A novel method for the synthesis of 4'-thiopyrimidine nucleosides using hypervalent iodine compounds.

Article abstract of DOI:10.1039/b305644a

The coupling reactions of cyclic sulfides with a silylated pyrimidine nucleobase using a hypervalent iodine reagent were investigated. The reaction of silylated uracil with cyclic sulfide 12 using PhI=O gave the desired beta-anomer 14 in moderate yield. 4

Full text of DOI:10.1039/b305644a

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A novel method for the synthesis of 4Ј-thiopyrimidine nucleosides
using hypervalent iodine compounds
Naozumi Nishizono,* Ryosuke Baba, Chika Nakamura, Kazuaki Oda and Minoru Machida*
Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu,
Hokkaido 061-0293, Japan. E-mail: nishizon@hoku-iryo-u.ac.jp
Received 20th May 2003, Accepted 10th September 2003
First published as an Advance Article on the web 1st October 2003
The coupling reactions of cyclic sulfides with a silylated pyrimidine nucleobase using a hypervalent iodine reagent
were investigated. The reaction of silylated uracil with cyclic sulfide 12 using PhI᎐O gave the desired β-anomer 14
᎐
in moderate yield. 4Ј-Thiouridine (22) was obtained by deprotection of 14.
model compounds. Some hypervalent iodine reagents were used
Introduction
in preliminary experiments (Scheme 1, entries 1–4 in Table 1).
Among them, [bis(trifluoroacetoxy)iodo]benzene gave 1-(tetra-
hydrothiophen-2-yl)thymine (2) in the highest yield. This seems
to be due to the oxidizability and solubility of hypervalent
iodine compounds. In order to optimize the reaction con-
ditions, the mole ratios of trimethylsilyl trifluoromethan-
sulfonate (TMSOTf ) and triethylamine to 1 were varied (entries
4–8 in Table 1). When 6 equivalent moles of TMSOTf and
triethylamine were used, the product was effectively obtained
in 80% yield (entry 8 in Table 1). As for the solvents used,
dichloromethane gave the best yield. Thus, it was found that the
position adjacent to the sulfur atom on the thiophene ring was
activated and that a C–N bond was subsequently formed.
Nucleoside antimetabolites occupy a pivotal position in the
fields of anticancer and antiviral agents.1 Recently, it has been
reported that certain 4Ј-thionucleosides, in which the oxygen
atom in the furanose ring is replaced by a sulfur atom, exhibit
potent antiviral2–5 and anticancer activities.6–8 In addition,
they have inherent properties such as a more stable glycosidic
linkage and increased metabolic stability.9,10 For example,
4Ј-thio-BVDU3 has a level of antiviral activity equivalent to
that of BVDU11 and also shows resistance to the hydrolysis
reaction by pyrimidine phosphorylase.12 Therefore, there has
been much effort to synthesize and evaluate new nucleoside
analogues.
In general, thionucleoside derivatives have been synthesized
by classical glycosidation of a nucleobase with the corre-
sponding thiosugar, although the stereoselectivity of such
thioglycosidation is not satisfactory even with the assistance
of neighboring C-2 acyloxy group participation.13–15 As an
alternative method, O’Neil and Hamilton reported the
synthesis of thionucleosides through the Pummerer reaction in
1992.16 Stereoselective synthesis of thionucleoside derivatives
using the Pummerer reaction has also been reported.17–19 Very
recently, stereoselective synthesis of the β-anomer of 4Ј-thio-
nucleosides based on electrophilic addition to 4-thiofuranoid
glycals has also been reported.20
Hypervalent iodine reagents have been extensively used
in organic syntheses because of their low toxicity, ready
availability and easy handling.21 These reagents have been used
mainly for C–C bond formation and for the oxidation of
alcohols, phenols and sulfides. Although a few examples of
C–N bond formation using these reagents have been reported,
they are limited to cases of the introduction of an azido group
by azidoiodane generated in situ from PhIO–TMSN3 and the
intramolecular cyclization of an imine nitrogen atom to the
activated hydrazone.21b Interestingly, Kita and co-workers have
reported the direct α-azidation of cyclic sulfides using a PhIO–
TMSN3 reagent system.22 Their paper prompted us to initiate
a study on application to nucleoside chemistry, and on the
properties of hypervalent iodine reagents, such as the oxid-
izability of hypervalent iodine compounds and the leaving
group ability of the phenyliodonio group, which have led us to
explore thioglycosidation.
Scheme 1
In the coupling of a nucleobase with a thiosugar, the control
of stereo- and regio-selectivities is essential. To investigate the
stereochemistry of the coupling reaction, di- and tri-substituted
tetrahydrothiophenes (10 and 12) were used as thiosugar
analogues. For the preparation of compound 10, starting
material cis-2-butene-1,4-diol (3) was converted to butene
dibenzoate (4) and subsequently O-isopropylidene derivatives
(5–7) (Scheme 2). O-Isopropylidene mesylate 7 was treated with
In this paper, we present the results of a study on the novel
synthesis of 4Ј-thionucleoside using hypervalent iodine reagents
in which the generation of a thionium cation is a key step.
Scheme 2 Reagents and conditions: i) BzCl, Et3N, CH2Cl2, 0 ЊC, 93%;
ii) OsO4, NMO, acetone, H2O; iii) 2,2-dimethoxypropane, TsOH,
acetone, 2 steps 86%; iv) NaOMe, MeOH, 96%; v) MsCl, pyridine, 76%;
vi) Na2S, DMF, 100 ЊC, 64%; vii) 80% AcOH, reflux, 87%;
viii) PMBzCl, pyridine, 93%.
Results and discussion
In order to investigate effective thioglycosidation, commercially
available tetrahydrothiophene (1) and thymine were selected as
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 6 9 2 – 3 6 9 7
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
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Table 1 Coupling reaction of tetrahydrothiophene (1) with thymine (2 equiv.) at 0 ЊC for 12 h
Entry
TMSOTf (equiv.)
Et3N (equiv.)
Hypervalent iodine (1.2 equiv.)
Solvent
Yield of 2 (%)
1
2
3
4
5
6
7
8
9
8
8
8
8
6
4
4
6
6
6
6
6
8
8
8
8
4
6
4
6
6
6
6
6
PhI᎐O
PhI(OAc)2
PhI(OH)OTs
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
Toluene
THF
5
10
20
42
0
29
63
80
52
45
62
54
᎐
PhI(OCOCF3)2
PhI(OCOCF3)2
PhI(OCOCF3)2
PhI(OCOCF3)2
PhI(OCOCF3)2
PhI(OCOCF3)2
PhI(OCOCF3)2
PhI(OCOCF3)2
PhI(OCOCF3)2
10
11
12
CH2Cl2–toluene
Table 2 Coupling reaction of meso-3,4-di-O-p-methoxybenzoylthiolane-3,4-diol (10) with thymine using Method A
Entry
Thymine (equiv.)
TMSOTf (equiv.)
Et3N (equiv.)
Yield of 13a (%)
β : αb
1
2
3
4
5
2
2
3
2
3
6
8
8
6
3
6
8
8
63
35
48
65
65
3 : 1
3 : 1
2 : 1
4 : 1
5 : 1
3 ϩ 3
4 ϩ 4
a Isolated yields of the anomer mixture. b Estimated from 1H NMR spectroscopy.
sodium sulfide to give O-isopropylidenethiolanediol 8, which
ultimately led to the formation of 10. Tri-substituted tetra-
hydrothiophene 12 was prepared, in several steps, from -ribose
according to the reported procedure (Scheme 3).23
Although such thiophene formation has been observed in
Pummerer-type reactions, the formation of the by-product has
been prevented by adding triethylamine in two portions.19
Similarly triethylamine was added twice in the reaction
of thymine with 10. Interestingly, the anomer ratio β : α was
improved up to 5 : 1, whereas the yield of the product was not
improved (entries 4 and 5 in Table 2).
From the above results, it was deduced that the generation
of a Pummerer-type intermediate is a key step. Therefore, to
effectively generate the intermediate, the order of addition of
reagents and substrate was considered, that is, a silylated
nucleobase was added to the initially formed Pummerer-type
intermediate, which arose from the reaction of iodosobenzene
and TMSOTf with the thiophene derivative (Scheme 4) (see
Method B in the Experimental section). Surprisingly, only the
desired β-anomer 13 was obtained in 61% yield (Scheme 4; in
the case of reagent ii).
Next, to investigate the regio- and stereo-selectivities of this
coupling reaction, the reaction of uracil with tri-substituted
tetrahydrothiophene 12 was examined, since uracil and cytosine
are components of ribonucleosides. The reactions of uracil with
12 were carried out at various temperatures according to
Method A, giving a 5 : 1 anomer mixture of 14 in 20–55% yields
(Scheme 5, Table 3). When the reaction was carried out at 0 ЊC,
the best result was obtained (entry 2 in Table 3). Furthermore,
to improve the yield and stereoselectivity, the reaction was
carried out at 0 ЊC according to Method B. The reaction
proceeded stereoselectively to give only β-anomer 14 in 53%
yield (Scheme 5).
Scheme 3
First, the reaction of thymine with 10 using hypervalent
iodine was examined (Scheme 4). The results are summarized in
Table 2 (see Method A in the Experimental section). Under the
conditions used for the synthesis of 2, the reaction gave 13 with
the anomer ratio β : α = 3 : 1 in moderate yield. The reactions
were carried out with various mole ratios of TMSOTf and
triethylamine to thymine, but with lower isolated yields (entries
2 and 3 in Table 2). These decreased yields seemed to be due to
the formation of a thiophene derivative as a by-product.
This high β-anomer selectivity seems to be based on the
generation of thionium cation 16 (X = OTMS) as well as one of
Scheme 4 Reagents and conditions: i) thymine, TMSOTf, Et3N,
Scheme
5
Reagents and conditions: i) uracil, TMSOTf, Et3N,
PhI(OCOCF3)2, CH2Cl2, 0 ЊC; ii) PhI᎐O, TMSOTf, Et3N, thymine,
PhI(OCOCF3)2, CH2Cl2, 0 ЊC; ii) PhI᎐O, TMSOTf, Et3N, uracil,
᎐
᎐
CH2Cl2, 0 ЊC, 61%.
CH2Cl2, 0 ЊC, 53%.
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Scheme 6 Reaction pathways.
Table 3 Coupling reaction of a 4-thio--ribitol derivative (12) with
uracil using Method A
Entry
Solvent
Temp./ЊC
Yield of 14 (%)a
1
2
3
4
CH2Cl2
CH2Cl2
CH2Cl2
ClCH2CH2Cl
Ϫ40
0
rt
48
55
50
20
Scheme 7
Reflux
a Isolated yields of the anomer mixture.
the Pummerer reactions (Scheme 6).17–20 The reaction would
be initiated by the attack of the hypervalent iodine on the
sulfur atom, and iodobenzene and a proton at the 2-position
of the tetrahydrothiophene ring might subsequently be regio-
selectively eliminated to generate a thionium cation 17 (pathway
a). The generated thionium cation 17 is attacked by a nucleo-
base from the favorable β-face due to neighboring group
participation of the 3-O-PMBz group to give only the
β-anomer 14. Thus, the coupling reaction in Method B showed
high stereoselectivity in comparison with that in Method A.
The difference between the stereoselectivities of the coupling
reactions in Methods A and B seems to be due to the cyclic
sulfonium salt (15 or 16) reacting via two pathways, a and b, i.e.,
via a thionium cation 17 and thiosugar 18, respectively. In
the case of pathway a, thionium cation 17 is subjected to neigh-
boring group participation by the 3-O-PMBz group, which is
similar to the pathway of the Pummerer reaction, to give the
β-anomer. On the other hand, in pathway b, the generated
thiosugar 18 reacts with a nucleobase to give a mixture of
α- and β-nucleoside due to classical glycosidation. It is well
known that the stereoselectivity in classical glycosidation
of thiosugar is not satisfactory even with the assistance of
neighboring C-2 acyloxy group participation, though the
reason is not clear.13–15 In Method A, the generation of
thiosugar 18 was suggested by the fact that the reaction of
disubstituted tetrahydrothiophene 10 with PhI(OAc)2 or
PhI(OCOCF3)2 gave thiosugar derivatives (19 or 20) in the
absence of a nucleobase under the conditions used in method
A (Scheme 7). Thus, it seems that both pathways a and b occur
in the reaction in method A, but only pathway a in the reaction
in Method B.
Scheme 8 Reagents and conditions: i) NH4F, MeOH; ii) NH3–MeOH,
2 steps 66%.
structure of 22 was confirmed by comparison of the analytical
data with those previously reported.19,24
In conclusion, this stereo- and regio-selective thioglycosid-
ation using a hypervalent iodine reagent provides a useful
method for the coupling of a thiosugar with a nucleobase. In
addition, the C–N bond formation that occurs using this
reagent is the first such example in an intermolecular reaction,
and so this method might be used as a new tool in synthetic
chemistry. Further studies are in progress.
Experimental section
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 spectrometer.
Chemical shifts are reported in ppm (δ) relative to TMS (0.0
ppm) as internal standard. Coupling constants, J, are given
in Hz. MS spectra were obtained on a JEOL JMS-HX110 and
JEOL JMS-700TZ. Column chromatography was conducted
using silica gel (Merck, Silica gel 60, 70–230 mesh).
1-(Tetrahydrothiophen-2-yl)thymine (2)
The resulting silylated thiouridine derivative 14 was treated
with NH4F and then deprotected using methanolic ammonia to
afford a free 4Ј-thiouridine (22) in 66% yield (Scheme 8). The
To a suspension of thymine (126 mg, 1.0 mmol) in CH2Cl2
(2 cm3) were added Et3N (0.42 cm3, 3.0 mmol) and TMSOTf
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 6 9 2 – 3 6 9 7
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(0.50 cm3, 3.0 mmol), and the mixture was stirred vigorously
at room temperature for 1 h under an argon atmosphere. The
mixture was then cooled in an ice–water bath, and tetrahydro-
thiophene (1) (0.44 cm3, 0.5 mmol) and PhI(OCOCF3)2 (129
mg, 0.6 mmol) were added. The resulting mixture was stirred
for 12 h, and the reaction was quenched by addition of ice.
The mixture was diluted with ethyl acetate and washed with
saturated NaHCO3 and brine. The organic layer was dried over
Na2SO4 and concentrated in vacuo. The residue was purified on
a silica gel column, eluted with hexane–AcOEt (1 : 1), to give
2 (86 mg, 80%) as a colourless solid. Mp 169–173 ЊC (hexane–
AcOEt); δH(300 MHz; CDCl3) 1.96 (3 H, s), 1.92–2.16 (3 H, m),
2.44–2.33 (1 H, m), 2.98 (1 H, dt, J 6.4 and 10.5), 3.21 (1 H, dt,
J 6.4 and 10.5), 6.32 (1 H, dd, J 5.2 and 6.7), 7.55 (1 H, d, J 1.3),
8.98 (1 H, br s, NH); δC(75 MHz; CDCl3) 12.7, 29.2, 33.5, 38.1,
63.8, 110.9, 136.5, 150.9, 163.8; m/z (FAB) 213.0682 (MHϩ.
C9H13N2O2S requires 213.0619). Anal. calcd. for C9H12N2O2S:
C, 50.92; H, 5.70; N, 13.20; S, 15.11. Found: C, 50.92; H, 5.63;
N, 13.11; S, 15.14%.
mixture was neutralized with saturated NH4Cl and partitioned
between ether and water. The separated organic layer was
washed with brine, dried over Na2SO4, and concentrated
in vacuo. The residue was purified on a silica gel column, eluted
with 5% ethanol in CHCl3, to give 6 (2.5 g, 96%) as a colourless
syrup. δH(300 MHz; CDCl3) 1.38 (3 H, s), 1.47 (3 H, s), 2.85
(2 H, br s, OH), 3.77 (4 H, m), 4.30 (2 H, m); δC(75 MHz;
CDCl3) 25.4, 27.8, 61.0, 76.8, 108.7; m/z (FAB) 163.0968 (MHϩ.
C7H15O4 requires 163.0970). Anal. calcd. for C7H14O4: C, 51.84;
H, 8.70. Found: C, 51.84; H, 8.61%.
meso-2,3-O-Isopropylidene-1,4-di-O-(methanesulfonyl)butane-
1,2,3,4-tetrol (7)
To a solution of 6 (2.0 g, 12 mmol) in pyridine (100 cm3) was
added methanesulfonyl chloride (2.8 cm3, 36 mmol) at 0 ЊC
under an argon atmosphere, and the mixture was stirred at 0 ЊC
for 6 h. The reaction was quenched by addition of ice, and the
solvent was removed under reduced pressure. The residue was
diluted with ethyl acetate and washed with water and brine. The
organic layer was dried over Na2SO4 and concentrated in vacuo.
The residue was purified by a silica gel column, eluted with
hexane–AcOEt (1 : 1), to give 7 (2.9 g, 76%) as a colourless
syrup. δH(300 MHz; CDCl3) 1.39 (3 H, s), 1.49 (3 H, s),
3.09 (6 H, s), 4.29–4.37 (4 H, m), 4.48 (2 H, m); δC(75 MHz;
CDCl3) 25.3, 27.7, 38.0, 66.7, 74.4, 110.4; m/z (EI) 303.0230
(Mϩ Ϫ CH3. C8H15O8S2 requires 303.0208).
cis-1,4-Di-O-benzoyl-2-butene-1,4-diol (4)
To a solution of cis-2-butene-1,4-diol (3) (4.0 g, 46 mmol) in
CH2Cl2 (200 cm3) were added Et3N (19 cm3, 138 mmol) and
benzoyl chloride (16 cm3, 138 mmol) at 0 ЊC under an argon
atmosphere, and the resulting mixture was stirred for 2 h at
room temperature. The reaction was quenched by addition of
ice, and the reaction mixture was partitioned between ether and
water. The separated organic layer was washed with water
and then with brine. The organic layer was dried over Na2SO4
and concentrated in vacuo. The residue was purified on a silica
gel column, eluted with hexane–AcOEt (7 : 1), to give 4 (12.7 g,
93%) as a colourless solid. Mp 60–63 ЊC (hexane–AcOEt);
δH(300 MHz; CDCl3) 5.01 (4 H, m), 5.95 (2 H, m), 7.41–7.59
(6 H, m), 8.04–8.07 (4 H, m); δC(75 MHz; CDCl3) 60.5, 128.4,
129.6, 130.0, 133.0, 166.3; m/z (EI) 296.1024 (MHϩ. C18H16O4
requires 296.1049). Anal. calcd. for C18H16O4: C, 72.96; H, 5.44.
Found: C, 73.07; H, 5.67%.
meso-3,4-O-Isopropylidenethiolane-3,4-diol (8)
To a solution of 7 (3.1 g, 9.7 mmol) in DMF (100 cm3) was
added Na2Sؒ9H2O (2.8 g, 11.6 mmol), and the resulting mixture
was stirred at 100 ЊC for 24 h under an argon atmosphere. The
mixture was diluted with ether and washed with water (twice)
and brine. The organic layer was dried over Na2SO4 and
concentrated in vacuo. The residue was purified on a silica gel
column, eluted with hexane–AcOEt (7 : 1), to give 8 (977 mg,
64%) as a colourless syrup. δH(300 MHz; CDCl3) 1.33 (3 H, s),
1.52 (3 H, s), 2.87 (4 H, m), 4.85 (2 H, m); δC(75 MHz; CDCl3)
24.6, 26.1, 38.6, 82.9, 110.9; m/z (EI) 160.0565 (Mϩ. C7H12O2S
requires 160.0558). Anal. calcd. for C7H12O2S: C, 52.47; H,
7.55. Found: C, 52.27; H, 7.42%.
meso-1,4-Di-O-benzoyl-2,3-O-isopropylidenebutane-1,2,3,4-
tetrol (5)
To a solution of 4 (8.0 g, 24 mmol) in acetone (100 cm3) were
added NMO (4.0 g, 34 mmol) and a 0.02 M solution of OsO4 in
t-BuOH (16 cm3, 0.3 mmol) at room temperature under an
argon atmosphere, and the resulting mixture was stirred at
room temperature for 12 h. The mixture was diluted with ethyl
acetate and washed with saturated Na2S2O4, water, and brine.
The organic layer was dried over Na2SO4 and concentrated
in vacuo. The residue was dissolved in acetone (500 cm3), and
then p-TsOH (500 mg) and acetone dimethyl acetal (50 cm3)
were added. The mixture was stirred at room temperature for
4 h and neutralized by saturated sodium bicarbonate. The
solvent was evaporated under reduced pressure. The residue
was partitioned between ether and water. The separated organic
layer was washed with brine, dried over Na2SO4, and concen-
trated in vacuo. The residue was purified on a silica gel column,
eluted with hexane–AcOEt (7 : 1), to give 5 (7.6 g, 86%) as
colourless needles. Mp 108–109 ЊC (hexane–AcOEt); δH(300
MHz; CDCl3) 1.43 (3 H, s), 1.53 (3 H, s), 4.44–4.64 (6 H, m),
7.40–7.60 (6 H, m), 8.04–8.08 (4 H, m); δC(75 MHz; CDCl3)
25.3, 27.7, 62.9, 74.7, 109.5, 128.4, 129.6, 129.7, 133.2, 166.2;
m/z (EI) 355.1196 (Mϩ Ϫ CH3. C20H19O6 requires 355.1182).
Anal. calcd. for C21H22O6: C, 68.10; H, 5.99. Found: C, 68.14;
H, 6.13%.
meso-Thiolane-3,4-diol (9)
To a solution of 8 (790 mg, 4.9 mmol) in methanol (50 cm3) was
added 80% acetic acid, and the mixture was refluxed for 8 h.
The solvent was removed under reduced pressure. The residue
was purified on a silica gel column, eluted with hexane–AcOEt
(1 : 3), to give 9 (512 mg, 87%) as a colourless solid. Mp 69–71
ЊC (hexane–AcOEt); δH(300 MHz; CDCl3) 2.39 (2 H, br s, OH),
2.82 (2 H, dd, J 5.1 and 11.2), 3.03 (2 H, dd, J 5.6 and 11.2),
4.30 (2 H, dd, J 5.1 and 5.6); m/z (EI) 120.0246 (Mϩ. C4H8O2S
requires 120.0245). Anal. calcd. for C4H8O2S: C, 39.98; H, 6.71;
S, 26.68. Found: C, 40.02; H, 6.76; S, 26.71%.
meso-3,4-Di-O-p-methoxybenzoylthiolane-3,4-diol (10)
To a solution of 9 (249 mg, 2.1 mmol) in pyridine (15 cm3) was
added p-methoxybenzoyl chloride (1.1 g, 6.6 mmol) at 0 ЊC
under an argon atmosphere, and the mixture was stirred
at room temperature for 4 h. The reaction was quenched by
addition of ice, and the reaction mixture was partitioned
between ether and water. The separated organic layer was
washed with water and then with brine. The organic layer was
dried over Na2SO4 and concentrated in vacuo. The residue was
purified on a silica gel column, eluted with hexane–AcOEt
(3 : 1), to give 10 (757 mg, 93%) as a colourless solid. Mp 112–
115 ЊC (hexane–AcOEt); δH(300 MHz; CDCl3) 3.30 (2 H, dd,
J 5.7 and 11.2), 3.14 (2 H, dd, J 5.3 and 11.2), 3.85 (6 H, s), 5.71
(2 H, m), 6.88 (4 H, d, J 8.8), 7.95 (4 H, d, J 8.8); δC(75 MHz;
meso-2,3-O-Isopropylidenebutane-1,2,3,4-tetrol (6)
To a solution of 5 (6.0 g, 16 mmol) in methanol (150 cm3) was
added 28% sodium methoxide (1 cm3) at room temperature, and
the mixture was stirred at room temperature for 30 min. The
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CDCl3) 31.1, 55.4, 74.7, 113.7, 122.0, 131.8, 163.6, 165.3; m/z
(FAB) 389.1051 (MHϩ. C20H21O6S requires 389.1059). Anal.
calcd. for C20H20O6S: C, 61.84; H, 5.19. Found: C, 61.65; H,
5.27%.
Method B. To a suspension of thymine (66 mg, 0.52 mmol) in
CH2Cl2 (2 cm3) were added Et3N (0.14 cm3, 1.04 mmol) and
TMSOTf (0.28 cm3, 1.56 mmol), and the mixture was stirred at
room temperature for 1 h to afford a silylated thymine solution.
To a solution of 10 (100 mg, 0.26 mmol) in CH2Cl2 (2 cm3) were
added iodosobenzene (133 mg, 0.31 mmol) and TMSOTf (0.94
cm3, 0.52 mmol) at 0 ЊC. After stirring for 5 min, the silylated
thymine solution was added to the mixture and Et3N (0.14 cm3,
1.04 mmol) was then added, and the resulting mixture was
stirred for 12 h. The reaction was quenched by the addition of
ice, and the mixture was partitioned between ethyl acetate and
water. The organic layer was washed with saturated NaHCO3
and brine, dried over Na2SO4, and concentrated in vacuo. The
residue was purified on a silica gel column, eluted with hexane–
AcOEt (1 : 1), to give 13 (76 mg, 61%) as a colourless solid.
1,4-Anhydro-3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-4-
thio-D-ribitol (11)
The title compound was prepared from -ribose according to
the reported procedure.23 δH(300 MHz; CDCl3) 0.95–1.09 (28
H, m), 2.64 (1 H, m), 2.84 (1 H, m), 2.84 (1 H, dd, J 1.6 and
12.1), 3.03 (1 H, ddd, J 1.5, 4.7 and 12.1), 3.50 (1 H, ddd, J 3.3,
4.7 and 8.3), 3.90 (1 H, dd, J 4.7 and 12.4), 4.04 (1 H, dd,
J 3.3 and 12.4), 4.23 (1 H, dd, J 3.9 and 8.3), 4.33 (1 H, m);
δC(75 MHz; CDCl3) 12.6, 12.7, 13.1, 13.3, 13.4, 17.1, 17.2, 17.3,
17.4, 32.4, 49.2, 61.0, 74.4, 77.5; m/z (FAB) 393.1972 (MHϩ.
C17H37O4SSi2 requires 393.1952). Anal. calcd. for C17H36O4SSi2:
C, 51.99; H, 9.24; S, 8.17. Found: C, 51.76; H, 9.00; S, 8.26%.
1-[2-O-(p-Methoxybenzoyl)-3,5-O-(1,1,3,3-tetraisopropyl-
disiloxane-1,3-diyl)-4-thio-ꢀ-D-ribofuranosyl]uracil (14)
Method B. To a suspension of uracil (45 mg, 0.4 mmol) in
CH2Cl2 (2 cm3) were added Et3N (0.11 cm3, 0.8 mmol) and
TMSOTf (0.22 cm3, 1.2 mmol), and the mixture was stirred at
room temperature for 1 h to afford a silylated uracil solution.
To a solution of 12 (105 mg, 0.2 mmol) in CH2Cl2 (2 cm3) were
added iodosobenzene (48 mg, 0.2 mmol) and TMSOTf (0.73
cm3, 0.4 mmol) at 0 ЊC. After stirring for 5 min, the silylated
uracil solution was added to the mixture and Et3N (0.11 cm3,
0.8 mmol) was then added, and the resulting mixture was
stirred for 12 h. The reaction was quenched by addition of ice,
and the mixture was partitioned between ethyl acetate and
water. The organic layer was washed with saturated NaHCO3
and brine, dried over Na2SO4, and concentrated in vacuo. The
residue was purified on a silica gel column, eluted with hexane–
AcOEt (1 : 1), to give 14 (67 mg, 53%) as a yellow solid. Mp
89–93 ЊC (hexane–AcOEt). δH(300 MHz; CDCl3) 0.89–1.15 (28
H, m), 3.72 (1 H, d, J 9.5), 3.87 (3 H, s), 4.05–4.17 (2 H, m), 4.44
(1 H, dd, J 3.9 and 9.5), 5.61 (1 H, d, J 3.9), 5.75 (1 H, dd, J 2.1
and 8.3), 6.00 (1 H, s), 6.93 (2 H, d, J 8.6), 8.02 (1 H, d, J 8.3),
8.20 (1 H, d, J 8.3), 8.82 (1 H, br s, NH); δC(75 MHz; CDCl3)
12.5, 131.1, 13.2, 13.3, 16.8, 16.9, 17.0, 17.2, 17.3, 17.4, 50.9,
55.4, 57.9, 62.3, 71.6, 78.1, 102.3, 113.7, 122.0, 131.9,
139.0, 141.0, 150.0, 163.6, 1642; m/z (FAB) 637.2438 (MHϩ.
C29H45N2O8SSi2 requires 637.2436). Anal. calcd. for C29H44-
N2O8SSi2: C, 54.69; H, 6.96; N, 4.40; S, 5.03. Found: C, 54.45;
H, 7.01; N, 4.18; S, 4.96%.
1,4-Anhydro-2-O-(p-methoxybenzoyl)-3,5-O-(1,1,3,3-tetra-
isopropyldisiloxane-1,3-diyl)-4-thio-D-ribitol (12)
To a solution of 11 (730 mg, 1.9 mmol) in pyridine (35 cm3) was
added p-methoxybenzoyl chloride (0.65 cm3, 3.8 mmol) at 0 ЊC
under a nitrogen atmosphere, and the mixture was stirred at
room temperature for 12 h. The reaction was quenched with ice,
and the mixture was partitioned between ethyl acetate and
water. The separated 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 a silica
gel column, eluted with hexane–AcOEt (15 : 1), to give 12 (980
mg, 98%) as a colourless syrup. δH(300 MHz; CDCl3) 1.11–0.87
(28 H, m), 2.90 (1 H, d, J 12.5), 3.23 (1 H, dd, J 4.5 and 12.5),
3.66 (1 H, ddd, J 3.0, 3.2 and 9.5), 3.87 (3 H, s), 3.96 (1 H, dd,
J 3.2 and 12.4), 4.10 (1 H, dd, J 3.0 and 12.4), 4.34 (1 H, dd,
J 3.8 and 9.5), 5.73 (1 H, dd, J 3.8 and 4.5), 6.90–6.95 (2 H, m),
8.00–8.05 (2 H, m); δC(75 MHz; CDCl3) 12.6, 12.7, 13.2, 13.3,
13.4, 17.0, 17.1, 17.2, 17.3, 17.4, 31.0, 496, 55.4, 59.9, 75.5, 75.7,
113.6, 122.7, 131.8, 163.4, 165.6; m/z (FAB) 527.2305 (MHϩ.
C25H43O6SSi2 requires 527.2241). Anal. calcd. for C25H43O6SSi2:
C, 56.99; H, 8.04; S, 6.09. Found: C, 56.90; H, 8.00; N, 6.04%.
(2R*, 3R*, 4S*)-1-(3,4-Di-O-p-methoxybenzoylthiolane-3,4-
diol-2-yl)thymine (13)
Method A. To a suspension of thymine (66 mg, 0.52 mmol) in
CH2Cl2 (2 cm3) were added Et3N (0.11 cm3, 0.78 mmol) and
TMSOTf (0.28 cm3, 1.56 mmol) at room temperature under a
nitrogen atmosphere. After the mixture had been stirred for 1 h,
a clear solution was obtained. A solution of 10 (100 mg, 0.26
mmol) in CH2Cl2 (2 cm3) was added to the mixture at 0 ЊC, and
PhI(OCOCF3)2 (133 mg, 0.31 mmol) was then added in one
portion. After stirring for 10 min, additional Et3N (0.109 cm3,
0.78 mmol) in CH2Cl2 (1 cm3) was added dropwise to the
reaction mixture. After the mixture had been stirred for 12 h,
the reaction was quenched by addition of ice, and the mixture
was partitioned between ethyl acetate 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 a silica gel column, eluted with
hexane–AcOEt (1 : 1), to give 13 (87 mg, 65%) as a colourless
solid. Mp 239–242 ЊC (hexane–AcOEt); δH(300 MHz; CDCl3)
2.00 (3 H, s), 3.23 (1 H, dd, J 2.6 and 12.5), 3.72 (1 H, dd, J 4.6
and 12.5), 3.83 (3 H, s), 3.88 (3 H, s), 5.62 (1 H, dd, J 3.9 and
7.9), 5.91 (1 H, m), 6.66 (1 H, d, J 7.9), 6.83–6.97 (4 H, m), 7.53
(1 H, s), 7.86–8.03 (5 H, m); δC(75 MHz; CDCl3) 12.8, 32.9,
55.5, 61.5, 72.5, 77.5, 112.4, 113.7, 113.8, 120.7, 121.3, 131.9,
132.0, 135.4, 150.5, 162.8, 163.7, 163.8, 164.9, 165.0; m/z (FAB)
513.1360 (MHϩ. C25H25 N2O8S requires 513.1332). Anal. calcd.
for C25H24 N2O8S: C, 58.59; H, 4.72; N, 5.47; S, 6.26. Found: C,
58.41; H, 4.77; N, 5.36; S, 6.10%.
2,3-Di-O-p-methoxybenzoyl-4-thio-DL-erythrofuranose (19)
To a solution of 10 (50 mg, 0.13 mmol) in CH2Cl2 (2 cm3) were
added PhI(OCOCF3)2 (56 mg, 0.13 mmol) and TMSOTf (0.24
cm3, 0.13 mmol) at 0 ЊC under a nitrogen atmosphere. After
stirring for 15 min, a solution of Et3N (0.18 cm3, 0.13 mmol) in
CH2Cl2 (1 cm3) was added dropwise to the mixture, and the
mixture was stirred for 2 h. The mixture was diluted with ethyl
acetate and then washed with water and brine. The organic
layer was dried over Na2SO4 and concentrated in vacuo. The
residue was purified on a silica gel column, eluted with hexane–
AcOEt (4 : 1), to give 19 (34 mg, 65%) as a colourless syrup.
δH(300 MHz; CDCl3) 2.53 (1 H, d, J 5.3), 2.80 (0.25 H, d,
J 11.6), 3.17 (1 H, dd, J 8.1 and 10.4), 3.31 (0.5 H, m), 3.59 (1 H,
dd, J 6.6 and 10.4), 3.84 (3.75 H, s), 3.87 (3.75 H, s), 5.41 (0.25
H, m), 5.48 (1 H, dd, J 2.4 and 5.3), 5.66–5.74 (1.25 H, m),
5.86 (1 H, m), 5.97 (0.25 H, m), 6.83–6.95 (5 H, m), 7.87–8.08
(5 H, m); m/z (FAB) 405.0997 (MHϩ. C20H21O7S requires
405.1009).
1-O-Acetyl-2,3-di-O-p-methoxybenzoyl-4-thio-DL-erythro-
furanose (20)
This compound was prepared using PhI(OAc)2 as the hyper-
valent iodine according to the procedure used for the prepar-
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 6 9 2 – 3 6 9 7
3696

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3 M. R. Dyson, P. L. Coe and R. T. Walker, J. Med. Chem., 1991, 34,
ation of 19. Silica gel column chromatography (hexane–AcOEt
= 1 : 1) gave 20 (62%) as a colourless syrup. δH(300 MHz;
CDCl3) 2.14 (3 H, s), 3.20 (1 H, dd, J 8.4 and 10.3), 3.48 (1 H,
dd, J 6.6 and 10.3), 3.84 (3 H, s), 3.87 (3 H, s), 5.79 (1 H, ddd,
J 3.5, 6.6 and 8.4), 5.85 (1 H, dd, J 2.0 and 3.5), 6.05 (1 H, d,
J 2.0), 6.81–6.95 (4 H, m), 7.85–8.11 (4 H, m); m/z (FAB)
447.1143 (MHϩ. C22H23O8S requires 447.1114).
2782–2786.
4 S. G. Rahim, N. Trivedi, M. V. Bogunovic-Batchelor, G. W. Hardy,
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1-(4-Thio-ß-D-ribofuranosyl)uracil (22)
To a solution of 14 (340 mg, 0.53 mmol) in methanol (10 cm3)
was added NH4F (393 mg, 10.6 mmol), and the mixture was
heated under reflux for 12 h. The solvent was removed under
reduced pressure, and the residue was dissolved in methanolic
ammonia (15 cm3). The mixture was kept for 24 h at room
temperature, and the solvent was removed under reduced
pressure. The residue was purified on a silica gel column, eluted
with CHCl3–EtOH (5 : 1), to give 22 (90 mg, 66%) as a
colourless solid. Mp 195–196 ЊC (lit.19,24 mp 195–196 ЊC)
(CHCl3–EtOH); δH(300 MHz; DMSO-d6) 3.19 (1 H, ddd, J 2.4,
5.4 and 6.2), 3.52 (1 H, ddd, J 5.3, 5.4 and 11.2), 3.62 (1 H, ddd,
J 5.3, 6.2 and 11.2), 4.02 (1 H, ddd, J 2.4, 2.8 and 3.5), 4.15
(1 H, ddd, J 3.5, 5.3 and 7.3), 5.18 (1 H, t, J 5.3), 5.26 (1 H, d,
J 2.8), 5.48 (1 H, d, J 5.3), 5.67 (1 H, d, J 8.1), 5.89 (1 H, d,
J 7.3), 7.99 (1 H, d, J 8.1), 11.31 (1H, br s, NH); δC(75 MHz;
DMSO-d6) 53.0, 62.3, 63.1, 73.0, 76.3, 102.1, 141.5, 151.1,
162.9; m/z (FAB) 261.0557 (MHϩ. C9H13N2O5S requires
261.0546).
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This work was partially supported by the Academic Science
Frontier Project of the Ministry of Education, Culture, Sports,
Science and Technology, Japan. We would like to thank 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).
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