Synthesis of thietane nucleoside with an anomeric hydroxymethyl group

Article abstract of DOI:10.1016/j.tet.2010.11.038

Thietane nucleoside 5 with an anomeric hydroxymethyl group was synthesized via the Pummerer reaction. The stereochemistry of the sulfoxide and the nature of the protecting group had no significant effect on the yield of the reaction. When a hypervalent iodine reagent was used, sulfide 16 with O-benzoyl protecting groups gave the ring-expanded nucleoside 21. Unfortunately, synthesized compound 6 did not exhibit anti-HSV activity. Copyright

Full text of DOI:10.1016/j.tet.2010.11.038

Tetrahedron 67 (2011) 358e363
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of thietane nucleoside with an anomeric hydroxymethyl group
*
*
Naozumi Nishizono , Yuji Akama, Masayuki Agata, Michiyasu Sugo, Yuki Yamaguchi, Kazuaki Oda
Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Thietane nucleoside 5 with an anomeric hydroxymethyl group was synthesized via the Pummerer re-
action. The stereochemistry of the sulfoxide and the nature of the protecting group had no significant
effect on the yield of the reaction. When a hypervalent iodine reagent was used, sulfide 16 with
O-benzoyl protecting groups gave the ring-expanded nucleoside 21. Unfortunately, synthesized com-
pound 6 did not exhibit anti-HSV activity.
Received 7 September 2010
Received in revised form 8 November 2010
Accepted 8 November 2010
Available online 13 November 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Thietane nucleoside
Pummerer reaction
Thymine
Hydroxy(tosyloxy)iodobenzene
Ring-expansion reaction
1. Introduction
Oxetanocin A (3) has an unusual structure with an unstable
oxetane ring in the sugar moiety; this compound possesses potent
The nucleosides of DNA and RNA are composed of a sugar moiety
(2-deoxyribose and ribose, respectively) linked to a purine or
pyrimidine base through a b-N-glycosidic bond. In addition to the
nucleosides of DNA and RNA, many other naturally occurring
nucleosides have been isolated, and their biological activity has been
evaluated.1 Examples of these nucleosides are shown in Fig. 1.
Among these compounds, bredinin2 and Ara-A3 are clinically used as
an immunosuppressant agent and anti-herpes agent, respectively.
antiviral activity against various viruses, such as HIV and HSV.4,5
Accordingly, many derivatives of oxetanocin A have been synthe-
sized, and their antiviral activity has been investigated.6 Among
these compounds, carbocyclic oxetanocin G exhibits potent antiviral
activity against VZV,7 and the thietane nucleoside with a cytosine
base shows antiviral activity against HIV.8 Furthermore, angustmy-
cin C (4), which has a hydroxymethyl group at the anomeric position,
possesses attractive antiviral and antimicrobial properties.9
Aiming to develop a new antiviral agent, we designed a thietane
nucleoside (5) having the structural features of both oxetanocin
A and angustmycin C. We selected thymine as the nucleobase
because some thietane nucleosides with a pyrimidine base have
been found to have interesting antiviral activity. We hypothesized
that target compound 5 could be synthesized by the Pummerer
reaction10 of a sulfoxide and silylated thymine (Scheme 1).
Scheme 1.
2. Results and discussion
Fig. 1. Nucleoside antibiotics.
First, sulfide 14 was synthesized from cis-2-butene-1,4-diol (6;
Scheme 2). This diol was protected with O-benzyl groups by
* Correspondingauthors.E-mail address: nishizon@hoku-iryo-u.ac.jp(N.Nishizono).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.11.038

N. Nishizono et al. / Tetrahedron 67 (2011) 358e363
359
treatment with benzyl bromide in the presence of sodium hydride
in DMF to give 7 (quantitative yield). The dihydroxylation of 7 with
catalytic OsO4 and NMO as co-oxidant gave 8, which was then
treated with NaIO4 to give 2-(benzyloxy)acetaldehyde (9) in 65%
yield from 7. The treatment of 9 with allylmagnesium chloride in
THF gave 10 in 93% yield. The epoxidation of 10 with m-CPBA gave
11, which was treated with sodium benzyloxide to afford 1211 as
a 1:1 diastereomeric mixture (70% from 10). The diastereomeric
mixture of 12 was treated with mesyl chloride in pyridine to give
13, which was then treated with sodium sulfide in DMF at 100 ꢀC to
give thietane 14 as a 1:1 diastereomeric mixture (69% from 12).
Scheme 5. Reagents and conditions: (i) silylated thymine, TMSOTf, Et3N, toluene, 0 ꢀ
to rt.
C
mixture at 0 ꢀC. After stirring the mixture for 24 h at room temper-
ature, the desired thietane nucleoside 18 (52%) was obtained as a 1:1
anomeric mixture along with alkene 19 (36%). Medium pressure
liquid chromatography allowed the separation of the anomeric mix-
ture to give 18a and 18b. The structure of the lesspolarcompound18b
was assigned to the
NOESY spectra. NOE correlation was observed between H-6 of the
thymine and H-30- , as well as between H-30- and H-40 (Fig. 2).
a
-anomer on the basis of its 1H, 13C NMR, and
a
a
Scheme 2. Reagents and conditions: (i) BnBr, NaH, DMF, 0 ꢀC to rt; (ii) OsO4, NMO,
acetone/H2O; (iii) NaIO4, MeOH, 0 ꢀC to rt; (iv) allylmagnesium chloride, THF, 0 ꢀC to rt;
(v) m-CPBA, CH2Cl2, ꢁ20 ꢀC to rt; (vi) NaOBn, BnOH; (vii) MsCl, pyridine, 0 ꢀC to rt;
(viii) Na2S, DMF, 100 ꢀC.
Sulfoxide 15aec was obtained by oxidation of diastereomeric
mixture 14 with NaIO4 in methanol (Scheme 3). The configuration
of each diastereomer, 15a and 15b, was assigned on the basis of
solvent- and Eu(fod)3-induced shifts in their 1H NMR spectra fol-
lowing the procedure reported by Folli et al.12
Fig. 2. Selected NOEs observed for 18a and 18b.
The Pummerer reaction was performed under the same condi-
tion using sulfoxides 15a and 15b (Scheme 5). The Pummerer re-
action of 15a gave 18 (47%) as a 1:1 diastereomeric mixture and 19
(41%). Sulfoxide 15b also coupled with silylated thymine to give 18
(52%) as a 1:1 diastereomeric mixture and 19 (39%). Although the
yield of the Pummerer reaction has been found to depend on the
stereochemistry of the sulfoxide,13 no significant effect of stereo-
chemistry was observed for the present sulfoxides.
Next, O-benzoyl protected sulfoxide 17b was used in the Pum-
merer reaction. Similar to the case of 16, the reaction of 17b with
silylated thymine gave thietane nucleoside 20 as a 1:1 diastereomeric
mixture in 56% yield (Scheme 6). The nature of the protecting group
also had no significant effect on the yield for these sulfoxides.
Scheme 3.
Sulfoxide 17, the hydroxy groups of which were protected with
benzoyl groups, was also prepared (Scheme 4). The configuration of
each diastereomer, 17a and 17b, as also assigned on the basis of
solvent- and Eu(fod)3-induced shifts in their 1H NMR spectra.
Scheme 6. Reagents and conditions: (i) silylated thymine, TMSOTf, Et3N, toluene, 0 ꢀ
C
to rt.
We recently reported a novel method for synthesizing 40-thio-
nucleosides via the condensation of a thiofuranoid and silylated
nucleobase in the presence of a hypervalent iodine compound.14,15
To investigate the scope of this method, it was adopted for the
synthesis of the thietane nucleoside. The reaction of thymine and 14
in the presence of PhI]O was examined. Although PhI]O gave the
best result in the case of the thymine nucleoside, the present re-
action resulted in a complex mixture with no detectable amount of
Scheme 4. Reagents and conditions: (i) TiCl4, CH2Cl2, 0 ꢀC to rt; (ii) BzCl, pyridine, 0 ꢀ
C
to rt; (iii) NaIO4, MeOH, 0 ꢀC to rt.
We first examined the Pummerer reaction of sulfoxide 15c, the
hydroxy groups of which were protected with benzyl groups
(Scheme 5). A solution of 15c in toluene was added to a solution of
silylated thymine in toluene at 0 ꢀC under an argon atmosphere.
Trimethylsilyl triflate and then triethylamine were added to the

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N. Nishizono et al. / Tetrahedron 67 (2011) 358e363
the desired compound. Similarly, the thietane nucleoside was not
obtained from the reaction with other hypervalent iodine reagents.
Next, sulfide 16 was used instead of 14. Surprisingly, the con-
densation reaction of 16 with thymine gave not the desired thie-
tane nucleoside but rather ring-expanded compound 21 in 30%
yield (Scheme 7). The deprotection of 21 gave 22 in 62% yield. The
structure of 22 was determined by comparison with an authentic
synthetic sample.16
This result suggests that 21 was formed via the reaction of
silylated thymine with 23, which was initially formed from cis-16 as
a result of Lewis acid activation. Thus, the use of the sulfide with O-
benzoyl protecting groups gave the interesting result of forming the
ring-expanded nucleoside.
Finally, the target compound 5 was obtained by deprotection of
18 and 20 (Scheme 10).
Scheme 7. Reagents and conditions: (i) thymine, TMSOTf, Et3N, PhI(OH)OTs, CH2Cl2,
0
ꢀC to rt; (ii) NaOMe, 0 ꢀC to rt.
To investigate this reaction in further detail, TMSOTf was added
to a solution of 16 (cis/trans¼2:1) in CH2Cl2 (Scheme 8). After stir-
ring for 30 min, only cis-16 was consumed and the newly formed
tetrahydrothiophene derivative 23 was obtained along with
unreacted trans-16 (Scheme 8). Although trans-16 was consumed
when the reaction time was extended, the yield of 23 did not
change. This ring expansion is considered to involve intramolecular
nucleophilic attack by the sulfur atom.17
Scheme 10. Reagents and conditions: (i) TiCl4, CH2Cl2, 0 ꢀC (70% from 18a, 72% from
18b); (ii) NH3/MeOH, rt (20a: 78% from 20a, 78% from 20b).
3. Conclusion
In summary, the thietane nucleoside was synthesized by con-
densation of the sulfide and silylated thymine. The stereochemistry
of the sulfoxide and the nature of the protecting group had no sig-
nificant effect on the yield of the reaction. When a hypervalent io-
dine reagent was used, the sulfide with O-benzoyl protecting groups
gave the ring-expanded nucleoside. Unfortunately, synthesized
Scheme 8.
The leaving ability of the benzoyl group is enhanced by the
coordination of the carbonyl oxygen to a Lewis acid; thereby, the
intramolecular nucleophilic attack of the sulfur atom can easily
proceed to afford the bicycle[2.1.0]episulphonium intermediate.
Then, regiospecific bridgehead attack by benzoate ion leads to the
thermodynamic product (23; Scheme 9).
compound 6 did not exhibit anti-HSV activity, even at 50 mM.
4. Experimental section
4.1. General
All melting points were determined on a Yamato melting point
apparatus (model MP-J3) and were uncorrected. The NMR spectra
were recorded on a JEOL JNM-ECA-500 spectrometer. The chemical
shifts are reported in parts per million (d) relative to TMS (0.0 ppm)
as the internal standard, and the signals are expressed as s (singlet),
d (doublet), t (triplet), q (quartet), m (multiplet), or br (broad). The
values of the coupling constant J are given in hertz. The MS spectra
were obtained on JEOL JMS-HX110, JEOL JMS-700TZ, and JEOL
AccuTOF LC-plus systems. TLC was performed on Merck silica gel 60
F254 plates. Column chromatography was conducted using silica gel
60 N (Kanto, 100e210 mm) or silica gel 60 (Kanto, 40e50 mm).
4.1.1. (Z)-1,4-Bis(benzyloxy)but-2-ene (7). To a suspension of 55%
NaH (13.0 g, 298 mmol) in DMF (250 mL), a solution of 6 (10.0 g,
114 mmol) in DMF (50 mL) was added at 0 ꢀC. After the mixture was
stirred at room temperature for 1 h, benzyl bromide (35.3 mL,
398 mmol) was added dropwise to the mixture. The resulting
mixture was stirred for 4 h at room temperature. The reaction was
then quenched by addition of saturated aqueous NH4Cl solution,
diluted with ether, and washed with water and brine. The organic
layer was dried over Na2SO4 and concentrated in vacuo. The residue
was purified by silica gel column chromatography (hexane/
AcOEt¼8:1) to give 7 (30.2 g, 99%) as a colorless oil.
1H NMR (500 MHz, CDCl3)
d: 7.36e7.25 (m, 10H), 5.82e5.76 (m,
2H), 4.49 (s, 4H), 4.06 (d, 4H, J¼4.3 Hz). 13C NMR (125 MHz, CDCl3)
d
: 138.3, 129.6, 128.3, 127.9, 127.8, 72.4, 65.9. FAB-LRMS m/z: 269
Scheme 9.
(MHþ). FAB-HRMS m/z: 269.1550 (calcd for C18H21O2: 269.1542).

N. Nishizono et al. / Tetrahedron 67 (2011) 358e363
361
4.1.2. meso-1,4-Bis(benzyloxy)butane-2,3-diol (8). To a solution of 7
(10.0 g, 38 mmol) in acetone (150 mL) and water (150 mL), NMO
(4.8 g, 41 mmol) and a 0.02 M solution of OsO4 in t-BuOH (2 mL,
0.04 mmol) were added at room temperature, and the resulting
mixture was stirred at room temperature for 12 h. The mixture was
diluted with ethyl acetate and washed with saturated aqueous
Na2S2O4 solution, water, and brine. The organic layer was dried over
Na2SO4 and concentrated in vacuo. The residue was purified by
silica gel column chromatography (hexane/AcOEt¼1:1) to give 8
(9.3 g, 86%) as a colorless oil.
With stirring, a solution of 11 (2.4 g, 12 mmol) in benzyl alcohol
(20 mL) was added to the reaction mixture and stirring at room
temperature was continued for 16 h. To quench the reaction, the
mixture was poured into 100 mL of water. The aqueous mixture was
extracted with ethyl acetate (200 mL). The separated organic layer
was washed with water and brine, dried over Na2SO4, and con-
centrated in vacuo. The residue was purified by silica gel column
chromatography (hexane/AcOEt¼1:1) to give 12 (3.2 g, 88% (1:1
diastereomixture)) as a colorless oil.
1H NMR (500 MHz, CDCl3)
d: 7.36e7.27 (m, 20/2H), 4.55 (s,
1H NMR (500 MHz, CDCl3)
d
: 7.37e7.28 (m, 10H), 4.54 (s, 4H),
8/2H), 4.14e4.04 (m, 4/2H), 3.52e3.38 (m, 8/2H), 3.19 (d, 2/2H,
3.85e3.82 (m, 2H), 3.69e3.60 (m, 4H), 2.67 (d, 2H, J¼5.0 Hz). 13C
J¼2.3 Hz), 2.78 (d, 2/2H, J¼3.4 Hz), 1.61e1.55 (m, 4/2H). 13C NMR
NMR (125 MHz, CDCl3)
d
: 138.7, 128.4, 127.8, 127.7, 73.5, 71.4, 71.1.
(125 MHz, CDCl3) d: 137.9, 128.5, 128.4, 127.7, 127.6, 126.9, 74.4, 74.2,
EI-LRMS m/z: 302 (Mþ). EI-HRMS m/z: 302.1518 (calcd for C18H22O4:
73.3, 70.4, 67.6, 65.3, 36.0, 35.8. EI-LRMS m/z: 316 (Mþ). EI-HRMS
m/z: 316.1667 (calcd for C19H24O4: 316.1674).
302.1518).
4.1.3. 2-Benzyloxyacetaldehyde (9). To a solution of 8 (22.3 g,
74 mmol) in methanol (200 mL), NaIO4 (23.7 g, 111 mmol) was
added at 0 ꢀC, and the resulting mixture was stirred at room tem-
perature for 8 h. The formed precipitate was removed by filtration.
Most of the solvent was removed by a rotary evaporator and the
residual oil was distilled under reduced pressure to give 9 (16.9 g,
76%) as a colorless oil, bp 120 ꢀC at 13 mm Hg.
4.1.7. 2,4-Bis(benzyloxymethyl)thietane (14). To a solution of 12
(9.8 g, 31 mmol) in pyridine (200 mL), methanesulfonyl chloride
(6.3 mL, 81 mmol) was added at 0 ꢀC, and the resulting mixture was
stirred for 2 h at room temperature. The reaction was quenched by
addition of ice water. The mixture was concentrated in vacuo. 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 and Na2S$9H2O (8.2 g, 34 mmol) were dissolved
in DMF (300 mL), and the resulting mixture was stirred for 24 h at
100 ꢀC. The mixture was diluted with ether, and washed with water
and brine. The organic layer was dried over Na2SO4 and concen-
trated in vacuo. The residue was purified by silica gel column
chromatography (hexane/AcOEt¼8:1) to give 14 (6.7 g, 69%
(cis/trans¼1:1)) as an yellow oil.
1H NMR (500 MHz, CDCl3)
d: 9.69 (s,1H), 7.38e7.34 (m, 5H), 4.61
(s, 2H), 4.08 (s, 2H). 13C NMR (125 MHz, CDCl3)
d: 200.4, 137.0, 128.7,
128.3, 128.1, 75.4, 73.7. EI-LRMS m/z: 150 (Mþ). EI-HRMS m/z:
150.0680 (calcd for C9H10O2: 150.0681).
4.1.4. 1-(Benzyloxy)pent-4-en-2-ol (10). To a 2.0 M solution of
allylmagnesium chloride in THF (100 mL, 200 mmol), a solution of 9
(10.0 g, 66 mmol) in THF (100 mL) was added at 0 ꢀC under an argon
atmosphere, and the mixture was stirred at room temperature for
15 min. The reaction was quenched by addition of saturated
aqueous NH4Cl solution, 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 silica gel column
chromatography (hexane/AcOEt¼4:1) to give 10 (11.8 g, 93%) as
a colorless oil.
1H NMR (500 MHz, CDCl3)
d: 7.41e7.36 (m, 20/2H), 4.60 (s,
4/2H), 4.56 (d, 4/2H, J¼5.1 Hz), 3.85e3.70 (m, 10/2H), 3.62e3.58 (m,
2/2H), 3.01 (q, 1/2H, J¼8.5 Hz), 2.73 (t, 2/2H, J¼6.8 Hz), 2.39 (m,
1/2H). 13C NMR (125 MHz, CDCl3)
d: 138.3, 128.7, 128.6, 128.4, 127.8,
76.3, 75.8, 73.3, 36.5, 35.7, 33.0, 32.8. EI-LRMS m/z: 314 (Mþ).
EI-HRMS m/z: 314.1340 (calcd for C19H22O2S: 314.1341).
4.1.8. 2,4-Bis(benzyloxymethyl)thietane 1-oxide (15). To a solution
of 14 (2.6 g, 8 mmol) in methanol (80 mL), NaIO4 (2.3 g, 11 mmol)
was added at 0 ꢀC, and the mixture was stirred for 8 h at room
temperature. The mixture was concentrated in vacuo. The residue
was purified by medium pressure chromatography (silica gel;
hexane/AcOEt¼5:4) to give 15a (660 mg, 25%) as a yellow oil, 15b
(581 mg, 22%) as a colorless syrup, and 15c (898 mg, 34%) as an
yellow oil.
1H NMR (500 MHz, CDCl3)
d: 7.38e7.26 (m, 5H), 5.83 (m, 1H),
5.15e5.08 (m, 2H), 4.56 (s, 2H), 3.88 (m, 1H), 3.52 (dd, 1H, J¼3.5 and
9.5 Hz), 3.38 (dd, 1H, J¼6.8 and 9.5 Hz), 2.37 (d, 1H, J¼3.5 Hz), 2.26
(t, 2H, J¼6.8 Hz). 13C NMR (125 MHz, CDCl3)
d: 137.9, 134.2, 128.4,
127.7, 127.6, 117.5, 73.8, 73.3, 69.6, 37.8. EI-LRMS m/z: 192 (Mþ). EI-
HRMS m/z: 192.1136 (calcd for C12H16O2: 192.1150).
4.1.5. 1-(Benzyloxy)-3-(oxiran-2-yl)propan-2-ol (11). To a solution
of 10 (10.8 g, 56 mmol) in CH2Cl2 (500 mL), m-CPBA (14.6 g,
85 mmol) was added at ꢁ20 ꢀC under an argon atmosphere, and the
mixture was stirred at room temperature for 18 h. The reaction was
quenched by addition of saturated aqueous NaHCO3 solution, di-
luted with chloroform, and washed with water and brine. The or-
ganic layer was dried over Na2SO4 and concentrated in vacuo. The
residue was purified by silica gel column chromatography (hexane/
AcOEt¼1:1) to give 11 (9.4 g, 80%, 1:1 diastereomeric mixture) as
a colorless oil.
Compound 15a: 1H NMR (500 MHz, CDCl3)
d: 7.37e7.28 (m,
10H), 4.59 (d, 4H, J¼2.8 Hz), 3.80 (dd, 2H, J¼4.8 and 10.8 Hz), 3.70
(dd, 2H, J¼5.7 and 10.8 Hz), 3.49e3.42 (m, 2H), 2.46 (m, 1H), 1.93 (q,
1H, J¼12.2 Hz). 13C NMR (125 MHz, CDCl3)
d: 137.8, 128.6, 127.9,
127.7, 73.3, 68.0, 63.3, 16.7. FAB-LRMS m/z: 331 (MHþ). FAB-HRMS
m/z: 331.1363 (calcd for C19H23O3S: 331.1368).
Compound 15b: 1H NMR (500 MHz, CDCl3)
d: 7.37e7.28 (m,
10H), 4.61 (d, 2H, J¼11.6 Hz), 4.48 (d, 2H, J¼11.6 Hz), 3.93e3.88 (m,
2H), 3.51e3.44 (m, 4H), 2.79 (m, 1H), 2.49 (m, 1H). 13C NMR
(125 MHz, CDCl3)
d: 137.9, 128.6, 127.9, 73.4, 64.5, 51.5, 27.2.
1H NMR (500 MHz, CDCl3)
d
: 7.37e7.29 (m, 10/2H), 4.57 (s,
FAB-LRMS m/z: 331 (MHþ). FAB-HRMS m/z: 331.1364 (calcd for
4/2H), 4.08e4.04 (m, 2/2H), 3.58e3.51 (m, 2/2H), 3.47 (m, 1/2H),
3.38 (dd, 1/2H, J¼7.4 and 9.4 Hz), 3.14e3.08 (m, 2/2H), 2.82e2.77
(m, 2/2H), 2.61e2.58 (m, 2/2H), 2.56e2.50 (m, 2/2H), 1.91e1.81 (m,
2/2H), 1.65 (m, 1/2H), 1.51 (ddd, 1/2H, J¼4.2, 7.2, and 14.3 Hz). FAB-
LRMS m/z: 209 (MHþ). EI-HRMS m/z: 209.1190 (calcd for C12H17O3:
209.1177).
C19H23O3S: 331.1368).
Compound 15c: 1H NMR (500 MHz, CDCl3)
d: 7.38e7.28 (m, 10H),
4.64e4.55 (m, 4H), 4.10 (dd, 1H, J¼7.1 and 10.8 Hz), 3.90 (dd, 1H,
J¼5.7 and 10.8 Hz), 3.81 (m, 1H), 3.68e3.63 (m, 3H), 2.51 (m, 1H),
2.33 (m, 1H). 13C NMR (125 MHz, CDCl3)
d: 138.1, 137.8, 128.6, 128.0,
127.9, 127.8, 73.5, 73.4, 68.3, 65.7, 64.3, 52.9, 19.6. FAB-LRMS m/z: 331
(MHþ). FAB-HRMS m/z: 331.1369 (calcd for C19H23O3S: 331.1368).
4.1.6. 1,5-Bis(benzyloxy)pentane-2,4-diol (12). To 50 mL of stirred
benzyl alcohol, 0.5 g of finely cut sodium metal (23 mmol) was
added, and the mixture was then stirred under nitrogen for 3 h.
4.1.9. 2,4-Bis(benzoyloxymethyl)thietane (16). To a solution of 16
(100 mg, 0.32 mmol) in CH2Cl2 (1 mL), a solution of TiCl4 (141 mL,

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N. Nishizono et al. / Tetrahedron 67 (2011) 358e363
1.28 mmol) in CH2Cl2 (1 mL) was added at 0 ꢀC under nitrogen, and
the mixture was stirred for 8 h at room temperature. The mixture
was concentrated in vacuo. The residue was purified by silica gel
column chromatography (10% ethanol in chloroform) to give the
crude diol. To a solution of the crude diol in pyridine (1 mL), ben-
d: 164.0,149.2,137.7,137.6,137.3,128.4,127.9,127.8,127.6,109.1, 74.7,
74.0, 73.4, 73.3, 65.0, 38.1, 34.0, 12.4. FAB-LRMS m/z: 439 (MHþ).
FAB-HRMS m/z: 439.1681 (calcd for C24H27N2O4S: 439.1692).
Compound 18b: 1H NMR (500 MHz, CDCl3)
d: 8.86 (br s, 1H),
7.30e7.09 (m, 11H), 4.47 (s, 2H), 4.40 (d, 1H, J¼12.0 Hz), 4.34 (d, 1H,
J¼12.0 Hz), 3.97 (d, 1H, J¼9.7 Hz), 3.83 (d, 1H, J¼9.7 Hz), 3.64e3.51
(m, 3H), 3.26 (dd, 1H, J¼9.5 and 14.0 Hz), 2.81 (dd, 1H, J¼4.3 and
zoyl chloride (112 m
L, 0.96 mmol) was added at 0 ꢀC under nitrogen,
and the mixture was stirred for 8 h at room temperature. The
mixture was concentrated in vacuo. 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 silica gel column chromatography (hexane/AcOEt¼4:1)
to give 16 (60 mg, 55%, cis/trans¼2:1) as a colorless solid.
14.0 Hz),1.86 (s, 3H).13C NMR (125 MHz, CDCl3)
d: 164.3,149.4,138.6,
138.5, 137.8, 137.4, 128.4, 128.3, 127.9, 127.8, 127.7, 127.6, 108.8, 75.3,
75.2, 74.1, 73.3, 73.2, 67.8, 36.4, 33.1,12.4. FAB-LRMS m/z: 439 (MHþ).
FAB-HRMS m/z: 439.1689 (calcd for C24H27N2O4S: 439.1692).
Compound 19: 1H NMR (500 MHz, CDCl3)
d: 7.39e7.28 (m, 10H),
1H NMR (500 MHz, CDCl3)
d: 7.94e7.79 (m, 6/3H), 7.49e7.46 (m,
6.25 (t, 1H, J¼1.7 Hz), 4.75 (s, 2H), 4.57 (d, 2H, J¼2.8 Hz), 3.86 (m,
3/3H), 7.37e7.34 (m, 6/3H), 4.56 (dd, 1/3H, J¼6.8 and 11.3 Hz), 4.49
(dd, 2/3H, J¼6.8 and 11.3 Hz), 4.42 (dd,1/3H, J¼6.8 and 11.3 Hz), 4.32
(dd, 2/3H, J¼6.8 and 11.3 Hz), 3.94e3.83 (m, 3/3H), 3.04 (dt, 1/3H,
J¼6.8 and 14.8 Hz), 2.82 (t, 1/3H, J¼7.1 Hz), 2.56 (dt, 1/3H, J¼6.8 and
1H), 3.79e3.68 (m, 2H), 3.46 (m, 1H), 3.05 (m, 1H). 13C NMR
(125 MHz, CDCl3) d: 138.1, 137.6, 136.4, 128.5, 128.0, 127.9, 127.8,
127.6, 109.5, 75.2, 73.6, 73.4, 37.8, 35.1. EI-LRMS m/z: 312 (Mþ).
EI-HRMS m/z: 312.1184 (calcd for C19H20O2S: 312.1184).
14.8 Hz). 13C NMR (125 MHz, CDCl3)
d: 166.2, 166.1, 133.1, 129.7,
129.6, 128.4, 69.4, 68.9, 35.1, 34.2, 32.4, 32.1. FAB-LRMS m/z: 343
4.1.12. 1-[2,4-Bis(benzoyloxymethyl)thietan-2-yl]thymine
(20). Prepared from 17b (100 mg, 0.3 mmol) using a procedure
similar to that described above for compound 19, 20a (39 mg, 28%)
and 20b (39 mg, 28%) were obtained as colorless foams.
(MHþ). FAB-HRMS m/z: 343.0986 (calcd for C19H19O4S: 343.1004).
4.1.10. 2,4-Bis(benzoyloxymethyl)thietane 1-oxide(17). To a solution
of 16 (38 mg, 0.11 mmol) in methanol (5 mL), NaIO4 (23 mg,
0.11 mmol) was added at 0 ꢀC, and the mixture was stirred for 8 h at
room temperature. The mixture was concentrated in vacuo. The
residue was purified by medium pressure chromatography (silica
gel; hexane/AcOEt¼1:4) to give 17a (1.2 mg, 3%) as a colorless
syrup, 17b (10.7 mg, 27%) as an yellow syrup, and 17c (4.8 mg, 12%)
as a colorless syrup.
Compound 20a: 1H NMR (500 MHz, CDCl3)
d: 8.95 (br s, 1H),
7.99e7.97 (m, 2H), 7.91e7.89 (m, 2H), 7.58e7.40 (m, 6H), 7.00 (s,
1H), 4.98 (d, 1H, J¼12.0 Hz), 4.86 (d, 1H, J¼11.5 Hz), 4.61 (dd, 1H,
J¼5.8 and 12.0 Hz), 4.37 (m, 1H), 3.95 (m, 1H), 3.38 (dd, 1H, J¼7.5
and 13.2 Hz), 3.20 (dd, 1H, J¼8.0 and 13.2 Hz), 1.79 (s, 3H). 13C NMR
(125 MHz, CDCl3) d: 166.3, 165.6, 163.9, 149.4, 136.2, 133.7, 133.5,
129.7, 129.6, 128.7, 128.6, 110.4, 68.1, 67.9, 64.3, 38.2, 33.2, 12.3.
FAB-LRMS m/z: 467 (MHþ). FAB-HRMS m/z: 467.1272 (calcd for
C24H23N2O6S: 467.1277).
Compound 17a: 1H NMR (500 MHz, CDCl3)
d: 8.05e8.03 (m, 4H),
7.58e7.55 (m, 2H), 7.46e7.43 (m, 4H), 4.65 (dd, 2H, J¼9.8 and
12.3 Hz), 4.54 (dd, 2H, J¼4.1 and 12.3 Hz), 3.70e3.63 (m, 2H), 3.07
Compound 20b: 1H NMR (500 MHz, CDCl3)
d: 9.14 (br s, 1H),
(m, 1H), 2.84 (m, 1H). 13C NMR (125 MHz, CDCl3)
d: 166.3, 133.4,
8.05e8.02 (m, 2H), 7.89e7.40 (m, 8H), 7.25 (s, 1H), 5.03 (d, 1H,
J¼11.3 Hz), 4.81 (d, 1H, J¼11.3 Hz), 4.69 (dd, 1H, J¼6.8 and 11.3 Hz),
4.57 (dd, 1H, J¼6.8 and 11.3 Hz), 3.86 (m, 1H), 3.58 (m, 1H), 3.17 (m,
129.9, 129.5, 128.5, 58.8, 49.9, 27.6. EI-LRMS m/z: 358 (Mþ).
EI-HRMS m/z: 358.0877 (calcd for C19H18O3S: 358.0875).
Compound 17b: 1H NMR (500 MHz, CDCl3)
d: 8.02e8.00 (m, 4H),
1H), 1.72 (s, 3H). 13C NMR (CDCl3)
d: 166.3, 165.6, 164.1, 133.7, 133.5,
7.57e7.53 (m, 2H), 7.40e7.36 (m, 4H), 4.70 (dd, 2H, J¼4.5 and
129.8, 129.7, 128.7, 128.6, 110.1, 69.7, 68.1, 51.9, 36.8, 32.1, 12.4.
FAB-LRMS m/z: 467 (MHþ). FAB-HRMS m/z: 467.1272 (calcd for
C24H23N2O6S: 467.1277).
12.5 Hz), 4.58 (dd, 2H, J¼5.7 and 12.5 Hz), 3.70e3.64 (m, 2H), 2.64
(m, 1H), 1.93 (m, 1H). 13C NMR (CDCl3)
d: 166.1, 133.5, 129.8, 129.2,
128.6, 62.4, 62.1, 16.6. EI-LRMS m/z: 358 (Mþ). EI-HRMS m/z:
358.0880 (calcd for C19H18O3S: 358.0875).
4.1.13. 1-(2,5-Di-O-benzoyl-3-deoxy-4-thio-
mine (21). To a suspension of thymine (38 mg, 0.30 mmol) in
CH2Cl2 (1 mL), TMSOTf (150 L, 0.90 mmol) and triethylamine
(63
L, 0.90 mmol) were added at 0 ꢀC, and the mixture was stirred
a-arabinofuranosyl)thy-
Compound 17c: 1H NMR (500 MHz, CDCl3)
d: 8.06e8.04 (m, 4H),
7.61e7.56 (m, 2H), 7.46e7.43 (m, 4H), 5.01 (dd, 1H, J¼7.2 and
12.3 Hz), 4.89 (dd, 1H, J¼5.8 and 12.3 Hz), 4.71 (dd, 1H, J¼4.5 and
12.5 Hz), 4.61 (dd, 1H, J¼6.2 and 12.5 Hz), 3.96e3.88 (m, 2H), 2.65
m
m
for 1 h at room temperature. A solution of 16 (50 mg, 0.15 mmol) in
CH2Cl2 (10 mL) was added to the mixture at 0 ꢀC, and PhI(OH)OTs
(94 mg, 0.24 mmol) was then added in one portion. The mixture
was stirred at room temperature for 24 h. The reaction was
quenched by addition of ice water, 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
silica gel column chromatography (hexane/AcOEt¼1:1) to give 21
(20 mg, 30%) as a colorless foam.
(m, 1H), 2.39 (m, 1H). 13C NMR (125 MHz, CDCl3)
d: 166.4, 166.2,
133.5, 133.4, 129.8, 128.6, 128.5, 63.4, 62.8, 31.0, 19.1. EI-LRMS m/z:
358 (Mþ). EI-HRMS m/z: 358.0877 (calcd for C19H18O3S: 358.0875).
4.1.11. 1-[2,4-Bis(benzyloxymethyl)thietan-2-yl]thymine (18). To a so-
lution of 17c (313 mg, 0.95 mmol) in toluene (5 mL), O,O0-bis(tri-
methylsilyl)thymine (487 mg, 1.90 mmol) in toluene (5 mL) and
TMSOTf (347
(268 L, 1.90 mmol) was then added to the mixture, and the
m
L, 1.90 mmol) were added at 0 ꢀC. Triethylamine
m
1H NMR (500 MHz, CDCl3)
d: 8.90 (br s, 1H), 8.03e7.98 (m, 4H),
resulting mixture was stirred for 24 h. The reaction was quenched
by addition of saturated aqueous NaHCO3 solution, 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 silica gel column chromatography (hexane/AcOEt¼1:1)
to give 18a (108 mg, 26%) as a yellow syrup, 18b (108 mg, 26%) as an
yellow syrup, and 19 (107 mg, 36%) as a yellow oil.
7.58e7.53 (m, 2H), 7.46e7.40 (m, 5H), 6.47 (d, 1H, J¼6.0 Hz), 5.56
(m, 1H), 4.54 (dd, 1H, J¼6.6 and 10.9 Hz), 4.42 (dd, 1H, J¼7.2 and
10.9 Hz), 4.21 (m, 1H), 2.73 (m, 1H), 2.24 (m, 1H), 1.95 (s, 3H). 13C
NMR (125 MHz, CDCl3) d: 166.0, 165.6, 163.3, 150.6, 135.7, 133.7,
133.4, 129.9, 129.7, 129.4, 128.8, 128.6, 128.5, 112.1, 79.4, 67.6, 65.4,
43.6, 35.8, 12.7. ESI-LRMS m/z: 489 (MNaþ). ESI-HRMS m/z:
489.1096 (calcd for C24H22N2NaO6S: 489.1096).
Compound 18a: 1H NMR (500 MHz, CDCl3)
d: 8.77 (br s, 1H),
7.28e7.12 (m, 10H), 6.93 (d, 1H, J¼1.1 Hz), 4.45 (s, 2H), 4.44 (s, 2H),
3.96 (d, 1H, J¼10.2 Hz), 3.90 (dd, 1H, J¼1.1 and 10.2 Hz), 3.59e3.56
(m, 2H), 3.48 (m, 1H), 3.09 (dd, 1H, J¼7.4 and 12.5 Hz), 2.79 (dd, 1H,
J¼7.4 and 12.5 Hz), 1.85 (d, 3H, J¼1.1 Hz). 13C NMR (125 MHz, CDCl3)
4.1.14. 1-(3-Deoxy-4-thio-a-arabinofuranosyl)thymine (22). To a so-
lution of 21 (65 mg, 0.13 mmol) in methanol (20 mL), a 0.5 M so-
lution of sodium methoxide in methanol (1.3 mL, 0.62 mmol) was
added at 0 ꢀC, and the mixture was stirred for 3 h at room

N. Nishizono et al. / Tetrahedron 67 (2011) 358e363
363
temperature. The mixture was concentrated in vacuo. The residue
was purified by silica gel column chromatography (methanol/
chloroform¼1:9) to give 22 (20 mg, 62%) as a colorless solid, mp
227e229 ꢀC.
FAB-LRMS m/z: 259 (MHþ). FAB-HRMS m/z: 259.0768 (calcd for
C10H15N2O4S: 259.0753).
4.1.17. 1-[(2S
*
,4R )-2,4-Bis(hydroxymethyl)thietan-2-yl]thymine
*
1H NMR (500 MHz, methanol-d4)
d
: 7.75 (d, 1H, J¼1.2 Hz), 5.98
(5b). From 18b: prepared from 18b (100 mg, 0.2 mmol) using
a procedure similar to that described above for compound 5a, 5b
(37 mg, 72%) was obtained as a colorless solid, mp 224e225 ꢀC.
From 20b: prepared from 20b (15 mg, 0.03 mmol) using a pro-
cedure similar to that described above for compound 5a, 5b (6 mg,
78%) was obtained as a colorless solid, mp 224e225 ꢀC.
(d, 1H, J¼6.0 Hz), 4.37 (m, 1H), 3.89 (m, 1H), 3.72 (dd, 1H, J¼5.2 and
10.9 Hz), 3.58 (dd, 1H, J¼6.6 and 10.9 Hz), 2.31 (m, 1H), 1.91 (d, 3H,
J¼1.2 Hz), 1.84 (m, 1H). 13C NMR (125 MHz, methanol-d4)
d: 153.0,
138.6, 112.1, 106.2, 79.3, 68.6, 67.1, 48.1, 38.5, 12.5. ESI-LRMS m/z:
281 (MNaþ). ESI-HRMS m/z: 281.5079 (calcd for C10H14N2NaO4S:
281.5072).
1H NMR (500 MHz, DMSO-d6)
d: 11.2 (s, 1H), 7.33 (s, 1H), 5.33 (t,
1H, J¼6.2 Hz), 4.99 (t, 1H, J¼5.4 Hz), 3.82e3.75 (m, 2H), 3.65 (m, 1H),
4.1.15. 1,4-Anhydro-2,5-di-O-benzoyl-3-deoxy-4-thio-
anose (23). To a solution of 16 (100 mg, 0.34 mmol) in CH2Cl2
(5 mL), TMSOTf (0.25
L,1.36 mmol) was added at 0 ꢀC, and mixture
a-arabinofur-
3.57 (m,1H), 3.32e3.19 (m, 2H), 2.69 (dd,1H, J¼4.0 and 13.6 Hz), 1.77
(s, 3H). 13C NMR (125 MHz, DMSO-d6)
d: 164.2, 149.6, 138.3, 107.2,
m
67.5, 67.4, 66.1, 34.7, 34.6,12.1. FAB-LRMS m/z: 259 (MHþ). FAB-HRMS
m/z: 259.0765 (calcd for C10H15N2O4S: 259.0753).
was stirred for 30 min at room temperature. The mixture was di-
luted 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 silica gel column chromatography (hexane/
AcOEt¼8:1) to give 23 (38 mg, 38%) as a colorless foam.
Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.11.038. These data include
MOL files and InChIKeys of the most important compounds
described in this article.
1H NMR (500 MHz, CDCl3)
d: 8.06e8.03 (m, 4H), 7.59e7.54 (m,
2H), 7.47e7.42 (m, 4H), 5.74 (m, 1H), 4.54 (dd, 1H, J¼8.0 and
10.9 Hz), 4.49 (dd, 1H, J¼7.5 and 10.9 Hz), 3.91e3.86 (m, 1H), 3.33
(dd, 1H, J¼5.4 and 12.0 Hz), 3.15 (ddd, 1H, J¼0.9, 3.7 and 12.0 Hz),
2.44 (m, 1H), 2.40 (m, 1H). 13C NMR (125 MHz, CDCl3)
d: 166.1,165.9,
References and notes
133.3, 133.1, 129.9, 129.8, 129.7, 128.5, 128.4, 77.4, 68.5, 43.9, 37.9,
36.9. ESI-LRMS m/z: 365 (MNaþ). ESI-HRMS m/z: 365.0814 (calcd
for C19H18NaO4S: 365.0824).
1. Nakamura, S.; Kondo, H. Heterocycles 1977, 8, 583e607.
2. Mizuno, K.; Tsujino, M.; Takada, M.; Hayashi, M.; Atsumi, K. J. Antibiot. 1974, 27,
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2648e2649.
4. Shimada, N.; Hasegawa, S.; Harada, T.; Tomisawa, T.; Fujii, T. J. Antibiot. 1986, 39,
1623e1625.
5. Hoshino, H.; Shimizu, N.; Shimada, N.; Takita, T.; Takeuchi, T. J. Antibiot. 1987,
40, 1077e1078.
6. Ichikawa, E.; Kato, K. Synthesis 2002, 1e28.
4.1.16. 1-[(2R
(5a). From 18a: to a solution of 18a (192 mg, 0.4 mmol) in CH2Cl2
(2 mL), a solution TiCl4 (176 L, 1.6 mmol) in CH2Cl2 (2 mL) was
added at 0 ꢀC under N2, and the mixture was stirred for 1 h at
ꢀC. The mixture was concentrated in vacuo. The residue was
*
,4R
*
)-2,4-Bis(hydroxymethyl)thietan-2-yl]thymine
m
0
purified by silica gel column chromatography (ethanol/
chloroform¼1:9) to give 5a (73 mg, 70%) as a colorless solid, mp
217e218 ꢀC.
7. Maruyama, T.; Hanai, Y.; Sato, Y.; Snoeck, R.; Andrei, G.; Hosoya, M.; Balzarini, J.;
DeClercq, E. Chem. Pharm. Bull. 1993, 41, 516e521.
8. Choo, H.; Chen, X.; Yadav, V.; Wang, J.; Schinazi, R. F.; Chu, C. K. J. Med. Chem.
2006, 49, 1635e1647.
From 20a: 20a (15 mg, 0.03 mmol) was dissolved in 5 mL of
methanolic ammonia. The solution was allowed to stand for 24 h at
room temperature. The reaction mixture was concentrated in
vacuo, and the residue was purified by silica gel column chroma-
tography (ethanol/chloroform¼1:9) to give 5a (6 mg, 78%) as
a colorless foam, mp 217e218 ꢀC.
9. Sakai, H.; Yuntsen, H.; Ishikawa, F. J. Antibiot. 1954, 7, 116e119.
10. O’Neil, I. A.; Hamilton, K. M. Synlett 1992, 791e792.
11. Harada, T.;Sakamoto, K.; Ikemura, Y.;Oku, A. TetrahedronLett.1988, 29, 3097e3100.
12. Folli, U.; Irossi, D.; Taddei, F. J. Chem. Soc., Perkin Trans. 2 1974, 933e936.
13. Naka, T.; Minakawa, N.; Abe, H.; Kaga, D.; Matsuda, A. J. Am. Chem. Soc. 2000,
122, 7233e7243.
14. Nishizono, N.; Baba, R.; Nakamura, C.; Oda, K.; Machida, M. Org. Biomol. Chem.
2003, 1, 3692e3697.
15. Nishizono, N.; Soma, K.; Baba, R.; Machida, M.; Oda, K. Heterocycles 2008, 75,
619e634.
1H NMR (500 MHz, DMSO-d6)
d: 11.3 (s, 1H), 7.22 (d, 1H,
J¼1.1 Hz), 5.42 (t, 1H, J¼6.4 Hz), 4.90 (t, 1H, J¼5.4 Hz), 3.85 (m, 1H),
3.79 (dd, 1H, J¼6.4 and 11.6 Hz), 3.55 (m, 1H), 3.49e3.40 (m, 2H),
2.96 (m, 1H), 2.70 (m, 1H), 1.78 (d, 3H, J¼1.1 Hz). 13C NMR (125 MHz,
16. See Supplementary data.
17. A related situation has been reported: (a) Jeong, L. S.; Nicklaus, M. C.; George, C.;
Marquez, V. E. Tetrahedron Lett.1994, 35, 7573e7576; (b) Miller, J. A.; Pugh, A. W.;
Ullah, G. M. Nucleosides Nucleotides Nucleic Acids 2000, 19, 1475e1486.
DMSO-d6) d: 164.2, 149.5, 137.7, 107.7, 66.4, 65.6, 64.6, 36.6, 12.1.