol) and
TMSOTf (271 µL, 1.50 mmol) at rt under a nitrogen atmosphere. After the mixture had been stirred
for 1 h, a clear solution was obtained. A solution of 3 (50 mg, 0.15 mmol) in dry CH2Cl2 (1 mL) was
added to the mixture at 0 °C, and PhI(OCOCF3)2 (97 mg, 0.23 mmol) was then added in one portion.
After stirring for 10 min, additional Et3N (126 µL, 0.90 mmol) was added to the reaction mixture. After
the mixture had been stirred for 24 h, the reaction was quenched by addition of ice, and the mixture
was partitioned between AcOEt and water. The organic layer was washed with saturated NaHCO3
and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was
purified on silica gel column, eluted with hexane-AcOEt (1 : 1), to give 4a (25 mg, 35%) as a colorless
foam. MS (FAB) m/z 481 (MH+). HRMS (FAB) calcd for C23H18ClN4O4S (MH+): 481.0737, found:
481.0733. 1H NMR (500 MHz, CDCl3) δ: 8.76 (s, 1 H), 8.54 ( s, 1 H), 8.06-7.36 (m, 10 H), 6.52 (d, 1 H,
J = 6.6 Hz), 6.23 (dd, 1 H, J = 3.4 and 6.6 Hz), 6.14 (m, 1 H), 3.97 (dd, 1 H, J = 4.0 and 12.0 Hz), 3.40
(dd, 1 H, J = 3.4 and 12.0 Hz). 13C NMR (125 MHz, CDCl3) δ: 165.4, 165.0, 152.2, 151.7, 151.5, 143.9,
133.8, 133.7, 132.4, 129.8, 129.0, 128.6, 128.5, 128.3, 78.4, 73.3, 61.4, 33.1.
(2R*, 3R*, 4S*)-6-Chloro-2-fluoro-9-(3,4-di-O-benzoylthiolan-3,4-diol-2-yl)-9H-purine (4b). This
compound was prepared using 6-chloro-2-fluoropurine (104 mg, 0.60 mmol) by the procedure described
for the preparation of 4a. Yellow foam product, 28 mg (36%). MS (FAB) m/z 499 (MH+). HRMS
(FAB) calcd for C23H17ClFN4O4S (MH+): 499.0643, found: 499.0640. 1H NMR (500 MHz, CDCl3) δ:
8.50 (s, 1 H), 8.07-7.29 (m, 10 H), 6.45 (d, 1 H, J = 5.7 Hz), 6.13-6.10 (m, 2 H), 3.96 (dd, 1 H, J = 4.6
and 12.0 Hz), 3.39 (dd, 1 H, J = 2.9 and 12.0 Hz). 13C NMR (75 MHz, CDCl3) δ: 165.5, 165.2, 157.3 (d,
J = 219.4 Hz), 153.6 (d, J = 16.7 Hz), 153.3 (d, J = 17.9 Hz), 144.6, 134.0, 133.9, 131.1, 129.9, 129.1,
128.8, 128.7, 128.2, 78.7, 73.4, 61.5, 33.4.
(2R*, 3R*, 4S*)-2,6-Dichloro-9-(3,4-di-O-benzoylthiolan-3,4-diol-2-yl)-9H-purine (4c).
This
compound was prepared using 2,6-dichloropurine (113 mg, 0.60 mmol) by the procedure described for the
preparation of 4a. Colorless foam product, 55 mg (72%). MS (FAB) m/z 515 (MH+). HRMS (FAB)

HETEROCYCLES, Vol. 75, No. 3, 2008
625
calcd for C23H17Cl2N4O4S (MH+): 515.0347, found: 515.0363. 1H NMR (500 MHz, CDCl3) δ: 8.53 (s, 1
H), 8.08-7.30 (m, 10 H), 6.49 (d, 1 H, J = 6.9 Hz), 6.13 (dd, 1 H, J = 4.0 and 6.9 Hz), 6.05 (m, 1 H), 3.96
(dd, 1 H, J = 4.6 and 12.0 Hz), 3.39 (dd, 1 H, J = 3.4 and 12.0 Hz). 13C NMR (75 MHz, CDCl3) δ:
165.4, 165.1, 153.3, 153.0, 152.2, 144.4, 133.9, 133.8, 131.4, 129.9, 128.9, 128.6, 128.1, 79.0, 73.3, 61.4,
33.4.
(2R*, 3R*, 4S*)-9-(Thiolan-3,4-diol-2-yl)-9H-adenine (1a). A solution of 4a (173 mg, 0.34 mmol) in
methanolic ammonia (saturated at 0 ºC, 10 mL) was heated for 24 h at 100 ºC in a steel container. The
solvent was removed in vacuo, and the residue was purified on silica gel column, eluted with
CHCl3-EtOH (5 : 1), to give 1a (86 mg, 99%) as colorless crystals, mp 247-249 ºC. MS (FAB) m/z
254 (MH+). HRMS (FAB) calcd for C9H12N5O2S (MH+): 254.0712, found: 254.7716. Anal. Calcd for
C9H11N5O2S·0.2H2O: C, 42.08; H, 4.47; N, 27.26. Found: C, 42.05; H, 4.41; N, 27.10. 1H NMR (500
MHz, DMSO-d6) δ: 8.38 (s, 1 H), 8.11 (s, 1 H), 7.22 (s, 2 H), 5.86 (d, 1 H, J = 6.8 Hz), 5.49 (d, 1 H, J =
6.3 Hz), 5.31 (d, 1 H, J = 4.0 Hz), 4.64 (m, 1 H), 4.32 (m, 1 H), 3.37 (dd, 1 H, J = 4.0 and 10.3 Hz), 2.76
(dd, 1 H, J = 2.9 and 10.3 Hz). 13C NMR (125 MHz, DMSO-d6) δ: 156.6, 153.0, 150.4, 140.4, 119.5,
78.8, 72.8, 62.0, 34.9.
(2R*, 3R*, 4S*)-2-Fluoro-9-(thiolan-3,4-diol-2-yl)-9H-adenine (1b). This compound was prepared
from 4b (137 mg, 0.27mmol) by the procedure described for the preparation of 1a. Colorless crystals,
59 mg (81%). mp 213 ºC (decomp). MS (FAB) m/z 272 (MH+). HRMS (FAB) calcd for
C9H11FN5O2S (MH+): 272.0617, found: 272.0614. Anal. Calcd for C9H10FN5O2S: C, 39.85; H, 3.72; N,
25.82. Found: C, 39.76; H, 3.83; N, 25.60. 1H NMR (500 MHz, DMSO-d6) δ: 8.43 (s, 1 H), 7.77 (s, 2
H), 5.76 (d, 1 H, J = 7.4 Hz), 5.54 (d, 1 H, J = 5.7 Hz), 5.35 (d, 1 H, J = 2.9 Hz), 4.56 (m, 1 H), 4.30 (m,
1 H), 3.37 (dd, 1 H, J = 3.4 and 10.9 Hz), 2.76 (dd, 1 H, J = 2.3 and 10.9 Hz).
(2R*, 3R*, 4S*)-2-Chloro-9-(thiolan-3,4-diol-2-yl)-9H-adenine (1c). This compound was prepared
from 4c (30 mg, 0.06 mmol) by the procedure described for the preparation of 1a. Colorless crystals, 11
mg (67%). mp 234-236 ºC. MS (FAB) m/z 288 (MH+). HRMS (FAB) calcd for C9H11ClN5O2S
(MH+): 288.0322, found: 288.0333. Anal. Calcd for C9H10ClN5O2S·0.6MeOH: C, 37.56; H, 4.07; N,
22.82. Found: C, 37.26; H, 4.01; N, 22.89. 1H NMR (500 MHz, DMSO-d6) δ: 8.43 (s, 1 H), 7.77 (s, 2
H), 5.77 (d, 1 H, J = 7.4 Hz), 5.53 (d, 1 H, J = 6.3 Hz), 5.34 (d, 1 H, J = 4.0 Hz), 4.56 (m, 1 H), 4.30 (dd,
1 H, J = 2.9 and 2.9 Hz), 3.37 (dd, 1 H, J = 4.0 and 10.9 Hz), 2.76 (dd, 1 H, J = 2.3 and 10.9 Hz). 13C
NMR (125 MHz, DMSO-d6) δ: 157.3, 153.7, 151.6, 140.9, 118.5, 79.1, 72.7, 61.9, 35.0.

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1,4-Anhydro-2,3-O-isopropylidene-4-thio-D-ribitol (7). To a solution of 6 (100 mg, 0.45 mmol) in
AcOEt (2 mL) was added Pb(OAc)4 (219 mg, 0.51 mmol) at 0 ºC and the reaction mixture was
stirred for 15 min. The mixture was filtered through a silica gel, washed with hexane-AcOEt (1 : 1), and
dried in vacuo. The residue was dissolved in MeOH (10 mL), and NaBH4 (19 mg, 0.5 mmol) was
added to the mixture at 0 ºC. After stirring for 30 min, the reaction was quenched by addition of acetic
acid, and the mixture was concentrated in vacuo. The residue was diluted with AcOEt and then
washed with water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo.
The residue was purified on silica gel column, eluted with hexane-AcOEt (1 : 1), to give 7 (64 mg, 76%)
as a colorless syrup. MS (EI) m/z 190 (M+). HRMS (EI) calcd for C8H14O3S (M+): 190.0663, found:
190.0674. 1H NMR (300 MHz, CDCl3) δ: 4.92 (ddd, 1H, J = 1.7, 5.1 and 5.3 Hz), 4.70 (dd, 1 H, J = 1.1
and 5.7), 3.61 (m, 2 H), 3.46 (dd, 1 H, J = 6.2 and 6.4 Hz), 3.10 (dd, 1 H, J = 5.0 and 12.8 Hz), 2.92 (dd,
1 H, J = 1.7 and 12.8 Hz), 2.04 (dd, 1 H, J = 5.3 and 7.2 Hz), 1.53 (s, 3 H), 1.33 (s, 3 H).
1,4-Anhydro-4-thio-D-ribitol (8). A solution of 7 (600 mg, 3.2 mmol) in 80% acetic acid (20 mL) was
refluxed with stirring for 5 h. After the solvent was removed in vacuo, the residue was purified on silica
gel column, eluted with CHCl3-EtOH (5 : 1), to give 8 (389 mg, 81%) as a colorless syrup. MS (FAB)
m/z 151 (MH+). HRMS (FAB) calcd for C5H11O3S (MH+): 151.0430, found: 151.0431. Anal. Calcd
for C5H10O3S: C, 39.98; H, 6.71; N, 21.23. Found: C, 39.88; H, 6.55; N, 21.38. 1H NMR (300 MHz,
CD3OD) δ: 4.21 (ddd, 1 H, J = 3.6, 5.1 and 5.3 Hz), 3.93 (dd, 1 H, J = 3.6 and 5.6 Hz), 3.70 (dd, 1 H, J =
5.9 and 11.2 Hz), 3.53 (dd, 1 H, J = 6.5 and 11.2 Hz), 3.32 (m, 1 H), 2.90 (dd, 1 H, J = 5.1 and 10.8 Hz),
2.73 (dd, 1 H, J = 5.3 and 10.8 Hz). 13C NMR (75 MHz, CD3OD) δ: 77.7, 75.8, 65.4, 52.6, 33.4.
1,4-Anhydro-3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-4-thio-D-ribitol (9a). To a solution of
8 (201 mg, 1.3 mmol) in dry pyridine (5 mL) was added 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane
(377 µL, 1.2 mmol) at 0 ºC under a nitrogen atmosphere, and the mixture was stirred at rt for
68 h. The reaction was quenched by addition of ice, and the mixture was partitioned between AcOEt
and water. The organic layer was washed with saturated brine, dried over Na2SO4 and
concentrated in vacuo. The residue was purified on silica gel column, eluted with hexane-AcOEt (5 : 1),
to give 9a (357 mg, 70%) as a colorless syrup. MS (FAB) m/z 393 (MH+). HRMS (FAB) calcd for
C17H37O4SSi2 (MH+): 393.1951, found: 393.1972. Anal. Calcd for C17H36O4SSi2: C, 51.99; H, 9.24; S,
8.17. Found: C, 51.76; H, 9.00; S, 8.26. 1H NMR (300 MHz, CDCl3) δ: 4.33 (m, 1 H), 4.23 (dd, 1 H, J
= 3.9 and 8.3Hz), 4.04 (dd, 1 H, J = 3.3 and 12.4 Hz), 3.90 (dd, 1 H, J = 4.7 and 12.4 Hz), 3.50 (ddd, 1 H,
J = 3.3, 4.7 and 8.3 Hz), 3.03 (ddd, 1 H, J = 1.5, 4.7 and 12.1 Hz), 2.84 (dd, 1 H, J = 1.6 and 12.1 Hz),

HETEROCYCLES, Vol. 75, No. 3, 2008
627
2.64 (m, 1 H), 1.09-0.95 (m, 28 H). 13C NMR (75 MHz, CDCl3) δ: 77.5, 74.4, 61.0, 49.2, 32.4, 17.4,
17.3, 17.2, 17.1, 13.4, 13.3, 12.7, 12.6.
1,4-Anhydro-3,5-O-(di-tert-butylsilylene)-4-thio-D-ribitol (9b). To a solution of 8 (201 mg, 1.3
mmol) in dry DMF (5 mL) was added di-tert-butylsilyl-bis-(trifluoromethanesulfonate) (377 µL, 1.2
mmol) and DMAP (849 mg, 6.7 mmol) at 0 ºC under a nitrogen atmosphere, and the mixture was stirred
at rt for 24 h. The reaction was quenched by addition of ice, and the mixture was
partitioned between AcOEt and water. The organic layer was washed with saturated brine, dried over
Na2SO4 and concentrated in vacuo. The residue was purified on silica gel column, eluted with
hexane-AcOEt (4 : 1), to give 9b (288 mg, 76%) as a colorless syrup. MS (FAB) m/z 291 (MH+).
HRMS (FAB) calcd for C13H27O3SSi (MH+): 291.1450, found: 291.1460. 1H NMR (500 MHz, CDCl3)
δ: 4.42 (dd, 1 H, J = 4.0 and 4.6 Hz), 4.33 (dd, 1 H, J = 4.6 and 9.7), 4.03-3.96 (m, 2 H), 3.63 (m, 1 H),
3.06 (dd, 1 H, J = 4.0 and 12.6 Hz), 2.89 (d, 1 H, J = 12.6 Hz), 2.33 (s, 1 H), 1.05 (s, 9 H), 1.01 (s, 9 H).
13C NMR (75 MHz, CDCl3) δ: 83.2, 72.6, 68.6, 43.9, 32.6, 27.3, 27.2, 22.7, 20.1.
1,4-Anhydro-2-O-(p-methoxybenzoyl)-3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-4-thio-D-ribi
tol (10a). To a solution of 9a (730 mg, 1.9 mmol) in dry pyridine (35 mL) was added
p-methoxybenzoyl chloride (650 µL, 3.8 mmol) at 0 ºC under a nitrogen atmosphere, and the mixture was
stirred at rt for 12 h. The reaction was quenched by addition of ice, and the mixture was
partitioned between AcOEt and water. The organic layer was washed with saturated brine, dried over
Na2SO4 and concentrated in vacuo. The residue was purified on silica gel column, eluted with
hexane-AcOEt (15 : 1), to give 10a (980 mg, 98%) as a colorless syrup. MS (FAB) m/z 527 (MH+).
HRMS (FAB) calcd for C25H43O6SSi2 (MH+): 527.2241, found: 527.2305.
Anal. Calcd for
C25H43O6SSi2: C, 56.99; H, 8.04; S, 6.09. Found: C, 56.90; H, 8.00; S, 6.04. 1H NMR (300 MHz,
CDCl3) δ: 8.05-8.00 (m, 2 H), 6.95-6.90 (m, 2 H), 5.73 (dd, 1 H, J = 3.8 and 4.5 Hz), 4.34 (dd, 1 H, J =
3.8 and 9.5 Hz), 4.10 (dd, 1 H, J = 3.0 and 12.4 Hz), 3.96 (dd, 1 H, J = 3.2 and 12.4 Hz), 3.86 (s, 3 H),
3.66 (ddd, 1 H, J = 3.0, 3.2 and 9.5 Hz), 3.23 (dd, 1 H, J = 4.5 and 12.5 Hz), 2.90 (d, 1 H, J = 12.5 Hz),
1.11-0.87 (m, 28 H).
1,4-Anhydro-2-O-benzoyl-3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-4-thio-D-ribitol
(10b).
This compound was prepared from 9a (301 mg, 0.8 mmol) and benzoyl chloride (111 µL, 1.0 mmol) by
the procedure described for the preparation of 10a. Colorless syrup product, 347 mg (90%). MS
(FAB) m/z 497 (MH+). HRMS (FAB) calcd for C24H41O5SSi2 (MH+): 497.2213, found: 497.2213. 1H
NMR (300 MHz, CDCl3) δ: 8.07-8.05 (m, 2 H), 7.58-7.43 (m, 3 H), 5.76 (dd, 1 H, J = 3.4 and 4.6 Hz),

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HETEROCYCLES, Vol. 75, No. 3, 2008
4.35 (dd, 1 H, J = 3.4 and 9.7 Hz), 4.09 (dd, 1 H, J = 2.9 and 12.6 Hz), 3.96 (dd, 1 H, J = 2.9 and 12.6
Hz), 3.66 (ddd, 1 H, J = 2.9, 2.9 and 9.7 Hz), 3.24 (dd, 1 H, J = 4.6 and 12.6 Hz), 2.90 (d, 1 H, J = 12.6
Hz), 1.11-0.83 (m, 28 H).
1,4-Anhydro-2-O-(p-methoxybenzoyl)-3,5-O-(di-tert-butylsilylene)-4-thio-D-ribitol (10c).
This
compound was prepared from 9b (663 mg, 2.28 mmol) and p-methoxybenzoyl chloride (364 µL, 3.42
mmol) by the procedure described for the preparation of 10a. Colorless foam product, 651 mg (67%).
MS (FAB) m/z 425 (MH+). HRMS (FAB) calcd for C21H33O5SSi (MH+): 425.1818, found: 425.1828.
1H NMR (500 MHz, CDCl3) δ: 8.04-8.02 (m, 2 H), 6.93-6.89 (m, 2 H), 5.75 (t, 1 H, J = 4.0 Hz), 4.36 (dd,
1 H, J = 4.6 and 9.7 Hz), 4.19 (dd, 1 H, J = 4.0 and 9.7 Hz), 4.03 (dd, 1 H, J = 9.7 and 12.1 Hz), 3.86 (s, 3
H), 3.81 (ddd, 1 H, J = 4.6, 9.7 and 12.1 Hz), 3.24 (dd, 1 H, J = 4.0 and 13.2 Hz), 2.95 (d, 1 H, J = 13.2
Hz), 1.03 (s, 9 H), 0.90 (s, 9 H). 13C NMR (125 MHz, CDCl3) δ: 165.5, 163.6, 131.9, 122.4, 113.6, 81.7,
74.4, 69.0, 55.5, 44.7, 31.8, 27.4, 27.0, 22.9, 20.0.
1,4-Anhydro-2-O-benzoyl-3,5-O-(di-tert-butylsilylene)-4-thio-D-ribitol (10d). This compound was
prepared from 9b (241 mg, 0.80 mmol) and benzoyl chloride (139 µL, 1.20 mmol) by the procedure
described for the preparation of 10a. Colorless foam product, 278 mg (88%). mp 101-102 ºC. MS
(FAB) m/z 395 (MH+). HRMS (FAB) calcd for C20H31O4SSi (MH+): 395.1712, found: 395.1709. 1H
NMR (500 MHz, CDCl3) δ: 8.06-8.08 (m, 2 H), 7.58-7.42 (m, 3 H), 5.80 (t, 1 H, J = 4.0 Hz), 4.37 (dd, 1
H, J = 4.0 and 10.3 Hz), 4.21 (dd, 1 H, J = 4.0 and 9.7 Hz), 4.04 (dd, 1 H, J = 10.3 and 10.9 Hz), 3.82
(ddd, 1 H, J = 4.0, 9.7 and 10.9 Hz), 3.26 (dd, 1 H, J = 4.0 and 13.2 Hz), 2.96 (d, 1 H, J = 13.2 Hz), 1.04
(s, 9 H), 0.89 (s, 9 H). 13C NMR (75 MHz, CDCl3) δ: 165.7, 133.2, 130.0, 129.8, 128.3, 81.6, 74.7, 68.9,
44.6, 31.7, 27.3, 26.9, 22.8, 19.9.
6-Chloro-9-[2-O-(p-methoxybenzoyl)-3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)4-thio-β-L-lyx
ofuranos-4-yl]-9H-purine (12a). To a suspension of 6-chrolopurine (62 mg, 0.40 mmol) in dry CH2Cl2
(2 mL) were added Et3N (56 µL, 0.40 mmol) and TMSOTf (145 µL, 0.80 mmol) at 0 ºC under a nitrogen
atmosphere. After the mixture had been stirred for 1 h at rt, a clear solution was obtained. A
solution of 10a (107 mg, 0.20 mmol) in dry CH2Cl2 (1 mL) was added to the mixture at 0 °C, and
PhI(OCOCF3)2 (129 mg, 0.30 mmol) was then added in one portion. After stirring for 10 min, additional
Et3N (56 µL, 0.40 mmol) was added to the reaction mixture. After the mixture had been stirred for 24 h,
the reaction was quenched by addition of ice, and the mixture was partitioned between AcOEt and water.
The organic layer was washed with saturated aqueous NaHCO3 and brine. The organic layer was dried
over Na2SO4 and concentrated in vacuo. The residue was purified on silica gel column, eluted with

HETEROCYCLES, Vol. 75, No. 3, 2008
629
hexane-AcOEt (5 : 1), to give 12a (76 mg, 54%) as a yellow syrup. MS (FAB) m/z 679 (MH+).
HRMS (FAB) calcd for C30H44ClN4O6SSi2 (MH+): 679.2209, found: 679.2183. 1H NMR (300 MHz,
CDCl3) δ: 8.73 (s, 1 H), 8.66 (s, 1 H), 8.02-7.99 (m, 2 H), 6.95-6.92 (m, 2 H), 6.25 (d, 1 H, J = 2.4 Hz),
5.38 (ddd, 1 H, J = 2.6, 6.8 and 8.3 Hz), 4.40 (m, 2 H), 3.89 (s, 3 H), 3.52 (dd, 1 H, J = 8.8 and 10.7 Hz),
3.21 (dd, 1 H, J = 6.8 and 8.8 Hz), 1.16-0.78 (m, 28 H). 13C NMR (75 MHz, CDCl3) δ: 165.9, 163.9,
152.2, 144.3, 132.5, 131.9, 121.3, 113.9, 113.7, 80.3, 75.5, 71.6, 64.2, 55.5, 30.5, 17.4, 17.3, 17.2, 17.1,
17.0, 16.9, 16.8, 13.3, 13.0, 12.8, 12.7.
6-Chloro-9-[2-O-benzoyl-3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)4-thio-β-D-ribofuranos-1-
yl]-9H-purine (11b) and 6-chloro-9-[2-O-benzoyl-3,5-O-(1,1,3,3-tetraisopropyldisiloxane- 1,3-diyl)-
4-thio-β-L-lyxofuranos-4-yl]-9H-purine (12b). To a suspension of 6-chrolopurine (90 mg, 0.58
mmol) in dry CH2Cl2 (3 mL) were added Et3N (82 µL, 0.58 mmol) and TMSOTf (265 µL, 1.46 mmol) at
0 ºC under a nitrogen atmosphere. After the mixture had been stirred for 1 h at rt, a clear solution
was obtained. A solution of 10b (70 mg, 0.15 mmol) in dry CH2Cl2 (1 mL) was added to the mixture at
0 °C, and PhI(OCOCF3)2 (92 mg, 0.22 mmol) was then added in one portion. After stirring for 10 min,
additional Et3N (82 µL, 0.58 mmol) was added to the reaction mixture. After the mixture had been stirred
for 96 h, the reaction was quenched by addition of ice, and the mixture was partitioned between AcOEt
and water. The organic layer was washed with saturated aqueous NaHCO3 and brine. The organic
layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by MPLC (hexane :
AcOEt = 1 : 1) to give 11b (16 mg, 16%) as a yellow foam, N-7 isomer of 11b (11 mg, 12%) as a yellow
foam and 12b (5 mg, 5%) as a yellow foam. 11b: MS (FAB) m/z 649 (MH+). HRMS (ESI) calcd for
C29H41ClN4O5SSi2Na (MNa+): 671.1922, found: 671.1913. 1H NMR (500 MHz, CDCl3) δ: 8.76 (s, 1 H),
8.62 (s, 1 H), 8.10-7.47 (m, 5 H), 6.09 (s, 1 H), 5.86 (d, 1 H, J = 3.4 Hz), 4.93 (dd, 1 H, J = 3.4 and 9.7
Hz), 4.21 (dd, 1 H, J = 3.4 and 12.6 Hz), 4.12 (d, 1 H, J = 12.6 Hz), 3.88 (d, 1 H, J = 9.7 Hz), 1.24-0.87
(m, 28 H).
N-7 isomer of 11b: MS (FAB) m/z: 649 (MH+).
HRMS (ESI) calcd for
C29H41ClN4O5SSi2Na (MNa+): 671.2123, found: 671.2390. 1H NMR (500 MHz, CDCl3) δ: 9.17 (s, 1 H),
8.92 (s, 1 H), 8.10-7.48 (m, 5 H), 6.46 (s, 1 H), 5.88 (d, 1 H, J = 3.4 Hz), 4.64 (dd, 1 H, J = 3.4 and 9.7
Hz), 4.20 (dd, 1 H, J = 2.9 and 12.6 Hz), 4.14 (d, 1 H, J = 12.6 Hz), 3.85 (dd, 1 H, J = 1.7 and 9.7 Hz),
1
1.24-0.81 (m, 28 H). 12b: H NMR (500 MHz, CDCl3) δ: 8.76 (s, 1 H), 8.63 (s, 1 H), 8.10-7.48 (m, 5
H), 6.29 (d, 1 H, J = 2.3 Hz), 5.39 (m, 1 H), 4.43 (d, 1 H, J = 11.7 Hz), 4.31 (d, 1 H, J = 11.7 Hz), 3.52
(dd, 1 H, J = 8.6 and 10.9 Hz), 3.23 (dd, 1 H, J = 6.9 and 8.9 Hz), 1.20-0.80 (m, 28 H).
6-Chloro-9-[2-O-(p-methoxybenzoyl)-3,5-O-(di-tert-butylsilylene)-4-thio-β-D-ribofuranos-1-yl]-9H-p
urine (11c). To a suspension of 6-chrolopurine (90 mg, 0.58 mmol) in dry CH2Cl2 (3 mL) were added

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HETEROCYCLES, Vol. 75, No. 3, 2008
Et3N (85 µL, 0.60 mmol) and TMSOTf (272 µL, 1.50 mmol) at 0 ºC under a nitrogen atmosphere. After
the mixture had been stirred for 1 h at rt, a clear solution was obtained. A solution of 10c (64
mg, 0.15 mmol) in dry CH2Cl2 (1 mL) was added to the mixture at 0 °C, and PhI(OCOCF3)2 (96 mg, 0.23
mmol) was then added in one portion. After stirring for 10 min, additional Et3N (85 µL, 0.60 mmol)
was added to the reaction mixture. After the mixture had been stirred for 96 h, the reaction was quenched
by addition of ice, and the mixture was partitioned between AcOEt and water. The organic layer was
washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4 and
concentrated in vacuo. The residue was by MPLC (hexane : AcOEt = 1 : 1) to give 11c (9 mg, 11%) as
a yellow foam and N-7 isomer of 11c (15 mg, 17%) as a yellow foam. 11c: MS (FAB) m/z 577 (MH+).
HRMS (FAB) calcd for C26H35ClN4O5SSi (MH+): 557.1708, found: 557.1705. 1H NMR (300 MHz,
CDCl3) δ: 8.77 (s, 1 H), 8.37 (s, 1 H), 8.06 (d, 2 H, J = 9.2 Hz), 6.95 (d, 2 H, J = 9.2 Hz), 6.10 (s, 1 H),
5.83 (d, 1 H, J = 4.0 Hz), 5.16 (dd, 1 H, J = 4.0 and 10.3 Hz), 4.49 (dd, 1 H, J = 4.6 and 10.3 Hz), 4.31
(dd, 1 H, J = 10.3 and 10.9 Hz), 4.01 (ddd, 1 H, J = 4.6, 10.3 and 10.9 Hz), 3.89 (s, 3 H), 1.08 (s, 9 H),
0.93 (s, 9 H). N-7 isomer of 11c: MS (FAB) m/z 577 (MH+). HRMS (FAB) calcd for
C26H34ClN4O5SSi (MH+): 557.1708, found: 557.1705. 1H NMR (500 MHz, CDCl3) δ: 8.92 (s, 1 H),
8.89 (s, 1 H), 8.06 (d, 2 H, J = 8.6 Hz), 6.96 (d, 2 H, J = 8.6 Hz), 6.53 (s, 1 H), 5.95 (d, 1 H, J = 3.4 Hz),
4.52 (dd, 1 H, J = 4.6 and 10.3 Hz), 4.47 (dd, 1 H, J = 3.4 and 10.3 Hz), 4.24 (t, 1 H, J = 10.9 Hz), 3.98
(ddd, 1 H, J = 4.6, 10.3 and 10.9 Hz), 3.89 (s, 3 H), 1.01 (s, 9 H), 0.81 (s, 9 H).
6-Chloro-9-[2-O-benzoyl-3,5-O-(di-tert-butylsilylene)-4-thio-β-D-ribofuranos-1-yl]-9H-purine (11d).
To a suspension of 6-chrolopurine (90 mg, 0.58 mmol) in dry CH2Cl2 (3 mL) were added Et3N (85 µL,
0.60 mmol) and TMSOTf (272 µL, 1.50 mmol) at 0 ºC under a nitrogen atmosphere. After the mixture
had been stirred for 1 h at rt, a clear solution was obtained. A solution of 10d (50 mg,
0.13 mmol) in dry CH2Cl2 (1 mL) was added to the mixture at 0 °C, and PhI(OCOCF3)2 (84 mg, 0.20
mmol) was then added in one portion. After stirring for 10 min, additional Et3N (85 µL, 0.60 mmol) was
added to the reaction mixture. After the mixture had been stirred for 96 h, the reaction was quenched by
addition of ice, and the mixture was partitioned between AcOEt and water. The organic layer was
washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4 and
concentrated in vacuo. The residue was purified by MPLC (hexane : AcOEt = 1 : 1) to give 11d (16 mg,
22%) as a yellow foam and N-7 isomer of 11d (12 mg, 17%) as a yellow foam. 11d: MS (FAB) m/z 547
(MH+). HRMS (FAB) calcd for C25H32ClN4O4SSi (MH+): 547.1602, found: 547.1603. 1H NMR (500
MHz, CDCl3) δ: 8.77 (s, 1 H), 8.37 (s, 1 H), 8.12-8.10 (m, 2 H), 7.64-7.47 (m, 3 H), 6.10 (s, 1 H), 5.87 (d,
1 H, J = 3.7 Hz), 5.16 (dd, 1 H, J = 3.7 and 10.3 Hz), 4.49 (dd, 1 H, J = 4.6 and 10.3 Hz), 4.30 (dd, 1 H, J =
10.3 and 10.9 Hz), 4.07 (ddd, 1 H, J = 4.6, 10.3 and 10.9 Hz), 1.08 (s, 9 H), 0.91 (s, 9 H). N-7 isomer of

HETEROCYCLES, Vol. 75, No. 3, 2008
631
11d: MS (FAB) m/z 547 (MH+). HRMS (FAB) calcd for C25H32ClN4O4SSi (MH+): 547.1602, found:
547.1596. 1H NMR (500 MHz, CDCl3) δ: 8.92 (s, 1 H), 8.90 (s, 1 H), 8.11-7.48 (m, 5 H), 6.55 (s, 1 H),
5.98 (d, 1 H, J = 4.0 Hz), 4.52 (dd, 1 H, J = 4.0 and 10.9 Hz), 4.48 (dd, 1 H, J = 4.0 and 10.3 Hz), 4.25 (t,
1 H, J = 10.9 Hz), 3.99 (ddd, 1 H, J = 4.6, 10.3 and 10.9 Hz), 1.01 (s, 9 H), 0.79 (s, 9 H).
1,4-Anhydro-5-O-benzoyl-2,3-O-isopropyridene-4-thio-D-ribitol (13a). To a solution of 7 (1.1 g, 5.5
mmol) in dry pyridine (40 mL) was added benzoyl chloride (922 µL, 8.3 mmol) at 0 ºC under a nitrogen
atmosphere, and the mixture was stirred at rt for 12 h. The reaction was quenched by
addition of ice, and the mixture was partitioned between AcOEt and water. The organic layer was
washed with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue
was purified on silica gel column, eluted with hexane-AcOEt (1 : 1), to give 13a (1.6 g, 99%) as a
colorless solid. mp 35-37 ºC. MS (FAB) m/z 295 (MH+). HRMS (FAB) calcd for C15H19O4S (MH+):
295.1004, found: 295.1000. 1H NMR (300 MHz, CDCl3) δ: 8.06-8.02 (m, 2 H), 7.61-7.43 (m, 3 H),
4.98 (ddd, 1 H, J = 1.3, 4.8 and 5.7 Hz), 4.80 (dd, 1 H, J = 1.1 and 5.7 Hz), 4.42 (dd, 1 H, J = 6.1 and
11.6 Hz), 4.32 (dd, 1 H, J = 8.1 and 11.6 Hz), 3.64 (ddd, 1 H, J = 1.1, 1.6 and 8.1 Hz), 3.18 (dd, 1 H, J =
4.8 and 13.0 Hz), 2.96 (dd, 1 H, J = 1.3 and 13.0 Hz), 1.54 (s, 3 H), 1.33 (s, 3 H). 13C NMR (75 MHz,
CDCl3) δ: 166.2, 133.2, 129.7, 129.6, 128.4, 111.3, 85.7, 83.5, 65.2, 52.5, 37.7, 26.5, 24.7.
1,4-Anhydro-5-O-(tert-butyldimethylsilyl)-2,3-O-isopropyridene-4-thio-D-ribitol (13b).
To
a
solution of 7 (500 mg, 2.6 mmol) and imidazol (481 mg, 6.5 mmol) in dry DMF (20 mL) was added
tert-butyldimethylsilyl chloride (579 mg, 3.9 mmol) at 0 ºC under a nitrogen atmosphere, and the mixture
was stirred at rt for 4 h. The reaction was quenched by addition of ice, and the mixture
was partitioned between Et2O and water. The organic layer was washed with brine, dried over Na2SO4
and concentrated in vacuo. The residue was purified on silica gel column, eluted with hexane-AcOEt
(1 : 1), to give 13b (771 mg, 97%) as a colorless syrup. MS (FAB) m/z 305 (MH+). HRMS (FAB)
calcd for C14H29O3SSi (MH+): 305.1607, found: 305.1627. 1H NMR (300 MHz, CDCl3) δ: 4.83 (ddd, 1
H, J = 1.3, 4.8 and 5.8 Hz), 4.73 (dd, 1 H, J = 0.9 and 5.8 Hz), 3.73 (dd, 1 H, J = 4.6 and 10.5 Hz), 3.53
(dd, 1 H, J = 6.4 and 10.5 Hz), 3.27 (ddd, 1 H, J = 0.9, 4.6 and 6.4 Hz), 3.10 (dd, 1 H, J = 4.8 and 12.5
Hz), 2.78 (dd, 1 H, J = 1.3 and 12.5 Hz), 1.46 (s, 3 H), 1.26 (s, 3 H), 0.83 (s, 9 H), 0.00 (s, 6 H). 13C
NMR (75 MHz, CDCl3) δ: 110.7, 86.2, 84.0, 65.8, 55.6, 38.5, 26.6, 25.9, 24.6, 18.3, -5.4.
6-Chloro-9-(5-O-benzoyl-2,3-O-isopropyridene-4-thio-β-D-ribofuranos-1-yl)-9H-purine (14a) and
6-Chloro-9-(5-O-benzoyl-2,3-O-isopropyridene-4-thio-β-L-lyxofuranos-4-yl)-9H-purine (15a). To
a suspension of 6-chrolopurine (465 mg, 3.0 mmol) in dry CH2Cl2 (15 mL) were added Et3N (423 µL, 3.0

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HETEROCYCLES, Vol. 75, No. 3, 2008
mmol) and TMSOTf (1.36 mL, 7.5 mmol) at 0 ºC under a nitrogen atmosphere. After the mixture had
been stirred for 1 h at rt, a clear solution was obtained. A solution of 13a (222 mg, 0.75
mmol) in dry CH2Cl2 (10 mL) was added to the mixture at 0 °C, and PhI(OCOCF3)2 (480 mg, 1.2 mmol)
was then added in one portion. After stirring for 10 min, additional Et3N (636 µL, 4.5 mmol) was added
to the reaction mixture. After the mixture had been stirred for 48 h, the reaction was quenched by addition
of ice, and the mixture was partitioned between AcOEt and water. The organic layer was washed with
brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by MPLC (hexane :
AcOEt = 1 : 1) to give 14a (47 mg, 14%) as a yellow foam, N-7 isomer of 14a (27 mg, 8%) as a yellow
foam and 15a (148 mg, 44 %) as a yellow foam. 14a: MS (FAB) m/z 447 (MH+). HRMS (FAB) calcd
for C20H20ClN4O4S (MH+): 447.0894, found: 447.0884. 1H NMR (300 MHz, CDCl3) δ: 8.80 (s, 1 H),
8.41 (s, 1 H), 7.90-7.34 (m, 5 H), 6.10 (d, 1 H, J = 1.7 Hz), 5.49 (dd, 1 H, J = 1.7 and 5.5 Hz), 5.16 (dd, 1
H, J = 1.9 and 5.5 Hz), 4.75 (dd, 1 H, J = 6.8 and 11.6 Hz), 4.53 (dd, 1 H, J = 6.2 and 11.6 Hz), 4.10 (ddd,
1 H, J = 1.9, 6.2 and 6.8 Hz), 1.66 (s, 3 H), 1.40 (s, 3 H). 13C NMR (125 MHz, CDCl3) δ: 166.0, 152.2,
151.6, 151.3, 144.2, 133.6, 132.8, 129.6, 129.2, 128.5, 113.1, 89.4, 85.8, 68.8, 65.6, 54.1, 27.4, 25.3.
N-7 isomer of 14a: MS (FAB) m/z 447 (MH+). HRMS (FAB) calcd for C20H20ClN4O4S (MH+):
447.0894, found: 447.0891. 1H NMR (300 MHz, CDCl3) δ: 8.89 (s, 1 H), 8.84 (s, 1 H), 8.00-7.42 (m, 5
H), 6.59 (d, 1 H, J = 2.2 Hz), 5.13 (dd, 1 H, J = 2.2 and 5.7 Hz), 4.99 (dd, 1 H, J = 2.9 and 5.7 Hz), 4.61
(dd, 1 H, J = 7.4 and 11.5 Hz), 4.51 (dd, 1 H, J = 6.9 and 11.5 Hz), 4.07 (ddd, 1 H, J = 2.9, 6.9 and 7.4
Hz), 1.64 (s, 3 H), 1.32 (s, 3 H). 13C NMR (125 MHz, CDCl3) δ: 166.2, 162.6, 153.0, 147.1, 143.4,
133.8, 129.8, 129.1, 128.7, 122.6, 113.5, 90.2, 84.9, 68.8, 65.1, 53.4, 27.3, 25.2. 15a: MS (FAB) m/z
447 (MH+). HRMS (FAB) calcd for C20H20ClN4O4S (MH+): 447.0894, found: 447.0889. 1H NMR
(300 MHz, CDCl3) δ: 8.89 (s, 1 H), 8.78 (s, 1 H), 7.78-7.35 (m, 5 H), 6.04 (d, 1 H, J = 5.3 Hz), 5.49 (d, 1
H, J = 12.1 Hz), 5.02 (dd, 1 H, J = 3.9 and 5.3 Hz), 4.93 (d, 1 H, J = 12.1 Hz), 3.24 (d, 1 H, J = 13.5 Hz),
3.11 (dd, 1 H, J = 3.9 and 13.5 Hz), 1.66 (s, 3 H), 1.43 (s, 3 H). 13C NMR (125 MHz, CDCl3) δ: 165.3,
151.8, 151.6, 145.9, 134.0, 133.5, 129.6, 128.8, 128.6, 112.5, 86.4, 84.6, 83.7, 66.3, 37.9, 26.1, 24.9.
6-Chloro-9-[5-O-(tert-butyldimethylsilyl)-2,3-O-isopropyridene-4-thio-β-D-ribofuranos-1-yl]-9H-pu
rine (14b). To a suspension of 6-chrolopurine (1.53 g, 9.9 mmol) in dry CH2Cl2 (70 mL) were added
Et3N (1.39 mL, 9.9 mmol) and TMSOTf (4.48 mL, 24.7 mmol) at 0 ºC under a nitrogen atmosphere.
After the mixture had been stirred for 1 h at rt, a clear solution was obtained. A solution
of 13b (1.13 g, 3.7 mmol) in dry CH2Cl2 (30 mL) was added to the mixture at 0 °C, and PhI(OCOCF3)2
(2.34 g, 5.6 mmol) was then added in one portion. After stirring for 10 min, additional Et3N (2.09 mL,
14.8 mmol) was added to the reaction mixture. After the mixture had been stirred for 72 h, the reaction
was quenched by addition of ice, and the mixture was partitioned between AcOEt and water. The

HETEROCYCLES, Vol. 75, No. 3, 2008
633
organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was
purified by MPLC (hexane : AcOEt = 1 : 1) to give 14b (474 mg, 28%) as a yellow foam and N-7 isomer
of 14b (166 mg, 10%) as a yellow foam. 14b: MS (FAB) m/z 457 (MH+). HRMS (FAB) calcd for
C19H30ClN4O3SSi (MH+): 457.1496, found: 457.1490. 1H NMR (300 MHz, CDCl3) δ: 8.79 (s, 1 H),
8.63 (s, 1 H), 6.11 (d, 1 H, J = 2.2 Hz), 5.15 (dd, 1 H, J = 2.2 and 5.3 Hz), 4.91 (dd, 1 H, J = 1.8 and 5.3
Hz), 3.91 (d, 2 H, J = 5.1 Hz), 3.83 (dd, 1 H, J = 1.8 and 5.1 Hz), 1.65 (s, 3 H), 1.31 (s, 3 H), 0.87 (s, 9 H),
0.06 (s, 3 H), 0.00 (s, 3 H). 13C NMR (125 MHz, CDCl3) δ: 152.2, 151.6, 151.3, 144.7, 132.6, 112.6,
90.2, 85.6, 68.5, 65.3, 57.0, 27.5, 26.0, 25.2, -5.2. N-7 isomer of 14b: MS (FAB) m/z 457 (MH+).
HRMS (FAB) calcd for C19H30ClN4O3SSi (MH+): 457.1496, found: 457.1494. 1H NMR (300 MHz,
CDCl3) δ: 9.10 (s, 1 H), 8.89 (s, 1 H), 6.58 (d, 1 H, J = 2.2 Hz), 4.92 (dd, 1 H, J = 2.2 and 5.1 Hz), 4.89
(dd, 1 H, J = 2.0 and 5.1 Hz), 3.94-3.72 (m, 3 H), 1.64 (s, 3 H), 1.35 (s, 3 H), 0.92 (s, 9 H), 0.16 (s, 3 H),
0.13 (s, 3 H). 13C NMR (125 MHz, CDCl3) δ: 162.7, 152.7, 148.2, 143.1, 121.5, 112.6, 91.2, 85.2, 69.3,
65.1, 56.5, 27.5, 26.1, 25.3, 18.6, -5.1.
6-Chloro-9-(4-thio-β-D-ribofuranos-1-yl)-9H-purine (16). To a solution of 14b (55 mg, 0.12 mmol)
in THF (5 mL) was added trifluoroacetic acid (4.5 mL) and water (0.5 mL) at rt, and the
mixture was stirred for 18 h. The solvent was removed in vacuo, and the residue was purified on silica
gel column, eluted with CHCl3-MeOH (3 : 1), to give 16 (24 mg, 66%) as a colorless foam. MS (FAB)
m/z 303 (MH+). HRMS (FAB) calcd for C10H12ClN4O3S (MH+): 303.0319, found: 303.0320. 1H NMR
(500 MHz, DMSO-d6) δ: 9.01 (s, 1 H), 8.78 (s, 1 H), 5.94 (d, 1 H, J = 6.3 Hz), 5.62 (d, 1 H, J = 6.3 Hz),
5.36 (d, 1 H, J = 4.6 Hz), 5.18 (dd, 1 H, J = 5.2 and 5.7 Hz), 4.67 (m, 1 H), 4.19 (m, 1 H), 3.79 (m, 1 H),
3.62 (m, 1 H), 3.31 (m, 1 H). 13C NMR (125 MHz, DMSO-d6) δ: 152.5, 152.2, 149.7, 147.1, 131.9, 77.6,
73.6, 63.6, 62.6, 54.1.
4´-Thioadenosine (2). A solution of 16 (24 mg, 0.08 mmol) in methanolic ammonia (saturated at 0 ºC,
10 mL) was heated for 24 h at 100 ºC in a steel container. The solvent was removed in vacuo, and the
residue was purified on silica gel column, eluted with CHCl3-MeOH (3 : 1), to give 2 (20 mg, 90%) as a
colorless solid, mp 253-256 ºC. MS (FAB) m/z 284 (MH+). HRMS (FAB) calcd for C10H14N5O3S
(MH+): 284.0818, found: 284.0813. 1H NMR (500 MHz, DMSO-d6) δ: 8.46 (s, 1 H), 8.16 (s, 1 H), 7.28
(br s, 2 H), 5.87 (d, 1 H, J = 6.6 Hz), 5.56 (d, 1 H, J = 6.3 Hz), 5.34 (d, 1 H, J = 4.6 Hz), 5.23 (dd, 1 H, J
= 5.2 and 5.7 Hz), 4.68 (ddd, 1 H, J = 3.4, 6.3 and 6.6 Hz), 4.22 (dt, 1 H, J = 3.4 and 4.6 Hz), 3.81 (ddd, 1
H, J = 5.2, 6.3 and 11.5 Hz), 3.65 (dd, 1 H, J = 5.7 and 11.5 Hz), 3.35 (m, 1 H). 13C NMR (125 MHz,
DMSO-d6) δ: 156.6, 153.0, 150.3, 140.4, 119.6, 77.5, 73.8, 63.8, 61.8, 53.8.

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HETEROCYCLES, Vol. 75, No. 3, 2008
ACKNOWLEDGEMENTS
We would like to thabk Ms S. Oka, Ms M. Kikuchi, and Ms Y. Takihata for MS spectra measurements
and Ms H. Matsumoto and Ms A. Maeda for elemental analysis (Center for Instrumental Analysis,
Hokkaido University).
REFERENCES
1. For review, see: (a) P. Gunaga, H. R. Moon, W. J. Choi, D. H. Shin, J. G. Park, and L. S. Jeong,
Current Med. Chem., 2004, 11, 2585. (b) S. F. Wnuk, Tetrahedron, 1993, 49, 9877. (c) M.
Yokoyama, Synthesis, 2000, 1637.
2. (a) W. B. Parker, S. C. Shaddix, L. M. Rose, W. R. Waud, D. S. Shewach, K. N. Tiwari, and J. A. S.
III, Biochemical Pharmacology, 2000, 60, 1925. (b) A. Verri, F. Focher, R. J. Duncombe, I.
Basnak, R. T. Walker, P. L. Coe, E. DeClercq, G. Andrei, R. Snoeck, J. Balzarini, and S. Spadari,
Biochem. J., 2000, 351, 319.
3. N. Nishizono, R. Baba, C. Nakamura, K. Oda, and M. Machida, Org. Biomol. Chem., 2003, 1, 3692.
4. (a) P. K. Chiang, Pharmacol. Ther., 1998, 77, 115. (b) S. Liu, M. S. Wolfe, and R. T. Borchardt,
Antiviral Res., 1992, 19, 247. (c) Y. Kitade, H. Kojima, F. Zulfiqur, H. S. Kim, and Y. Wataya,
Bioorg. Med. Chem. Lett., 2003, 13, 3963. (d) Y. Kitade, A. Kozaki, and C. Yatome, Tetrahedron
Lett., 2001, 42, 433. (e) M. S. Wolfe and R. T. Borchardt, J. Med. Chem., 1991, 34, 1521. and
references cited therein.
5. L. S. Jeong, D. Z. Jin, H. O. Kim, D. H. Shin, H. R. Moon, P. Gunaga, M. W. Chun, Y. C. Kim, N.
Melman, Z. G. Gao, and K. A. Jacobson, J. Med. Chem., 2003, 46, 3775.
6. (a) C. Leydier, L. Bellon, J.-L. Barascut, J. Deydier, G. Maury, H. Pelicano, M. A. E. Alaoui, and
J.-L. Imbach, Nucleosides Nucleotides, 1994, 13, 2035. (b) T. Naka, N. Minakawa, H. Abe, D.
Kaga, and A. Matsuda, J. Am. Chem. Soc., 2000, 122, 7233.