Synthesis of thietane nucleosides by glycosidation of thietanose derivatives with nucleobases

Article abstract of DOI:10.1016/j.tet.2007.09.002

Thietane nucleosides were synthesized by the glycosidation of glycosyl fluoride with nucleobase.

Full text of DOI:10.1016/j.tet.2007.09.002

Tetrahedron 63 (2007) 11622–11625
Synthesis of thietane nucleosides by glycosidation of thietanose
derivatives with nucleobases
*
Naozumi Nishizono, Michiyasu Sugo, Minoru Machida and Kazuaki Oda
*
Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan
Received 27 June 2007; revised 3 September 2007; accepted 3 September 2007
Available online 7 September 2007
Abstract—Thietane nucleosides were synthesized by the glycosidation of glycosyl fluoride with nucleobase.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
fluoride even in the case of thietanose, it might be possible
to use it as a stable glycosyl donor. In this study, we selected
a known thietane nucleoside and its analogue, which are
easily prepared as target compounds, and examined their
synthesis by the glycosidation of thietanose derivatives
with nucleobases.
Oxetanocin A (1), isolated from Bacillus megaterium NK84-
0216 in 1986,1,2 is a nucleoside antibiotic containing an
oxetane ring in place of a furanose moiety. Because of its
unique structure and broad antiviral spectrum, oxetanocin
A and its analogues have been synthesized and evaluated
for their biological activities.3 For example, oxetanocin G,
where the adenine base is replaced with a guanine base, ex-
hibits potent antiviral activity against HIV-1 and HSV.4,5 The
carbocyclic analogue of oxetanocin G has been identified as
an effective anti-HBV and anti-HSV agent.6
2. Results and discussion
Precursors 6 and 7 for glycosyl fluoride were prepared from
2,2-bis(bromomethyl)-1,3-propanediol (2), as shown in
Scheme 1. Thus, 2,2-bis(bromomethyl)-1,3-propanediol
(2) was converted to isopropylidene-protected derivative 3
with 2,2-dimethoxypropane in the presence of a catalytic
amount of p-toluenesulfonic acid with a yield of 97%; this
was followed by treatment with sodium sulfide in DMF at
100 ꢀC to give thietane 4 with a yield of 98%. The protecting
group in 4 was converted to a benzoyl group to give 6, which
was oxidized using NaIO4 in methanol to give sulfoxide 7
with a yield of 83%.
More recently, thietane nucleosides, where the oxetane ring
is replaced with a thietane ring, have also been synthe-
sized,7–9 and some of them exhibited antiviral activity
against HIV-1.7 Despite their biological activities, the diffi-
culty involved in synthesizing thietane nucleosides has
impeded the investigation of structure–activity relationships
and their development as clinical agents. In addition, all the
thietane nucleosides reported to date have been synthesized
by using Pummerer reaction, and an other method has not
been reported so far. Therefore, new methods to synthesize
thietane nucleosides are required.
OH
OH
O
O
Br
Br
Br
Br
a
b
c
S
O
O
2
3 (97%)
4 (98%)
Because of the stronger C–F bond, glycosyl fluoride was not
used as a glycosyl donor. However, after the use of glycosyl
fluoride as a glycosyl donor with a fluorophilic activator—
SnCl2–AgClO4—was introduced by Mukaiyama in 1981,10
a number of specific fluorophilic reagents have been devel-
oped for effective O-glycosidation reactions. Glycosyl fluo-
ride is now used as a versatile sugar donor in the synthesis of
natural products and carbohydrates because of its enhanced
stability and ease of handling as compared to other glycosyl
halides.11 We hypothesized that by preparing glycosyl
OH
OH
OBz
OBz
OBz
OBz
e
d
S
S
O
S
5
6 (80% from 4)
7 (83%)
Scheme 1. Reagents and conditions: (a) 2,2-dimethoxypropane, p-TsOH,
acetone; (b) Na2S$9H2O, DMF, 100 ꢀC; (c) p-TsOH, MeOH; (d) BzCl,
DMAP, Et3N, CH2Cl2; (e) NaIO4, MeOH.
Since diethylaminosulfur trifluoride (DAST) was found to
be an excellent reagent for the replacement of free hydroxyl
groups with fluorine, it is widely used as the most convenient
reagent.12 DAST also converts sulfoxides and sulfides to
* Corresponding authors. E-mail: nishizon@hoku-iryo-u.ac.jp
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.09.002

N. Nishizono et al. / Tetrahedron 63 (2007) 11622–11625
11623
a-fluoro thioethers.13,14 Recently, bis(2-methoxyethyl)ami-
Cl
N
nosulfur trifluoride (Deoxo-Fluor) was disclosed as a new
broad spectrum fluorinating agent with enhanced thermal
stability by Lal and co-workers.15 Therefore, we investi-
gated the preparation of glycosyl fluoride using DAST and
Deoxo-Fluor as fluorinating reagents.
N
N
N
F
OBz
OBz
OBz
silylated 6-chloropurine
Lewis acid, CH2Cl2
S
+ N-7 isomer
S
OBz
8
10
First, we attempted the fluorination of sulfide 6. Treatments
of 6 with DAST and Deoxo-Fluor in dichloromethane pro-
duced glycosyl fluoride 8 with yields of 92 and 83%, respec-
tively (Scheme 2). Sulfoxide 7 as well as sulfide 6 reacted
with Deoxo-Fluor to produce glycosyl fluoride 8 with a yield
of 86%. As described above, we were able to prepare glyco-
syl fluoride even in the case of thietane derivatives, and 8
was also stable after being purified by silica gel column
chromatography.
Yield (%)
Lewis acid
BF3-Et2O
10 (N-7 isomer)
16 (10)
SnCl2, AgClO4
27 (15)
Scheme 4.
Finally, a free nucleoside 11 was obtained in 87% yield by
the deprotection of 9. A purine nucleoside 12 was also ob-
tained in 81% yield by the treatment of 10 with methanolic
ammonia at 100 ꢀC (Scheme 5).
DAST (92%) or Deoxo-Fluor
OBz
OBz
(83%), SbCl3, CH2Cl2
S
O
F
O
OBz
OBz
6
CH3
CH3
HN
HN
S
O
N
OBz
OBz
O
N
8
O
S
OBz
OBz
CH3NH2
CH3OH
OH
OH
DAST (22%) or Deoxo-Fluor
(86%), SbCl3, CH2Cl2
S
S
7
9
11 (87%)
Scheme 2.
Cl
NH2
Next, we attempted the glycosidation of 8 with nucleo-
bases. The treatment of glycosyl fluoride 8 with silylated
thymine in the presence of TMSOTf–AgOTf as an activat-
ing reagent produced thietane nucleoside 9 with a yield
of 22% (Scheme 3). The best results were obtained when
AgClO4–SnCl2 was used instead of TMSOTf–AgOTf to
afford 9 with a yield of 56%.
N
N
N
N
N
N
N
OBz
N
OH
NH3 / CH3OH
100 °C
S
S
OBz
OH
12 (81%)
10
Scheme 5.
O
CH3
HN
O
N
F
3. Conclusion
OBz
OBz
OBz
OBz
silylated thymine
Lewis acid, CH2Cl2
S
S
In summary, the synthesis of thietane nucleoside has been
achieved by the glycosylation reaction of glycosyl fluoride
with nucleobases. This study reports for the first time the
successful synthesis of thietane nucleoside by glycosylation
reaction. Thus, it is evident that thietane nucleosides can be
synthesized by the condensation of thietanose derivatives
with a nucleobase.
8
9
Lewis acid
Yield (%)
TMSOTf, AgOTf
SnCl2, AgClO4
22
56
Scheme 3.
Subsequently, the glycosidation of 8 with silylated 6-chloro-
purine was examined. As in the case of silylated thymine,
glycosyl fluoride 8 reacted with silylated 6-chloropurine in
the presence of AgClO4–SnCl2 to produce 10 with a yield
of 27% along with the N-7 isomer of 10 with a yield of
15% (Scheme 4). It is well known that because of a strain
in the oxetane ring, oxetanocin derivatives are treated with
a Lewis acid to give its furanosyl derivatives by a ring expan-
sion.16 Although a thietane ring also has a ring strain, a gly-
cosyl bond of thietanose is more stable than a glycosyl bond
of oxetanose. Consequently, thietane nucleosides were ob-
tained with a moderate yield by the glycosylation reaction
of glycosyl fluoride with nucleobases in the presence of
the Lewis acid.
4. Experimental section
4.1. General
All melting points were determined on the Yamato melting
point apparatus (model MP-2) and were uncorrected. The
NMR spectra were recorded on JEOL JNM-LA-300 and
JEOL JNM-ECA-500 spectrometers. The chemical shifts
are reported in parts per million (d) relative to TMS
(0.0 ppm) as the internal standard, and the signals were ex-
pressed as s (singlet), d (doublet), t (triplet), m (multiplet),
or br (broad). The values of the coupling constant J were pro-
vided in hertz. The MS spectra were obtained on JEOL JMS-
HX110andJEOLJMS-700TZ.TLCwasperformedonMerck

11624
N. Nishizono et al. / Tetrahedron 63 (2007) 11622–11625
Silica gel 60 F254 plates. Column chromatography was con-
ducted using silica gel (Merck, Silica gel 60, 70–230 mesh).
4.1.4. 3,3-Bis[(benzoyloxy)methyl]thietan-1-oxide (7). To
a solution of 6 (2.8 g, 8.2 mmol) in methanol (200 mL), we
added NaIO4 (2.1 g, 9.9 mmol) at 0 ꢀC; this mixture was
stirred at room temperature for 21 h. A white solid was
formed in the mixture; it was removed by filtration. Next,
the mixture was concentrated under reduced pressure. The
residue was purified on a silica gel column, eluted with hex-
ane–ethyl acetate (1:2), to give 7 (2.4 g, 83%) as a white
solid. Mp 115–116 ꢀC (hexane–ethyl acetate). 1H NMR
(300 MHz, CDCl3) d: 8.09–7.46 (m, 10H), 4.46 (s, 2H),
4.42 (s, 2H), 3.79 (d, 2H, J¼13.1 Hz), 3.44 (d, 2H,
J¼13.1 Hz). 13C NMR (75 MHz, CDCl3) d: 165.0, 132.7,
132.6, 128.8, 128.1, 127.9, 127.7, 66.4, 65.7, 55.1, 35.6.
EI-LRMS m/z 358 (M+). EI-HRMS m/z 358.0887 (calcd
for C19H18O5S: 358.0875). Anal. Calcd for C19H18O5S: C,
63.67; H, 5.06; S, 8.95. Found: C, 63.56; H, 5.06; S, 8.73.
4.1.1. 2,2-Bis(bromomethyl)-1,3-O-isopropylidene-1,3-
propanediol (3). To a solution of 2,2-bis(bromomethyl)-
1,3-propanediol (15.0 g, 57 mmol) in acetone (200 mL),
we added 2,2-dimethoxypropane (50 mL) and p-toluenesul-
fonic acid monohydrate (100 mg, 0.5 mmol) at room temper-
ature; this mixture was stirred for 2 h at room temperature.
The reaction mixture was neutralized using saturated sodium
bicarbonate and the solvent was then evaporated under re-
duced pressure. The residue was 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
hexane–ethyl acetate (6:1), to give 3 (16.6 g, 97%) as a color-
1
less solid. Mp 59–60 ꢀC (hexane–ethyl acetate). H NMR
(300 MHz, CDCl3) d: 3.80 (s, 4H), 3.58 (s, 4H), 1.42 (s,
6H). 13C NMR (75 MHz, CDCl3) d: 99.2, 65.1, 38.0, 36.1,
23.7. EI-LRMS m/z 285 (M+ꢁCH3), 287 (M+ꢁCH3+2),
289 (M+ꢁCH3+4). Anal. Calcd for C8H14Br2O2: C, 31.82;
H, 4.67; Br, 52.92. Found: C, 31.87; H, 4.68; Br, 52.78.
4.1.5. 3,3-Bis[(benzoyloxy)methyl]-2-fluorothietane (8).
[Fluorination of sulfide 6] To a solution of 6 (100 mg,
0.29 mmol) in dry CH2Cl2, we added DAST (77 mL,
0.58 mmol) and SbCl3 (1 mg) at room temperature under
a nitrogen atmosphere; this mixture was stirred at room tem-
perature for 20 h. The reaction mixturewas diluted with ethyl
acetate and washed with saturated sodium bicarbonate, wa-
ter, 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–ethyl acetate (6:1), to give
8 (101 mg, 92%) as an yellow oil.
4.1.2. 30,30-O-Isopropylidene-3,3-bis(hydroxymethyl)thia-
cyclobutane (4). A solution of 3 (17.0 g, 55 mmol) and
Na2S$9H2O (15.0 g, 62 mmol) in DMF (200 mL) was stirred
at 100 ꢀC for 10 h. The reaction mixture was diluted with
ether and washed with water and brine. The organic layer
was dried over Na2SO4 and concentrated in vacuo. The resi-
due was purified on a silica gel column, eluted with hexane–
ethyl acetate (7:1), to give 4 (9.4 g, 98%) as a yellow solid.
When Deoxo-Fluor (74 mL, 0.4 mmol) was used instead of
DAST, 87 mg of 8 was obtained (83%).
1
Mp 51–52 ꢀC (hexane–ethyl acetate). H NMR (300 MHz,
CDCl3) d: 3.88 (s, 4H), 2.97 (s, 4H), 1.39 (s, 6H). 13C
NMR (75 MHz, CDCl3) d: 98.1, 68.6, 41.3, 31.0, 23.8. EI-
LRMS m/z 174 (M+). EI-HRMS m/z 174.0720 (calcd for
C8H14O2S: 174.0714). Anal. Calcd for C8H14O2S$0.1H2O:
C, 54.58; H, 8.13. Found: C, 54.43; H, 7.93.
[Fluorination of sulfoxide 7] To a solution of 7 (1.1 g,
3.1 mmol) in dry CH2Cl2, we added Deoxo-Fluor
(1.13 mL, 6.12 mmol) and SbCl3 (10 mg) at room tempera-
ture under a nitrogen atmosphere; this mixture was stirred at
room temperature for 24 h. The reaction mixture was diluted
with ethyl acetate and washed with saturated sodium bicar-
bonate, 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–ethyl acetate
(6:1), to give 8 (949 mg, 86%) as an yellow oil.
4.1.3. 3,3-Bis[(benzoyloxy)methyl]thietane (6). A solution
of 4 (1.0 g, 5.7 mmol) and p-toluenesulfonic acid monohy-
drate (200 mg, 1 mmol) in methanol (50 mL) was stirred
at room temperature for 1 h. The reaction mixture was neu-
tralized using saturated sodium bicarbonate and the solvent
was then evaporated under reduced pressure. The residue
was partitioned between ether and water. The separated
organic layer was washed with brine, dried over Na2SO4,
and concentrated in vacuo. The residue was dissolved in
dry CH2Cl2, and triethylamine (2.1 mL, 15.0 mmol), benzo-
yl chloride (1.6 mL, 13.7 mmol), and DMAP (10 mg) were
added to the mixture at 0 ꢀC. After the resulting mixture
was stirred at 0 ꢀC for 3 h, the reaction was quenched by add-
ing ice. The reaction mixture was partitioned between ethyl
acetate 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 hexane–ethyl acetate (7:1), to give 6 (1.6 g, 80%) as
When DAST (824 mL, 6.2 mmol) was used instead of
Deoxo-Fluor, 242 mg of 8 was obtained (22%).
1H NMR (300 MHz, CDCl3) d: 8.00–8.07 (m, 4H), 7.62–
7.54 (m, 2H), 7.48–7.41 (m, 4H), 6.07 (d, 1H, J¼63.1 Hz),
4.81 (d, 1H, J¼11.7 Hz), 4.71 (d, 1H, J¼11.7 Hz), 4.61 (s,
2H), 3.27 (d, 1H, J¼9.1 Hz), 2.98 (d, 1H, J¼9.1 Hz). 13C
NMR (75 MHz, CDCl3) d: 166.2, 166.0, 133.5, 133.3,
129.7, 129.6, 129.5, 129.2, 128.6, 128.5, 94.8 (d,
J¼245.5 Hz) , 65.0, 62.9 (d, J¼11.7 Hz), 52.9 (d,
J¼21.0 Hz), 25.5. EI-LRMS m/z 360 (M+). EI-HRMS m/z
360.0815 (calcd for C19H17O4FS: 360.0831).
1
a yellow solid. Mp 79–82 ꢀC (hexane–ethyl acetate). H
4.1.6. 1-[3,3-Bis(benzoyloxymethyl)thietan-2-yl]thymine
(9). A mixture of thymine (87 mg, 0.68 mmol) and HMDS
(4 mL) was refluxed for 3 h until the solution became clear.
After evaporation, the residue was dissolved in dry CH2Cl2
(3 mL). A solution of 8 (122 mg, 0.34 mmol) in dry
CH2Cl2 (2 mL), AgClO4 (71 mg, 0.34 mmol), and SnCl4
(65 mg, 0.34 mmol) was added to the mixture at 0 ꢀC, and
NMR (300 MHz, CDCl3) d: 8.24–7.35 (m, 10H), 4.58 (s,
4H), 3.21 (s, 4H). 13C NMR (75 MHz, CDCl3) d: 166.3,
133.3, 129.6, 128.5, 66.8, 46.3, 28.8. EI-LRMS m/z 342
(M+). EI-HRMS m/z 342.0952 (calcd for C19H18O4S:
342.0926). Anal. Calcd for C19H18O4S: C, 66.30; H, 5.33;
S, 9.36. Found: C, 66.38; H, 5.36; S, 9.63.

N. Nishizono et al. / Tetrahedron 63 (2007) 11622–11625
11625
the mixture was stirred at room temperature for 18 h. The re-
action mixture was diluted with ethyl acetate and washed
with saturated sodium bicarbonate, water, and brine. The or-
ganic layer was dried over Na2SO4, and concentrated in va-
cuo. The residue was purified on a silica gel column, eluted
with hexane–ethyl acetate (1:1), to give 9 (88 mg, 56%) as
(125 MHz, DMSO-d6) d: 164.4, 151.6, 138.7, 108.5, 64.1,
60.5, 56.4, 56.3, 24.7, 12.9. EI-LRMS m/z 258 (M+). EI-
HRMS m/z 258.0685 (calcd for C10H14N2O4S: 258.0674).
Anal. Calcd for C10H14N2O4S: C, 46.50; H, 5.46; N, 10.85;
S, 12.41. Found: C, 46.40; H, 5.44; N, 10.77; S, 12.42.
1
a white foam. H NMR (300 MHz, CDCl3) d: 9.12 (s, 1H),
4.1.9. 9-[3,3-Bis(hydroxymethyl)thietan-2-yl]adenine
(12). A solution of 10 (122 mg, 0.25 mmol) in methanolic
ammonia (saturated at 0 ꢀC, 10 mL) was heated for 16 h at
100 ꢀC in a steel container. The solvent was removed in
vacuo, and the residue was purified on a silica gel column,
eluted with 15% methanol in chloroform, to give 12
(54 mg, 81%) as a colorless solid. Mp 246–247 ꢀC (metha-
8.11–7.95 (m, 5H), 7.62–7.56 (m, 2H), 7.49–7.42 (m, 4H),
6.27 (s, 1H), 4.83 (d, 1H, J¼11.6 Hz), 4.63 (d, 1H, J¼
11.6 Hz), 4.57 (d, 1H, J¼12.2 Hz), 4.42 (d, 1H, J¼
12.2 Hz), 3.25 (d, 1H, J¼9.6 Hz), 3.01 (d, 1H, J¼9.6 Hz),
1.81 (s, 3H). 13C NMR (75 MHz, CDCl3) d: 165.1, 164.8,
161.9, 149.7, 135.8, 132.7, 132.4, 128.8, 128.5, 128.4,
128.8, 127.6, 127.5, 109.6, 65.4, 62.0, 55.6, 52.5, 24.0,
11.4. EI-LRMS m/z 466 (M+). EI-HRMS m/z 466.1189
(calcd for C24H22N2O6S: 466.1199).
1
nol). H NMR (500 MHz, DMSO-d6) d: 8.53 (s, 1H), 8.11
(s, 1H), 7.26 (br s, 2H), 6.00 (s, 1H), 5.15 (t, 1H,
J¼5.5 Hz), 4.50 (t, 1H, J¼4.8 Hz), 3.62 (dd, 1H, J¼5.5
and 11.1 Hz), 3.55 (dd, 1H, J¼5.5 and 11.1 Hz), 3.39 (dd,
1H, J¼4.8 and 11.1 Hz), 3.28 (dd, 1H, J¼4.8 and
11.1 Hz), 3.00 (s, 2H). 13C NMR (125 MHz, DMSO-d6) d:
156.0, 152.5, 150.0, 140.7, 118.8, 63.4, 60.2, 55.9, 52.9,
24.3. FAB-LRMS m/z 268 (MH+). FAB-HRMS m/z
268.0876 (calcd for C10H14N5O2S: 268.3155). Anal. Calcd
for C10H13N5O2S: C, 44.93; H, 4.90; N, 26.20; S, 12.00.
Found: C, 44.93; H, 4.86; N, 26.20; S, 11.76.
4.1.7. 9-[3,3-Bis(benzoyloxymethyl)thietan-2-yl]-6-chloro-
purine (10).
A mixture of 6-chloropurine (50 mg,
0.32 mmol) and HMDS (4 mL) was refluxed for 3 h until
the solution became clear. After evaporation, the residue
was dissolved in dry CH2Cl2 (2 mL). A solution of 8
(96 mg, 0.27 mmol) in dry CH2Cl2 (1 mL), AgClO4
(56 mg, 0.27 mmol), and SnCl4 (51 mg, 0.27 mmol) was
added to the mixture at 0 ꢀC, and the mixture was stirred at
room temperature for 18 h. The reaction mixture was diluted
with ethyl acetate and washed with saturated sodium bicar-
bonate, 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–ethyl acetate (2:1),
to give 10 (36 mg, 27%) as a colorless oil and the N-7 isomer
(20 mg, 15%) of 10 as a colorless oil. 1H NMR (500 MHz,
CDCl3) d: 8.66 (s, 1H), 8.38 (s, 1H), 7.96–7.95 (m, 2H),
7.48–7.11 (m, 8H), 6.32 (s, 1H), 4.64 (s, 2H), 4.50 (d, 1H,
J¼12.0 Hz), 4.21 (d, 1H, J¼12.0 Hz), 3.24 (d, 1H,
J¼10.0 Hz), 2.95 (d, 1H, J¼10.0 Hz). 13C NMR (125 MHz,
CDCl3) d: 166.1, 165.1, 152.1, 151.9, 151.2, 144.3, 133.6,
1332.2, 129.8, 129.2, 128.9, 128.6, 128.4, 128.0, 66.1, 62.9,
53.5, 53.4, 25.0. EI-LRMS m/z 494 (M+). EI-HRMS m/z
494.0805 (calcd for C24H19N4O4ClS: 494.0816).
Acknowledgements
We would like to thank Ms S. Oka, Mr. A. Miyao, and Ms A.
Tokumitsu for MS Spectra mesurements and Ms M. Kiuchi
and Ms A. Tokumitsu for elemental analysis (Center for
Instrumental Analysis, Hokkaido University).
References and notes
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Data for the N-7 isomer of 10: 1H NMR (500 MHz, CDCl3)
d: 9.26 (s, 1H), 8.60 (s, 1H), 8.13–8.10 (m, 2H), 7.66–7.24
(m, 8H), 6.87 (s, 1H), 4.93 (d, 1H, J¼11.9 Hz), 4.68–4.66
(m, 2H), 4.29 (d, 1H, J¼12.5 Hz), 3.42 (d, 1H, J¼9.6 Hz),
3.02 (d, 1H, J¼9.6 Hz). 13C NMR (125 MHz, CDCl3) d:
166.0, 164.9, 162.4, 152.5, 148.7, 142.4, 133.8, 133.5,
129.7, 129.0, 128.9, 128.7, 128.4, 127.7, 122.8, 65.3, 62.6,
55.5, 53.7, 24.5. EI-LRMS m/z 494 (M+). EI-HRMS m/z
494.0835 (calcd for C24H19N4O4ClS: 494.0816).
8. Ichikawa, E.; Yamamura, S.; Kato, K. Tetrahedron Lett. 1999,
40, 7385–7388.
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4.1.8. 1-[3,3-Bis(hydroxymethyl)thietan-2-yl]thymine
(11). A methylamine (40% in methanol, 50 mL) was added
to 9 (572 mg, 1.2 mmol), and the resulting mixture was
stirred at room temperature for 2 h. The mixture was concen-
trated in vacuo, and the residue was purified on a silica gel
column, eluted with 10% methanol in chloroform, to give
11 (269 mg, 87%) as a colorless solid. Mp 204–209 ꢀC
1
(methanol). H NMR (300 MHz, DMSO-d6) d: 9.50 (br s,
1H), 8.18 (s, 1H), 5.85 (s, 1H), 4.98 (dd, 1H, J¼5.4 and
5.7 Hz), 4.64 (dd, 1H, J¼4.5 and 4.6 Hz), 3.59 (dd, 1H,
J¼5.7 and 10.8 Hz), 3.48–3.32 (m, 3H), 2.87 (d, 1H,
J¼8.9 Hz), 2.79 (d, 1H, J¼8.9 Hz), 1.85 (s, 3H). 13C NMR
16. Kato, K.; Minami, T.; Takita, T.; Nishiyama, S.; Yamamura, S.;
Naganawa, H. Tetrahedron Lett. 1996, 30, 2269–2270.