Synthesis of 1-(5,6-dihydro-2H-thiopyran-2-yl)uracil by a Pummerer-type thioglycosylation reaction: the regioselectivity of allylic substitution

Article abstract of DOI:10.1016/j.tet.2009.09.046

1-(5,6-Dihydro-2H-thiopyran-2-yl)uracil derivatives, a new 4′-thio-D4-nucleoside analogue, were synthesized by reacting 5,6-dihydro-2H-thiopyran sulfoxide and persilylated uracil in a Pummerer-type thioglycosylation reaction. The reaction of 5-alkyl subst

Full text of DOI:10.1016/j.tet.2009.09.046

Tetrahedron 65 (2009) 9091–9102
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Synthesis of 1-(5,6-dihydro-2H-thiopyran-2-yl)uracil by a Pummerer-type
thioglycosylation reaction: the regioselectivity of allylic substitution
*
*
Yuichi Yoshimura , Yoshiko Yamazaki, Yukako Saito, Hiroki Takahata
Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan
a r t i c l e i n f o
a b s t r a c t
1-(5,6-Dihydro-2H-thiopyran-2-yl)uracil derivatives, a new 40-thio-D4-nucleoside analogue, were syn-
thesized by reacting 5,6-dihydro-2H-thiopyran sulfoxide and persilylated uracil in a Pummerer-type
thioglycosylation reaction. The reaction of 5-alkyl substituted dihydrothiopyran sulfoxide 7 only gave 1-
(dihydrothiopyran-2-yl)uracil 9. On the other hand, the reaction with a 5-siloxy substituted derivative of
Article history:
Received 21 August 2009
Received in revised form
10 September 2009
Accepted 10 September 2009
Available online 15 September 2009
7 resulted in a mixture of products with the uracil moiety at either the
a prolonged reaction time resulted in the exclusive formation of the 4-substituted dihydrothiopyran
derivative 10. The result suggests that an equilibrium is operative in the formation of the - and
-adducts and that the latter should be more thermodynamically stable than the former. This conclusion
was also supported by theoretical calculations.
a- or the g-position. The use of
a
g
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
NH2
N
NH2
N
The search for new biologically active nucleosides is an impor-
tant task for medicinal chemists especially for investigators who
are attempting to develop antiviral drugs and antitumor agents. In
previous studies, we reported on the design and synthesis of var-
ious nucleoside derivatives.1,2 Among these, 40-thionucleosides,
which contain a sulfur atom in place of the oxygen of the furanose
ring, are particularly interesting targets as both antiviral and anti-
tumor agents.2 We previously reported on the design and synthesis
of a variety of 40-thionucleosides that have antiviral and antineo-
plastic activities,2 as represented by 40-thioFAC 1.2b,e,i,j As a part of
our ongoing studies to identify new antiviral agents, we envisioned
the synthesis of 1-(5,6-dihydro-2H-thiopyran-2-yl)cytosine 2,3
which was designed based on the known anti-HIV 40-thionucleo-
side 3 (Chart 1).
N
O
O
N
2'
1'
6'
4'
S
3'
S
1'
OH
F
HO
5'
4'
2'
3'
OH
2
1
O
NH2
NH
N
N
O
HO
S
O
N
OH
S
HO OH
4
In general, there are several problems associated with the syn-
thesis of 40-thionucloesides: (1) the construction of a 4-thiosugar
skeleton, (2) the subsequent formation of a glycosidic bond be-
tween the 4-thiosugar portion and a nucleobase. As a solution for
3
O
N
O
R
NH
the second problem, we developed
a Pummerer-type thio-
HN
O
glycosylation reaction, in which the 4-thiosugar sulfoxide is directly
coupled with a persilylated nucleobase.2a,b,g,3,4 The method proved
to be useful for producing 40-thiocucleosides. As a result, it was
O
N
S
S
HO
OH
OH
5
6
* Corresponding authors. Tel.: þ81 22 727 0145.
Chart 1.
E-mail address: yoshimura@tohoku-pharm.ac.jp (Y. Yoshimura).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.046

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Y. Yoshimura et al. / Tetrahedron 65 (2009) 9091–9102
possible to prepare a variety of 40-thionucleosides including the 40-
thioribonucleoside 44 using the Pummerer-type thioglycosylation
reaction.5 In our attempts to synthesize a dihydrothiopyrano-
nucleoside, the thioglycosylation step is a key factor in obtaining
the desired nucleoside, because the reaction can occur at either the
Among the several reports describing the synthesis of dihy-
drothiopyran, the method involving the use of ring closing me-
tathesis (RCM) appeared to be the most promising approach. Our
strategy was to synthesize an allyl butenyl sulfide derivative, and an
RCM reaction was attempted. The known monosilylated allyl al-
cohol 12 was obtained from 2-butene-1,4-diol 11 in 99% yield.7a,c
The enantiomerically pure epoxy alcohol 13 can be prepared using
the Sharpless asymmetric epoxidation, as has previously been
described.7b,c However, we were interested in obtaining the target
compound as a racemic mixture, because the antiviral evaluation of
the racemic target compounds would provide data regarding both
enantiomers in a single procedure. Thus, we prepared a racemic
mixture of 13 and treated the allyl alcohol 12 with m-CPBA in
CH2Cl2 to give 13 in 95% yield. The epoxide ring of 13 was cleaved by
a known method with minor modifications to give the vinyl diol 14
regioselectively.7b,c,8 Selective monotosylation at the primary hy-
droxyl group of 14, however, was unsuccessful. The typical reaction
for tosylation (TsCl, Et3N, DMAP, CH2Cl2) resulted in the pre-
dominant formation of the ditosylated derivative (data not shown).
This problem was overcome by using a more bulky 2,4,6-triiso-
propylbenzenesulfonyl (TPS) group, instead of a tosyl group. The
reaction of 14 with TPSCl, triethylamine, and DMAP in CH2Cl2 gave
the desired mono-TPS derivative 15 in 97% yield. The formation of
the di-TPS derivative could be suppressed by appropriately
adjusting the reaction conditions. A nucleophilic substitution re-
action of 15 with allyl mercaptan and DBU in Et2O gave allyl butenyl
sulfide 16 and an oxetane derivative 17 in 51 and 16% yields, re-
spectively, after acetylation (condition A). This result suggests that
intramolecular oxetane formation competed with the introduction
of the ally sulfide moiety. The formation of the undesired oxetane
17 was successfully suppressed when the substitution reaction was
performed using allyl mercaptan as the solvent. The allyl sulfide 18
was obtained in 77% yield with only trace amounts of the oxetane
derivative 17 (conditions B). An attempt to convert the oxetane
derivative 17 to 18 by treatment with allyl mercaptan and DBU was
not successful. This result suggests that the substitution of the TPS
group occurs via a direct SN2 reaction (Scheme 2) and that oxetane
17 was not involved to the formation of the allyl sulfide.
a
- or the
g-position of the dihydrothiopyran sulfoxide 7 (Scheme 1).
H
O
N
O
S
S
N
R
9
path a
bis(TMS)uracil
TMSOTf
O
S
path a
iPr2NET
R
R
8
7
path b
path b
H
O
N
O
N
R
S
10
Scheme 1. The Pummerer-type thioglycosylation reaction using dihydrothiopyran
sulfoxide.
It is difficult to predict the regioselectivity of this vinylogous
Pummerer-type reaction.6 It is noteworthy, however, that we suc-
cessfully synthesized 40-thio-20-methylene-nucleosides 5, which
was produced in a Pummerer-type thioglycosylation reaction of the
corresponding 2-methylene-4-thiosugar sulfoxide and silylated
uracils.2a,g This result encouraged us to pursue the synthesis of
dihydrothiopyrano-nucleoside using the Pummerer-type reaction
strategy. We herein report on the synthesis of dihydrothiopyran
sulfoxide and its conversion to the dihydrothiopyrano-nucleoside 6
bya Pummerer-type thioglycosylation reaction.3 Some of the factors
that influence the regioselectivity of the reaction are also discussed.
In order to construct a dihydrothiopyran skeleton, an RCM re-
action of 18, as described above, was attempted. After acetylation of
the hydroxyl group, the RCM reaction of 16 with the first Grubbs
catalyst was attempted. However, the reaction was sluggish and the
starting 16 was recovered in 83%. When the same reaction was
performed in refluxing benzene, dihydrothiopyran 19 was obtained
in 20% yield with 57% of 16 being recovered. In contrast to these
results, the use of the second Grubbs catalyst in refluxing benzene
2. Results and discussion
To prepare the thiosugar portion of the molecule, it was nec-
essary to synthesize a 5-subsutituted dihydrothiopyran skeleton.
CH2=CHMgCl
OH
mCPBA
CuI, Et2O
CH2Cl2
O
rt, overnight
−10 °C, 45 min
OH
RO
OH
TBDPSO
OH
13 (95%)
TBDPSO
(79%)
TBDPSCl
11: R = H
14
NaH, THF
rt, 1h
12: R = TBDPS (99%)
ArSO2Cl
OR
DMAP, Et3N
CH2Cl2, rt, 5h
OH
O
S
OTPS
+
TBDPSO
(97%)
TBDPSO
TBDPSO
Conditions A:
15
1) DBU, allyl mercaptan
Et2O, rt, 13d
17 (16%)
17 (trace)
16: R = Ac (51%)
2) Ac2O, Et3N, DMAP, CH2Cl2
overnight
Conditions B:
DBU, allyl mercaptan
rt, 6h
18: R = H (77%)
Scheme 2. Synthesis of an allyl butenyl sulfide derivative 18.

Y. Yoshimura et al. / Tetrahedron 65 (2009) 9091–9102
9093
greatly improved the reaction and gave 19 in 92% yield.9 Upon
treatment with NaIO4 in EtOH/H2O overnight, compound 19 was
oxidized to give a diastereomeric mixture of a sulphoxide de-
rivative 20 in 90% yield. Following our initial plan, the sulfoxide 20
was subjected to the Pummerer-type thioglycosylation reaction.
The conditions optimized for the synthesis of 40-thiouridine were
applied to the reaction of 20.4 Treatment of the sulphoxide 20 with
bis(trimethylsilyl)uracil, TMSOTf, and DIPEA in toluene and CH2Cl2
(1:1, v/v) at ꢀ40 ꢁC gave the dihydrothiopyranyluracil derivatives
21 and 22 in 41 and 29% yields, respectively. Adducts produced by
reaction at the 40-position were not observed. The stereochemistry
of the dihydrothiopyranyluracil derivative 21 was elucidated by
NOE experiments of 23, which was obtained by deprotection with
sodium methoxide and subsequent treatment with TBAF. The final
product was determined to be the cis-isomer. On the other hand,
the deprotection procedure was applied to 22 giving dihy-
drothiopyranyluracil 24, the structure of which was determined by
X-ray crystallographic analysis (Scheme 3).3
above. Treatment of 30 with TBAF gave the ring-expanded 40-thio-
D4U 6 in 80% yield. NOE experiments of 6 revealed that the major
product of the Pummerer-type thioglycosylation had a cis-stereo-
chemistry. Similarly, deprotection of 31 gave the trans-isomer 32 in
excellent yield. It is noteworthy that the Pummerer-type thio-
glycosylation of 29 as well as of 20 both gave cis-isomers as major
products. However, the reason for the predominant formation of
these cis-isomers is currently unclear (Scheme 4).
As a final target, we selected a dihydrothiopyrano-uridine de-
rivative, which contains a hydroxyl group in place of a hydroxy-
methyl group at the 50-position. The target itself has a unique
structure and has potential biological activity. In addition, it would
be expected to serve as an important synthetic intermediate in the
preparation of novel nucleoside analogues including phospho-
nomethyl derivatives.11 The synthesis of the compound is also of
interest in terms of the influence of substituent group at the 50-
position on the regioselectivity of the Pummerer-type thio-
glycosylation reaction.
1) Ac2O, Et3N
DMAP
OH
NaIO4
OAc
OAc
CH2Cl2
EtOH, H2O
rt, overnight
O
rt, overnight
S
S
S
(99%)
TBDPSO
TBDPSO
TBDPSO
19
(90%)
2) 2nd Grubbs cat.
PhH, reflux, 12h
(92%)
18
20
Bis(TMS)uracil
TMSOTf
AcO
H
AcO
H
DIPEA
S
5'
4'
PhCH3, CH2Cl2
−40 °C, 50 min
H
S
H
O
O
+
TBDPSO
2'
TBDPSO
N
3'
N
NH
NH
O
21 (41%)
O
22 (29%)
1) NaOMe
2) TBAF
THF
1) NaOMe
MeOH
2) TBAF
THF
MeOH
rt, overnight
(97%)
rt, 6h
rt, overnight
(74%)
rt, 6h
O
(87%)
(99%)
HO
HO
H
HO
HO
23
H
NH
O
H
H
N
H
S
H
O
S
H
H
N
H
O
OH
OH
N
NH
H
S
H
NH
O
23
24
O
Scheme 3. Synthesis of dihydrothiopyrano-uridine derivatives 23 and 24.
Our next target was the dihydrothiopyrano-uridine 6, a ring-
expanded apio-nucleoside10 analogue of 40-thio-D4-uridine. As in
the case described above, the RCM-reaction of 18, without pro-
tection of the secondary hydroxyl group, using the second Grubbs
catalyst resulted in the formation of the dihydrothiopyran de-
rivative 25 in 85% yield. After deprotection of the TBDPS group,
oxidative scission of the cis-diol by treating 26 with NaIO4 followed
by sodium borohydride treatment gave 3-hydroxymethyl-3,6-
dihydrothiopyran 27 in 57% yield. The selective diol cleavage of 26
was possible, since the cleavage reaction was faster than the oxi-
dation of the sulfide to the sulfoxide. As expected, the oxidation to
sulfoxide 29, after protection of the primary hydroxyl group with
a TBDPS group, was carried out by treatment with NaIO4 and the
reaction gave 29 in good yield. Using the same conditions described
above, the Pummerer-type thioglycosylation reaction of 29 with
bis(trimethylsilyl)uracil gave the desired ring-expanded 40-thio-
apio-uridine derivatives 30 and 31 in 45 and 22% yields, re-
The dihydrothiopyran 37, a precursor of the substrate of the
Pummerer-type thioglycosylation, was synthesized following
a previously reported method.9 Commercially available butadiene
monoxide 33 was treated with allyl mercaptan in the presence of
DBU to give a mixture of 34 and 35 in 39 and 60% yields, re-
spectively, after silica gel column separation. After protecting the
secondary hydroxyl group of 35 by reaction with TBSCl, the
resulting 36 was subjected to the RCM reaction catalyzed by
the second Grubbs’ catalyst, which gave 5-O-TBS-dihydrothiopyran
37 in 92% yield. The oxidation of 37, as described above, gave the
sulfoxide 38 in good yield (Scheme 5).
As in the case of sulfoxides 20 and 28, the Pummerer-type
thioglycosylation reaction of 38 was performed and the results are
summarized in Table 1.
The reaction of a diastereomeric mixture of 38 (1:1) with
bis(TMS)uracil in the presence of TMSOTf and diisopropylethyl-
amine was complete within 40 min at ꢀ40 ꢁC and gave a mixture of
dihydrothiopyrano-nucleosides in a ratio of 3:3:1 (entry 1). Among
spectively. No g-adducts were detected, as in the case described

9094
Y. Yoshimura et al. / Tetrahedron 65 (2009) 9091–9102
1) NaIO4
EtOH, H2O
0 °C, 1h
2) NaBH4, rt, 3.5h
(57%, 2 steps)
1) 2nd Grubbs cat.
PhH, reflux, 12h
(85%)
OH
OH
2) TBAF, THF, rt
overnight (97%)
RO
HO
S
S
S
TBDPSO
R = TBDPS
27
18
25 : R = TBDPS
26 : R = H
TBDPSCl
imidazole
NaIO4, EtOH,
H2O
CH2Cl2, rt, 2h
O
rt, overnight
TBDPSO
S
TBDPSO
S
(99%)
(94%)
29
28
O
NOE
H
TBAF
THF, rt
HN
O
TBDPSO
S
H
H
S
H
O
overnight
N
N
Bis(TMS)uracil
TMSOTf, DIPEA
PhCH3, CH2Cl2
−40 °C, 50 min
OH
H
NH
(80%)
H
H
30 (45%)
O
6
NOE
+
TBAF
H
H
THF, rt
overnight
TBDPSO
S
H
O
HO
S
O
N
NH
N
NH
(96%)
H
O
32
31 (22%)
O
Scheme 4. Synthesis of ring-expanded 40-thio-D4U 31.
Table 1
allyl mercaptan
S
O
HO
DBU
Summary of the Pummerer-type thioglycosylation reaction of sulfoxide 38
O
O
O
N
rt, 18.5 h
TMSOTf (3 eq)
bis(TMS)uracil (3 eq)
i-Pr2NEt (10 eq)
O
S
33
NH
NH
NH
34 (39 %)
N
O
N
O
O
S
S
+
PhCH
3 / CH2Cl2
TBSO
S
S
TBSO
40 (trans)
TBSO
OTBS
38
39 (cis)
41
RO
Entry 38
Time/temperature
Ratio of the products
Total yield
(%)
35: R = H (60 %)
TBSCl, imidazole
DMAP, CH2Cl2,
rt, overnight
39
40
41
36: R = TBS (quant)
1
2
3
4
5
Mixture
40 min/ꢀ40 ꢁ
C
3
3.6
0
2.7
0
3
3.6
0
2.7
0
1
1
1
1
1
62
68
53
89
75
Less polar 1.5 h/ꢀ40 ꢁC
reflux, 22.5 h
(92%)
2nd Grubbs' Catalyst
(5 mol%)
16 h/ꢀ40 ꢁC/5 h/rt
More polar 10 min/ꢀ40 ꢁC
benzene
3 h/ꢀ40 ꢁC
S
the three products obtained, the major a-adducts were isolated and
their structures determined as follows. The mixture of 39, 40, and
41 was treated with TBAF to give a mixture of free nucleosides, from
which the trans-isomer 42 was obtained in 37% by simple crystal-
lization. The structure of 42 was confirmed by NOE experiments as
shown in Chart 2. On the other hand, benzoylation of the N3-po-
sition of the uracil ring and subsequent careful purification by silica
gel column chromatography gave isomerically pure 45 in 44% yield
and a mixture of 43 and 44 (56%). Compound 45 was deprotected
by TBAF followed by NaOMe treatment to give the free dihy-
drothiopyrano-uridine derivative 46 in good yield. NOE experi-
ments of 46, as shown in Chart 2, clearly revealed that 45 had
a cis-stereochemistry (Scheme 6).
TBSO
37
NaIO4
rt, overnight
(95%)
EtOH / H2O
O
S
TBSO
38
Scheme 5. Synthesis of 5-siloxydihydrothiopyran sulfoxide 38.

Y. Yoshimura et al. / Tetrahedron 65 (2009) 9091–9102
9095
NOE
corresponded to a
g
-adduct. This aspect of the reaction is discussed
O
O
NOE
below. Another interesting aspect of the Pummerer-type thio-
glycosylation of 38 was whether the reaction was affected by dif-
ference of the stereochemistry of the sulfoxide.2g,5b We carefully
separated the diastereomers by silica gel column chromatography.
Thus, both of the isomers were separately subjected to the reaction,
but it was not possible to determine the stereochemistries of
the sulfoxides. The less polar isomer showed similar results to those
obtained when a mixture was used (entry 2). The reaction of the
more polar isomer, on the other hand, was complete within 10 min
and gave a mixture of products in 89% yield with a similar ratio as
mentioned above (entry 4). These data strongly suggest that the
reaction proceeded via a common allylic sulfenium ion in both
cases. The difference in the reaction velocity can be explained by
the ease of formation of the allylic sulfenium ion from the more
polar sulfoxide, compared to the less polar isomer. In other words,
the elimination of trimethylsilanol, which occurs by way of the
HO
H
NH
O
HN
O
H
H
H
H
S
S
N
N
H
OH
H
H
H
H
NOE
NOE
46
NOE
42
Chart 2.
O
1) TBAF
THF
88%
NH
39, 40, 41
N
O
2) Crystallization
37%
S
1) BzCl
Et3N
HO
DMAP
42
CH2Cl2
2) Separation
silylation of oxygen and the subsequent abstraction of an a-proton
of the sulfoxide should proceed faster in the case of the more polar
O
O
N
isomer than in the less polar one.5b
Bz
Bz
O
N
N
In contrast to the results for the 5-siloxymethyl derivatives 20
and 28, the 5-siloxy derivative 38 produced the g-adduct as a side-
N
O
S
product (vide supra). It was interesting to find that prolonging the
reaction time and increasing the reaction temperature resulted in
the selective formation of the
meric sulfoxides (entries 3 and 5).
It is possible that the -adduct 41 is formed from the a-adducts
39 and 40 via regeneration of an allylic sulfenium ion. To confirm
this, the products of entry 1, largely 39 and 40 were retreated under
the conditions used for the Pummerer-type thioglycosylation. As
S
OTBS
TBSO
g-adduct 41 from both of the iso-
44
43
(56%, mixture )
g
+
O
Bz
N
expected, the starting materials were consumed and the g-adduct
N
S
O
41 was isolated in 67% yield after silica gel column chromatography
(Scheme 7). The relative stereochemistry of 41 was estimated as cis
based on an NMR analysis (vide infra). From this result as well as
those described above, the following reaction mechanism is pro-
posed, as shown in Scheme 8.
TBSO
45 (44%)
1) TBAF
AcOH
THF
2) NaOMe
MeOH
(95 %)
O
O
(99%)
TMSOTf
bis(TMS)uracil
i-Pr2NEt
O
NH
NH
NH
N
O
N
O
S
PhCH3 / CH2Cl2
67 %
N
O
S
S
TBSO
OTBS
39, 40
41
HO
46
Scheme 7. Isomerization of the
a
-adducts 39 and 40 to the g-adduct 41.
Scheme 6. Synthesis and isolation of 5-hydroxydihydrothiopyranyluracils 42 and 46.
The reaction intermediate is an allylic sulfenium ion 8 gener-
ated from the reaction of sulfoxide 7, TMSOTf, and diisopropyl-
ethylamine. An attack by the persilylated uracil at the 2-position
The most remarkable result in entry 1 is the fact that the
reaction mixture contained a minor product, which presumably
H
O
N
O
S
N
path a
9
R
bis(TMS)uracil
TMSOTf
O
S
path a
S
iPr2NET
R = OTBS
R
R
H
N
8
7
path b
O
O
path b
N
R
S
10
Scheme 8. Equilibrium between a- and g-adducts.

9096
Y. Yoshimura et al. / Tetrahedron 65 (2009) 9091–9102
of 8 (
a
-attack) gives rise to the
-attack of 8 would be the kinetically favored process, since
the attack occurs at the less hindered site. However, the results
suggest that an equilibrium exists between the - and -adducts
a
-adduct 9 (path a). It is likely that
depicted in Figure 1. On the other hand, the optimized conformer of
trans-48 obtained by theoretical calculations indicates a gauche–
gauche conformation around C50–C60 since both of the bulky uracil
and siloxy groups occupy axial positions (data not shown). From
these considerations, compound 41 obtained by isomerization of the
the
a
a
g
and that the latter should be the thermodynamically controlled
product (Scheme 8). In order to obtain further support for this
hypothesis, we selected 5-trimethylsiloxy derivatives 47 and 48 as
simplified model compounds and their structures were estimated
by theoretical calculations. Optimized conformers of every com-
pound were surveyed by molecular mechanics (MM) calculations
and were subjected to theoretical calculations by density func-
tional theory (DFT) quantum mechanical calculations at the
a-adducts was determined as a cis-isomer. Therefore, there is no
doubt that the cis-isomer of the -adduct is a thermodynamic
g
product of the Pummerer-type thioglycosylation. However, we do
not have clear explanation for the reason why the formation of any
trace of trans-48 was not observed despite the small energy gap
between cis- and trans-48 estimated by calculations.
Among the many reported examples of the Pummerer reaction,
B3LYP/6-31G
*
level. The results are summarized in Table 2.
the reactions of a,b-unsaturated sulfoxides are known to proceed
Table 2
Summary of the calculated energy of model compounds 47 and 48. The theoretical calculations were performed by density functional theory (DFT) quantum mechanical
calculations at the B3LYP/6-31G
*
level using SPARTANÔ (Wavefunction, Inc.). The results are shown by the relative energy to that of cis-47 as a standard
H
N
H
N
H
N
H
N
O
O
O
O
O
O
O
O
S
N
S
N
N
N
S
S
TMSO
TMSO
OTMS
OTMS
cis-47
trans-47
cis-48
trans-48
cis-47
trans-47
cis-48
ꢀ19.1
trans-48
ꢀ17.4
rel. E (kJ/mol)
0
2.4
In a series of
have a higher energy by þ2.4 kJ/mol compared to that of the cis-47.
It should also be noted that both of the -adducts were shown to
have lower energies than that of cis-47: trans-48 should be more
stable than cis-47 by 17.4 kJ/mol. The most stable product estimated
by theoretical calculations was cis-48, which should be more stable
than cis-47 by 19.1 kJ/mol. The structure of the optimized con-
former of cis-48, obtained by MM and DFT calculations, is shown in
Figure 1.
a
-adducts, the trans-isomer of 47 was revealed to
via either a vinylogous or an additive mechanism.6 In the former
reaction, the -unsaturated sulfoxides bearing a -hydrogen
generates a conjugated sulfenium ion to which a nucleophile is able
to attack at either its - or
-position.6 As can be seen, the vinyl-
ogous Pummerer reaction contains an issue of the regioselectivity
of substitution, however, the factors that rule the selectivity of the
reaction are not yet clear.6 The reaction described above belongs to
a category of the vinylogous Pummerer reaction, since the reaction
intermediate is the same allylic sulfenium ion. The results point out
an important feature of the reaction in which an equilibrium be-
a
,b
g
g
a
g
tween
difficult to predict the regioselectivity of vinylogous Pummerer
reactions, since the ratio of - and -adducts is very likely to be
influenced by the reaction conditions used. In addition, it is obvious
that the substituent groups of the -unsaturated sulfoxides are
a- and g-adducts exists. This serves as a reminder that it is
a
g
a,b
important: nature of the allylic sulfenium ion depends on the
functional groups attached to it and this no doubt influences
the equilibrium of the reaction. Indeed, our results showed that the
Pummerer-type thioglycosylation of 5-alkyl substituted dihy-
O
drothiopyran sulfoxides gave only
derivative gave a mixture of - and
issue clarified in this study is that the
a
g
-adducts, and that a 5-siloxy
-products. Another significant
-adduct appears to be
a
NH
g
a thermodynamic product. This conclusion is supported by the ex-
perimental results as well as theoretical calculations. The above
findings can be useful in understanding several reported results
including other dihydrothiopyran derivatives12 and a 4-thiofur-
anose derivative bearing a 2-exo-methylene.2a,g
H
6'
N
O
4'
5'
O
Si
H
H
S
H
In summary, we report on the synthesis of a novel ring-expanded
40-thio-apio-D4U derivative. The synthesis of 3-hydroxymethyl-3,6-
dihydrothiopyran, the sugar portion of the target compound, started
from 2-butene-1,4-diol and was achieved by the RCM-reaction after
the introduction of vinyl and allyl sulfide moieties. The dihy-
drothiopyran was converted to the corresponding sulfoxide, the
Pummerer-type thioglycosylation of which proceeded exclusively at
Figure 1. The structure of the optimized conformer of cis-48. (up) The 3D-structure of
optimized cis-48 drawn by a ball-and-stick model. (down) Schematic view of the
optimized conformer of cis-48.
It can be seen that a 50-proton of cis-48 has a trans–gauche
conformation related to two of the 60-protons. This is in good
agreement with the structure of 41 deduced by 1H NMR data, since it
was observed that the coupling constants between 50- and 60-pro-
tons were 9.4 and 3.1 Hz (see Experimental section). Furthermore,
the fact that compound 41 has a coupling constant of 7.1 Hz corre-
sponding to H-40 and H-50 is consistent with the structure of cis-48
the
contrast, when the same reaction was applied to the synthesis of
5-siloxydihydrothiopyrano-nucleosides, a mixture of the - and
-products was produced. It is interesting to note that the -adduct
a
-position and gave the desired 40-thio-apio-D4U derivative. In
a
g
a

Y. Yoshimura et al. / Tetrahedron 65 (2009) 9091–9102
9097
could be converted to the
of an equilibrium during the formation of the
that the latter should be more thermodynamically stable than the
former. This conclusion was theoretically supported by DFT
calculations.
g
-adduct. The results suggest the existence
45 min. The reaction was quenched by the addition of concd NH4OH
followed by satd NH4Cl. After the whole mixture was extracted with
ether three times, the combined organic layer was washed with satd
NH4Cl and brine, then dried over MgSO4. After filtration, the filtrate
was concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (n-hexane/ethyl acetate¼2:1)
to give 14 (5.11 g, 79%) as a syrup.
a
- and -adducts and
g
3. Experimental section
1H NMR (400 MHz, CDCl3)
d 1.04 (s, 9H), 2.33–2.36 (m, 1H), 3.62
3.1. Experimental procedures and characterization data
(d, J¼5.8 Hz, 2H), 3.67–3.75 (m, 2H), 3.89–3.93 (m, 1H), 5.09 (dd,
J¼1.9, 17.4 Hz, 1H), 5.15 (dd, J¼1.9, 10.6 Hz, 1H), 5.82 (ddd, J¼9.2,
10.6, 17.4 Hz, 1H), 7.35–7.44 (m, 6H), 7.62–7.64 (m, 4H). 13C NMR
Melting points are uncorrected. NMR spectra were recorded at
400 and 600 MHz (1H), 100 and 150 MHz (13C) using CDCl3, CD3OD,
and DMSO-d6 with tetramethylsilane as internal standard. Mass
spectra were obtained by EI or FAB mode. Silica gel for chroma-
tography was Fuji Silysia PSQ 100B. All the reactions described
below were performed under argon atmosphere.
(100 MHz, CDCl3)
d 19.2, 26.8, 48.3, 64.3, 66.1, 72.6, 118.8, 127.8,
129.9, 133.0, 134.6, 135.5. IR (neat, cmꢀ1): 614, 702, 740, 824, 999,
1113, 1428, 2858, 2931. FABMS (m/z): 371 (Mþþ1). HRMS calcd for
C22H30O3Si: 371.2043, found 371.2031.
3.5. ((1R
*
,2S )-2-(2-(tert-Butyldiphenylsilanyloxy)-1-
*
3.2. (Z)-4-(tert-Butyldiphenylsilanyloxy)-but-2-ene-1-ol (12)
hydroxyethyl)but-3-enyl)-2,4,6-triisopropyl-
benzenesulfonate (15)
To a suspension of NaH (800 mg, 20 mmol) in THF (40 mL) was
added cis-2-butene-1,4-diol (1.63 mL, 20 mmol) at room tempera-
ture. After being stirred for 1 h, tert-butyldiphenylchlorosilane
(5.14 mL, 20 mmol) was added to the mixture and the whole was
stirred at room temperature for 1 h. The reaction mixture was di-
luted with ether and washed with 10% aq K2CO3 and brine. The
water layer was extracted with ether and the combined organic
layer was dried over MgSO4. After filtration, the filtrate was con-
centrated under reduced pressure. The residue was purified by
silica gel column chromatography (n-hexane/ethyl acetate¼2:1) to
To a solution of 14 (1.29 g, 3.47 mmol) in CH2Cl2 (10 mL) were
added
2,4,6-triisopropylbenzenesulfonyl
chloride
(2.10 g,
6.94 mmol), NEt3 (967
m
L, 6.94 mmol), and DMAP (42 mg,
0.347 mmol) and the mixture was stirred at room temperature
for 5 h. The reaction was quenched with satd NaHCO3. The
resulting mixture was partitioned between CHCl3 and brine, and
the organic layer was dried over MgSO4. After filtration, the fil-
trate was concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (n-hexane/ethyl
give 11 (6.48 g, 99%) as an oil. 1H NMR (400 MHz, CDCl3)
d
1.05 (s,
acetate¼9:1) to give 15 (2.14 g, 97%) as
a
syrup. 1H NMR
(400 MHz, CDCl3) 1.04 (s, 9H), 1.24–1.27 (m, 18H), 2.0 (s, 1H),
9H), 4.00 (t, J¼5.6 Hz, 2H), 4.26 (d, J¼5.8 Hz, 2H), 5.60–5.74 (m, 2H),
d
7.37–7.46 (m, 6H), 7.67–7.70 (m, 4H). 13C NMR (100 MHz, CDCl3)
2.39 (d, J¼3.9 Hz, 1H), 2.64 (d, J¼7.7 Hz, 1H), 2.88–2.95 (m, 1H),
3.60 (d, J¼6.8 Hz, 2H), 3.97 (d, J¼2.9 Hz, 1H), 4.03 (dd, J¼6.3,
9.7 Hz, 1H), 4.08–4.13 (m, 3H), 4.25 (dd, J¼8.2, 9.7 Hz, 1H), 5.07–
5.15 (m, 2H), 5.70 (dt, J¼9.7, 17.4 Hz, 1H), 7.36–7.44 (m, 6H), 7.64
d
19.1, 26.7, 58.7, 60.2, 127.7, 129.7, 130.0, 130.9, 133.4, 135.6. IR (neat,
cmꢀ1): 463, 472, 491, 1642, 3435. FABMS (m/z): 327 (Mþþ1). HRMS
calcd for C20H26O2Si: 327.1780, found 327.1789. Anal. Calcd for
C20H26O2Si: C, 73.57; H, 8.03. Found: C, 73.65; H, 8.26.
(d, J¼6.3 Hz, 4H). 13C NMR (100 MHz, CDCl3)
d 19.2, 23.5, 24.7,
26.8, 29.6, 34.2, 45.6, 65.9, 69.1, 70.0, 119.9, 123.7, 127.8, 129.4,
129.8, 132.4, 132.9, 135.5, 150.8, 153.7. IR (neat, cmꢀ1): 1639, 3410.
FABMS (m/z): 637 (Mþþ1). HRMS calcd for C37H52O5SSi:
637.3383, found 637.3401.
3.3. ((2R
*
,3S )-3-(tert-Butyldiphenylsilanyloxymethyl)-
*
oxiranyl)methanol (13)
To a solution of 12 (3.14 g, 9.62 mmol) in CH2Cl2 (10 mL) was
added m-CPBA (3.90 g, 14.7 mmol) and the mixture was stirred at
room temperature overnight. The reaction was quenched with satd
NaHCO3 and the whole was extracted with CHCl3. The organic layer
was washed with 10% Na2S2O3, satd NaHCO3 and brine, then dried
(MgSO4). After filtration, the filtrate was concentrated under re-
duced pressure. The residue was purified by silica gel column
chromatography (n-hexane/ethyl acetate¼2:1) to give 13 (3.13 g,
3.6. ((2R
*
,3R )-3-((Allylthio)methyl)-1-(tert-butyldiphenyl-
*
silanyloxy)pent-4-en-2-yl)acetate (16) and (((2R
vinyloxetan-2-yl)methoxy)(tert-butyl)-
diphenylsilane (17)
*
,3S )-3-
*
To a solution of 15 (410 mg, 0.624 mmol) in ether (1 mL) were
added allyl mercaptan (519 L, 6.44 mmol) and DBU (192 L,
1.29 mmol) and the mixture was stirred at room temperature for 5
days. Ether (2 mL), allyl mercaptan (519 L, 6.44 mmol), and DBU
(192 L, 1.29 mmol) were added and the mixture was stirred at
room temperature for 8 days. The mixture was diluted with ether
and washed with satd NH4Cl, 10% Na2S2O3, and brine. The water
layer was extracted with ether and the combined organic layer
was dried over MgSO4. After filtration, the filtrate was concen-
trated under reduced pressure. The residue was purified by silica
gel column chromatography (5–10% AcOEt in n-hexane) to give
crude 18 and 17. A crude mixture of 18 was dissolved in CH2Cl2
m
m
95%) as a syrup. 1H NMR (400 MHz, CDCl3)
d 1.06 (s, 9H), 2.09 (br s,
1H), 3.18–3.25 (m, 2H), 3.62 (dd, J¼6.3, 12.3 Hz, 1H), 3.68 (dd, J¼4.6,
12.3 Hz, 1H), 3.75 (dd, J¼5.2, 11.8 Hz, 1H), 3.89 (dd, J¼5.4, 11.8 Hz,
1H), 7.38–7.46 (m, 6H), 7.66–7.69 (m, 4H). 13C NMR (100 MHz,
m
m
CDCl3)
d 19.1, 26.7, 56.2, 56.4, 60.7, 62.2, 127.8, 129.9, 132.8, 132.9,
135.49, 135.53. IR (neat, cmꢀ1): 454, 461, 466, 480, 612, 1427, 1645,
3434. FABMS (m/z): 343 (Mþþ1). HRMS calcd for C20H26O3Si:
343.1730, found 343.1725.
3.4. (2S
*
,3R )-4-(tert-Butyldiphenylsilanyloxy)-2-
*
vinylbutane-1,3-diol (14)
(5 mL). To this mixture were added Et3N (188
mL, 1.35 mmol),
acetic anhydride (69 L, 0.734 mmol), and DMAP (7.5 mg,
m
To a suspension of CuI (6.66 g, 35.0 mmol) in dry ether (240 mL)
was added a solution of vinylmagnesium chloride in THF (1.44 M in
THF, 60.7 mL, 87.5 mmol) was added at ꢀ10 ꢁC. After being stirred
for 1 h at 0 ꢁC, the mixture was allowed to cool to ꢀ10 ꢁC. To this
mixture was added a solution of 13 (5.99 g, 17.5 mmol) in dry ether
(40 mL) and the mixture was stirred at the same temperature for
0.061 mmol) and the mixture was stirred at room temperature
overnight. The mixture was diluted with ether and washed with
satd NaHCO3 and brine, then dried (Na2SO4). After filtration, the
filtrate was concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (n-hexane/ethyl
acetate¼20:1) to give 16 (153 mg, 51%) as a syrup.

9098
Y. Yoshimura et al. / Tetrahedron 65 (2009) 9091–9102
Data for 16: 1H NMR (400 MHz, CDCl3)
d
1.04 (s, 9H), 2.01 (s, 3H),
CDCl3) d 19.2, 21.1, 25.2, 26.3, 26.7, 35.7, 62.9, 76.5, 125.5, 127.7,
2.45 (dd, J¼8.2, 13.0 Hz, 1H), 2.56 (dd, J¼6.0, 13.0 Hz, 1H), 2.65–2.72
(m, 1H), 3.10 (d, J¼7.2 Hz, 2H), 3.62 (dd, J¼5.8, 10.2 Hz, 1H), 3.72 (dd,
J¼6.3, 10.2 Hz, 1H), 5.04–5.20 (m, 5H), 5.61–5.79 (m, 2H), 7.36–7.43
129.8, 133.2, 135.6, 170.5. IR (neat, cmꢀ1): 702, 742, 1044, 1113,
1236, 1428, 1740, 2857, 2931. FABMS (m/z): 441 (Mþþ1). HRMS
calcd for C25H32O3SSi: 441.1920, found 441.1918.
(m, 6H), 7.65 (d, J¼7.7 Hz, 4H). 13C NMR (100 MHz, CDCl3)
d 19.2,
21.0, 26.7, 32.1, 35.0, 44.3, 63.0, 74.5, 117.0, 118.5, 127.7, 129.7, 133.2,
134.3, 135.6, 135.9, 170.3. IR (neat, cmꢀ1): 702, 1113, 1233, 1638.
EIMS (m/z): 468 (Mþ). HRMS calcd for C27H36O3SSi: 468.2154,
found 468.2145. Anal. Calcd for C27H36O3SSi: C, 69.19; H, 7.74.
Found: C, 68.89; H, 7.76.
3.9. (R
*
)-2-(tert-Butyldiphenylsilanyloxy)-1-((R )-3,6-
*
dihydro-1-oxy-2H-thiopyran-3-yl)ethyl acetate (20)
To a solution of 19 (1.00 g, 2.27 mmol) in EtOH/H2O (1:1, 40 mL)
was added NaIO4 (972 mg, 4.54 mmol) at room temperature and the
mixture was stirred at the same temperature overnight. The
resulting insoluble materials were removed by suction. After the
filtrate was concentrated under reduced pressure, the residue was
purified by silica gel column chromatography (n-hexane/ethyl
acetate¼1:1) to give 20 (976 mg, 94%) as a mixture of diastereomers
(3:2). A part of the mixture was separated by repeating silica gel
column chromatography.
Crude 17 was re-chromatographed by a silica gel column (ben-
zene) to give 17 (37 mg, 16%) as a syrup.
Data for 17: 1H NMR (400 MHz, CDCl3)
d 0.99 (s, 9H), 2.66–2.72
(m, 1H), 3.54 (dd, J¼4.8, 8.7 Hz, 1H), 3.60–3.66 (m, 2H), 4.02 (dd,
J¼6.8, 8.7 Hz, 1H), 4.09 (dd, J¼3.4, 7.7 Hz, 1H), 4.79–4.86 (m, 2H),
5.37–5.46 (m, 1H), 7.28–7.38 (m, 6H), 7.54–7.60 (m, 4H). 13C NMR
(100 MHz, CDCl3)
d 19.1, 26.9, 52.6, 71.4, 74.5, 78.6, 116.2, 127.7,
129.8, 133.6, 135.8, 136.8. IR (neat, cmꢀ1): 613, 702, 1111, 1428, 2858,
Data for 20 (less polar): 1H NMR (400 MHz, CDCl3)
d 1.06 (s, 9H),
2931. EIMS (m/z): 295 (Mþꢀt-Bu).
2.04 (s, 3H), 2.76 (t, J¼11.1 Hz, 1H), 3.19–3.23 (m, 2H), 3.29–3.38 (m,
1H), 3.75 (dd, J¼4.3, 11.6 Hz, 1H), 3.72–3.77 (m, 1H), 3.83 (dd, J¼4.8,
11.1 Hz, 1H), 4.96 (dd, J¼4.8, 5.8 Hz, 1H), 5.60–5.65 (m, 1H), 5.70 (d,
J¼10.6 Hz, 1H), 7.38–7.47 (m, 6H), 7.63–7.67 (m, 4H). 13C NMR
3.7. (2R
*
,3R )-3-((Allylthio)methyl)-1-(tert-butyl-
*
diphenylsilanyloxy)pent-4-en-2-ol (18)
(100 MHz, CDCl3)
d 19.1, 20.8, 26.7, 36.2, 49.4, 49.8, 62.3, 64.1, 75.0,
To a solution of 15 (1.87 g, 2.94 mmol) in allyl mercaptan (5 mL)
was slowly added DBU (878 mL, 5.88 mmol) and the mixture was
118.8, 127.7, 129.0, 129.9, 132.6, 135.4, 170.1. IR (neat, cmꢀ1): 1645,
2095. FABMS (m/z): 457 (Mþþ1). HRMS calcd for C25H32O4SSi:
457.1869, found 457.1882.
stirred at room temperature for 6 h. The mixture was diluted with
ether and washed with satd NH4Cl, 10% Na2S2O3, and brine. The
water layer was extracted with ether and the combined organic
layer was dried over MgSO4. After filtration, the filtrate was con-
centrated under reduced pressure. The residue was purified by
silica gel column chromatography to give 18 (960 mg, 77%). 1H NMR
Data for 20 (more polar): 1H NMR (400 MHz, CDCl3)
d 1.05 (s,
9H), 2.04 (s, 3H), 2.59 (dd, J¼10.6, 13.3 Hz, 1H), 3.10 (dd, J¼3.9,
13.3 Hz, 1H), 3.18–3.23 (m, 1H), 3.34–3.38 (m, 2H), 3.74 (dd, J¼4.3,
11.1 Hz, 1H), 3.83 (dd, J¼5.8, 11.1 Hz, 1H), 5.10 (q, J¼5.3 Hz, 1H),
5.65–5.68 (m, 1H), 5.83 (d, J¼11.1 Hz, 1H), 7.37–7.46 (m, 6H), 7.63–
(400 MHz, CDCl3)
d
1.06 (s, 9H), 2.33 (d, J¼3.4 Hz, 1H), 2.35 (br s,
7.66 (m, 4H). 13C NMR (100 MHz, CDCl3)
d 19.1, 20.9, 26.6, 30.1, 45.3,
1H), 2.53 (dd, J¼7.2, 12.6 Hz, 1H), 2.69 (dd, J¼6.8, 12.6 Hz, 1H), 3.09
(d, J¼7.2 Hz, 2H), 3.61 (d, J¼6.3 Hz, 2H), 3.91–3.96 (m, 1H), 5.02–
5.13 (m, 4H), 5.71–5.81 (m, 2H), 7.37–7.44 (m, 6H), 7.61–7.70 (m,
46.2, 62.9, 75.0, 118.1, 127.7, 128.2, 129.8, 132.8, 135.5, 170.2. IR (neat,
cmꢀ1): 1642, 2095. FABMS (m/z): 457 (Mþþ1). HRMS calcd for
C25H32O4SSi: 457.1869, found 457.1879.
4H). 13C NMR (100 MHz, CDCl3)
d 19.2, 26.8, 32.6, 35.1, 45.7, 66.2,
72.2, 117.0, 117.8, 127.8, 129.8, 133.1, 134.3, 135.5, 136.5. IR (neat,
cmꢀ1): 701, 1113, 1636, 3414. EIMS (m/z): 426 (Mþ). HRMS calcd for
C25H34O2SSi: 426.2049, found 426.2037.
3.10. 1-((2R
silanyloxy)-ethyl)-5,6-dihydro-2H-thiopyran-2-yl)-
pyrimidine-2,4(1H,3H)-dione (21) and 1-((2S ,5S )-
*
,5S )-5-(1-Acetoxy-2-(tert-butyldiphenyl-
*
*
*
5-(1-acetoxy-2-(tert-butyldiphenylsilanyloxy)-
ethyl)-5,6-dihydro-2H-thiopyran-2-yl)-
pyrimidine-2,4(1H,3H)-dione (22)
3.8. ((R
*
)-2-(tert-Butyldiphenylsilanyloxy)-1-((R )-3,6-
*
dihydro-2H-thiopyran-3-yl)ethyl)acetate (19)
To a solution of 18 (289 mg, 0.677 mmol) in CH2Cl2 (10 mL) were
added Et3N (207 L, 1.49 mmol), acetic anhydride (77 L,
To a solution of 20 (100 mg, 0.219 mmol) in PhCH3/CH2Cl2 (1:1,
3 mL) were added bis(trimethylsilyl)uracil (169 L, 0.657 mmol)
and N,N-diisopropylethylamine (381 mL, 2.19 mmol). After cooled
m
m
m
0.812 mmol), and DMAP (8 mg, 0.068 mmol) and the mixture was
stirred at room temperature overnight. The mixture was diluted with
ether and washed with satd NaHCO3 and brine, then dried (Na2SO4).
After filtration, the filtrate was concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (n-
hexane/ethyl acetate¼9:1) to give 16 (315 mg, 99%). Compound 16
was dissolved in dry benzene (50 mL). To this mixture was added
tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5- dihydro-
imidazol-2-yl-idene][benzylidine]ruthenium(IV) dichloride (sec-
ond Grubbs catalyst, 17 mg, 0.020 mmol, 3 mol %). After the
mixture was kept under reflux for 4 h, second Grubbs catalyst
(12 mg, 0.013 mmol, 2 mol %) was added. The mixture was kept
under reflux for 8 h. The solvents were removed under reduced
pressure and the residue was purified by silica gel column
chromatography (n-hexane/ethyl acetate¼5:1) to give 19 (263 mg,
to ꢀ40 ꢁC, trimethylsilyl trifluoromethanesulfonate (129
mL,
0.657 mmol) was added and the mixture was stirred at the same
temperature for 50 min. After the reaction was quenched with
satd NaHCO3, the resulting insoluble materials were removed by
filtration. The filtrate was extracted with CHCl3 three times, and
the combined organic layer was dried over MgSO4. After filtration,
the filtrate was concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (n-hexane/ethyl
acetate¼1:2) to give a mixture of 21 and 22. The mixture was
separated by repeating silica gel column chromatography to give
21 (50 mg, 41%) and 22 (35 mg, 29%) as an amorphous foam.
Data for 21: 1H NMR (400 MHz, CDCl3)
d 1.06 (s, 9H), 2.07 (s, 3H),
2.53 (dd, J¼10.1,14.0 Hz,1H), 2.68 (dd, J¼4.8,14.0 Hz,1H), 2.90–2.96
(m, 1H), 3.78 (dd, J¼4.3, 11.6 Hz, 1H), 3.83 (dd, J¼4.8, 11.6 Hz, 1H),
5.00–5.04 (m, 1H), 5.65 (dd, J¼2.4, 8.2 Hz, 1H), 5.76 (ddd, J¼2.4, 4.3,
11.1 Hz, 1H), 6.03–6.04 (m, 1H), 6.21 (d, J¼11.1 Hz, 1H), 7.35 (d,
J¼8.2 Hz, 1H), 7.38–7.47 (m, 6H), 7.63–7.66 (m, 4H), 8.60 (br s, 1H).
92%) as a syrup. 1H NMR (400 MHz, CDCl3)
d 1.04 (s, 9H), 2.04 (s,
3H), 2.56 (dd, J¼8.2, 13.0 Hz, 1H), 2.71 (dd, J¼4.5, 13.0 Hz, 1H),
2.82–2.89 (m, 1H), 2.98 (d, J¼17.5 Hz, 1H), 3.17 (dq, J¼2.9, 17.5 Hz,
1H), 3.76 (dd, J¼3.9, 11.6 Hz, 1H), 3.82 (dd, J¼5.3, 11.6 Hz, 1H),
4.97–5.01 (m, 1H), 5.67 (dd, J¼2.4, 11.1 Hz, 1H), 5.86–5.91 (m,
1H), 7.36–7.45 (m, 6H), 7.63–7.67 (m, 4H). 13C NMR (100 MHz,
13C NMR (100 MHz, CDCl3)
d 19.2, 20.9, 23.2, 26.7, 35.8, 50.5, 62.8,
75.2, 102.6, 123.4, 127.8, 127.9, 130.0, 132.7, 135.5, 135.7, 140.7, 150.2,
163.0, 170.3. IR (KBr, cmꢀ1): 703, 1114, 1239, 1377, 1428, 1691, 1706,

Y. Yoshimura et al. / Tetrahedron 65 (2009) 9091–9102
9099
1743. EIMS (m/z): 550 (Mþ). HRMS calcd for C29H34N2O5SSi:
50 ꢁC)
d 24.4, 36.1, 50.1, 63.6, 72.9, 102.1, 122.9, 136.9, 141.7, 150.3,
550.1958, found 550.1969.
163.1. IR (KBr, cmꢀ1): 1017, 1242, 1424, 1461, 1679, 3431. EIMS (m/z):
Data for 22: 1H NMR (400 MHz, CDCl3)
d
1.06 (s, 9H), 2.04 (s, 3H),
270 (Mþ). HRMS calcd for C11H14O4N2S: 270.0674, found 270.0674.
2.78 (dd, J¼5.3, 14.5 Hz, 1H), 2.84 (dd, J¼4.3, 14.5 Hz, 1H), 3.02 (br s,
1H), 3.77 (dd, J¼3.9,12.1 Hz,1H), 3.82 (dd, J¼5.3,12.1 Hz,1H), 5.11 (dt,
J¼4.3,7.7 Hz,1H), 5.74–5.78(m, 2H),6.11–6.12(m,1H), 6.20(dq, J¼2.2,
11.1 Hz, 1H), 7.37–7.46 (m, 7H), 7.63–7.65 (m, 4H), 8.87 (br s, 1H). 13C
3.13. ((R
*
)-2-(tert-Butyldiphenylsilanyloxy)-1-((R )-3,6-
*
dihydro-2H-thiopyran-3-yl))ethanol (25)
NMR (100 MHz, CDCl3)
d
19.1, 20.9, 24.7, 26.7, 33.6, 50.5, 62.8, 75.3,
To a solution of 18 (916 mg, 2.15 mmol) in dry benzene (200 mL)
was added tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-
4,5-dihydroimidazol-2-yl-idene][benzylidine]ruthenium(IV) dichlo-
102.9, 124.5,127.7, 129.8, 132.7, 134.8, 135.4,140.8, 150.3, 163.4, 170.1. IR
(neat, cmꢀ1): 506, 703, 759, 1113, 1235, 1375, 1694. EIMS (m/z): 551
(Mþþ1). HRMS calcd for C29H34N2O5SSi: 550.1958, found 550.1976.
ride (second Grubbs catalyst, 55 mg, 6.44
mixturewaskept under refluxfor 5 h, second Grubbscatalyst(36 mg,
4.29 mol, 2 mol %)wasadded. Themixturewaskept under refluxfor
mmol, 3 mol %). After the
3.11. 1-((2S
*
,5R
*
)-5,6-Dihydro-5-(1,2-dihydroxyethyl)-2H-
m
thiopyran-2-yl)pyrimidine-2,4(1H,3H)-dione (23)
14 h. The solvents were removed under reduced pressure and the
residuewas purified bysilica gel column chromatography (n-hexane/
ethyl acetate¼9:1) to give 25 (725 mg, 85%) as a syrup. 1H NMR
To a solution of 21 (346 mg, 0.628 mmol) in MeOH (10 mL) was
added a solution of NaOMe (108 mg in 2 mL of MeOH) and the
mixture was stirred at room temperature overnight. The reactionwas
quenched by addition of dry ice and the solvents were removed
under reduced pressure. The residue was partitioned between CH2Cl2
and H2O and the separated organic layer was dried over Na2SO4. After
filtration, the filtrate was concentrated under reduced pressure. The
residue was passed through a short silica gel column (n-hexane/ethyl
acetate¼1:2) to give a deacetylated product (309 mg, 97%). The
deacetylated product was dissolved in THF (10 mL). To this mixture
was added TBAF (1 M THF solution, 0.310 mL, 0.310 mmol) and the
mixture was stirred at room temperature for 6 h. After the solvents
were removed under reduced pressure, the residue was purified by
silica gel column chromatography (CHCl3/MeOH¼4:1) to give 23
(142 mg, 87%). Analytically pure 23 was obtained by crystallization
from MeOH. Mp 146–148 ꢁC. UV (MeOH): lmax 205, 268 nm. 1H NMR
(400 MHz, CDCl3)
d
1.07 (s, 9H), 2.53 (dd, J¼6.3, 11.6 Hz, 1H),
2.57–2.66 (m, 2H), 2.78 (d, J¼3.9 Hz, 1H), 3.02 (d, J¼15.9 Hz, 1H), 3.13
(dd, J¼1.9, 15.9 Hz, 1H), 3.65–3.74 (m, 3H), 5.84 (dd, J¼2.5, 11.0 Hz,
1H), 5.92–5.96 (m,1H), 7.38–7.47 (m, 6H), 7.64–7.67 (m, 4H).13C NMR
(100 MHz, CDCl3) d 19.2, 25.2, 26.9, 27.0, 37.0, 65.2, 74.9,125.79,127.8,
128.2, 129.9, 133.0, 135.5. IR (neat) cmꢀ1: 1642, 2083, 3435. FABMS
(m/z): 399 (Mþþ1). HRMS calcd for C23H30O2SSi: 399.1814, found
399.1821.
3.14. (R
*
)-1-((R )-3,6-dihydro-2H-thiopyran-3-yl)ethane-
*
1,2-diol (26)
To a solution of 25 (509 mg, 1.28 mmol) in THF (2 mL), was
added TBAF (1 M THF solution,1.92 mL,1.92 mmol) and the mixture
was stirred at room temperature overnight. After the solvents were
removed under reduced pressure, the residue was purified by silica
gel column chromatography (n-hexane/ethyl acetate¼1:2) to give
(400 MHz, DMSO-d6)
d 2.45 (overlapped with DMSO, 1H), 2.58 (dd,
J¼5.3, 13.5 Hz, 1H), 2.65 (dd, J¼11.6, 13.5 Hz, 1H), 3.41–3.51 (m, 3H),
4.64–4.67 (m,1H), 4.90 (d, J¼4.8 Hz,1H), 5.59 (d, J¼7.7 Hz,1H), 5.77–
5.83 (m, 2H), 6.36–6.41 (m,1H), 7.62 (d, J¼7.7 Hz,1H),11.42 (br s,1H).
26 (199 mg, 97%) as a syrup. 1H NMR (400 MHz, CDCl3)
d 2.52 (br s,
1H), 2.64 (dd, J¼6.8, 13.5 Hz, 1H), 2.78 (dd, J¼4.8, 13.5 Hz, 1H), 3.07–
3.17 (m, 2H), 3.63 (dd, J¼7.2, 11.6 Hz, 1H), 3.67 (dd, J¼3.4, 11.6 Hz,
1H), 3.73–3.77 (m, 1H), 5.85 (dt, J¼1.93, 11.1 Hz, 1H), 5.97–6.03 (m,
13C NMR (100 MHz, DMSO-d6)
d 22.0, 38.0, 49.6, 63.0, 72.9, 101.5,
122.1, 136.9, 141.5, 150.2, 163.1. IR (KBr, cmꢀ1): 1215,1384,1468, 1667,
1701, 2931, 3203, 3346. EIMS (m/z): 270 (Mþ). HRMS calcd for
C11H14O4N2S: 270.0674, found 270.0674.
1H). 13C NMR (100 MHz, CDCl3)
d 25.1, 27.0, 37.1, 64.3, 75.2, 126.1,
127.9. IR (neat) cmꢀ1: 1645, 2090, 3400. EIMS (m/z): 160 (Mþ).
HRMS calcd for C7H12O2S: 160.0558, found 160.0553.
3.12. 1-((2S
*
,5S )-5,6-Dihydro-5-(1,2-dihydroxyethyl)-2H-
*
thiopyran-2-yl)pyrimidine-2,4(1H,3H)-dione (24)
3.15. (3,6-Dihydro-2H-thiopyran-3-yl)methanol (27)
To a solution of 22 (59 mg, 0.107 mmol) in MeOH (5 mL) was
added a solution of NaOMe (1 M in MeOH, 1 mL) and the mixture
was stirred at room temperature overnight. The reaction was
quenched by addition of dry ice and the solvents were removed
under reduced pressure. The residue was partitioned between
CH2Cl2 and H2O and the separated organic layer was dried over
Na2SO4. After filtration, the filtrate was concentrated under reduced
pressure. The residue was passed through a short silica gel column
(n-hexane/ethyl acetate¼1:2) to give a deacetylated product (34 mg,
74% conversion yield with recovering 9 mg of 22). The deacetylated
product was dissolved in THF (5 mL). To this mixture was added
TBAF (1 M THF solution, 0.10 mL, 0.10 mmol) and the mixture was
stirred at room temperature for 6 h. After the solvents were removed
under reduced pressure, the residue was purified by silica gel
column chromatography (CHCl3/MeOH¼4:1) followed by reverse-
phase ODS (ChromatorexÒ, Fuji silysia chemical Co) column chro-
matography (0–5% MeOH in H2O) to give 24 (18 mg, 99%) as a crystal
(crystallized from MeOH). Mp 206–208 ꢁC. UV (MeOH): lmax 201,
To a solution of 26 (30 mg, 0.187 mmol) in EtOH/H2O (1/1, 4 mL)
was added NaIO4 (40 mg, 0.187 mmol). After the mixture was stir-
red at room temperature for 1 h, NaBH4 (14 mg, 0.347 mmol) was
added. The mixture was stirred at room temperature for 3.5 h. The
resulting insoluble materials were removed by suction. After the
filtrate was concentrated under reduced pressure, the residue was
partitioned between AcOEt and 10% Na2S2O3. The organic layer was
washed with satd NaHCO3 and brine, then dried over Na2SO4. After
filtration, the filtrate was concentrated under reduced pressure,
and the residue was purified by silica gel column chromatography
(n-hexane/ethyl acetate¼1:1) to give 27 (14 mg, 57%) as a syrup. 1H
NMR (400 MHz, CDCl3) d 1.91 (br s, 1H), 2.47–2.55 (m, 1H), 2.71 (dd,
J¼5.8, 13.5 Hz, 1H), 2.85 (dd, J¼4.3, 13.5 Hz, 1H), 3.03–3.09 (m, 1H),
3.12–3.18 (m, 1H), 3.66–3.71 (m, 2H), 5.69–5.74 (m, 1H), 5.96–6.01
(m, 1H). 13C NMR (100 MHz, CDCl3)
d 25.3, 27.1, 37.1, 65.4, 126.4,
128.4. IR (neat, cmꢀ1): 1645, 3435. EIMS (m/z): 130 (Mþ). HRMS
calcd for C6H10OS: 130.0452, found 130.0450.
267 nm. 1H NMR (400 MHz, DMSO, 50 ꢁC)
d
2.53–2.59 (m, 1H), 2.80–
3.16. ((3,6-Dihydro-2H-thiopyran-3-yl)methoxy)-
(tert-butyl)diphenylsilane (28)
2.87 (m, 2H), 3.41–3.48 (m, 2H), 3.52–3.56 (m, 1H), 4.44 (br s, 1H),
4.61 (br s, 1H), 5.61 (dd, J¼1.9, 7.7 Hz, 1H), 5.78 (ddd, J¼2.4, 3.9,
11.1 Hz, 1H), 5.97 (dd, J¼2.4, 4.3 Hz, 1H), 6.34 (ddd, J¼1.9, 4.3, 11.1 Hz,
1H), 7.53 (d, J¼7.7 Hz, 1H), 11.28 (s, 1H). 13C NMR (100 MHz, DMSO,
To a solution of 27 (71 mg, 0.545 mmol) in CH2Cl2 (5 mL) were
added tert-butyldiphenylchlorosilane (210 mL, 0.818 mmol) and

9100
Y. Yoshimura et al. / Tetrahedron 65 (2009) 9091–9102
imidazole (56 mg, 0.818 mmol) and the mixture was stirred at
room temperature for 2 h. The mixture was diluted with CHCl3 and
washed with H2O and brine, then dried (Na2SO4). After filtration,
the filtrate was concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (n-hexane/
CH2Cl2¼1:2) to give 28 (198 mg, 99%) as a syrup. 1H NMR (400 MHz,
7H), 7.57–7.64 (m, 4H), 9.42 (s, 1H). 13C NMR (100 MHz, CDCl3)
d
19.2, 23.4, 26.8, 37.8, 50.4, 66.2, 102.5, 123.2, 127.7, 129.9, 132.9,
135.5, 137.6, 140.9, 150.4, 163.4. IR (neat, cmꢀ1): 702, 741, 1112, 1239,
1378, 1428, 1460, 1682, 3422. EIMS (m/z): 478 (Mþ). HRMS calcd for
C26H30N2O3SSi: 478.1746, found 478.1759.
Data for 31: 1H NMR (400 MHz, CDCl3)
d 1.06 (s, 9H), 2.69 (br s,
CDCl3)
d
1.06 (s, 9H), 2.57 (br s, 1H), 2.73 (dd, J¼6.3, 13.5 Hz, 1H),
1H), 2.85 (dd, J¼3.9, 14.0 Hz, 1H), 2.94 (dd, J¼3.9, 14.0 Hz, 1H), 3.66
(dd, J¼5.3, 10.1 Hz, 1H), 3.75 (dd, J¼8.7, 10.1 Hz, 1H), 5.72–5.76 (m,
2H), 5.96–5.97 (m, 1H), 6.13 (ddd, J¼1.9, 4.8, 10.6 Hz, 1H), 7.38–7.47
(m, 7H), 7.63–7.66 (m, 4H), 9.22 (s, 1H). 13C NMR (100 MHz, CDCl3)
2.85 (dd, J¼4.8, 13.5 Hz, 1H), 3.05 (s, 2H), 3.60–3.69 (m, 2H), 5.61 (d,
J¼10.6 Hz, 1H), 5.83–5.88 (m, 1H), 7.35–7.47 (m, 6H), 7.65–7.67 (m,
4H). 13C NMR (100 MHz, CDCl3)
d 19.2, 25.5, 26.8, 27.1, 37.7, 65.9,
125.6, 127.6, 128.7, 129.6, 133.6, 135.5. IR (neat) cmꢀ1: 701, 1112,
1428, 1642, 2858, 2931. EIMS (m/z): 368 (Mþ). HRMS calcd for
C22H28OSSi: 368.1630, found 368.1635.
d 19.2, 23.9, 26.8, 36.2, 50.4, 63.3, 102.7, 124.1, 127.8, 129.8, 133.1,
133.3, 135.5, 140.9, 150.2, 163.1. IR (neat, cmꢀ1): 703, 740, 1111, 1238,
1378, 1427, 1461, 1645, 3434. EIMS (m/z): 478 (Mþ). HRMS calcd for
C26H30N2O3SSi: 478.1746, found 478.1736.
3.17. ((3,6-Dihydro-1-oxy-2H-thiopyran-3-yl)methoxy)-
(tert-butyl)diphenylsilane (29)
3.19. 1-((2S
*
,5R )-5,6-Dihydro-5-(hydroxymethyl)-2H-
*
thiopyran-2-yl)pyrimidine-2,4-(1H,3H)-dione (6)
To a solution of 28 (246 mg, 0.67 mmol) in EtOH/H2O (1:1,
20 mL) was added NaIO4 (972 mg, 4.54 mmol) was added at room
temperature and the mixture was stirred at the same temperature
overnight. The resulting insoluble materials were removed by
suction. After the filtrate was concentrated under reduced pressure,
the residue was purified by silica gel column chromatography (n-
hexane/ethyl acetate¼1:1) to give 28 (241 mg, 94%) as a mixture of
diastereomers (less polar/more polar¼1:2). A part of the mixture
was separated by repeating silica gel column chromatography.
To a solution of 30 (137 mg, 0.286 mmol) in THF (20 mL) was
added TBAF (1 M THF solution, 429 mL, 0.429 mmol) and the mix-
ture was stirred at room temperature overnight. After the solvents
were removed under reduced pressure, the residue was purified by
silica gel column chromatography (ethyl acetate/EtOH¼9:1) to give
6 (55 mg, 80%) as a crystal (crystallized from MeOH). Mp 157–
159 ꢁC. UV (MeOH): lmax 205, 267 nm. 1H NMR (400 MHz, CD3OD,
35 ꢁC)
d
2.38–2.46 (m, 1H), 2.55 (dd, J¼10.1, 13.5 Hz, 1H), 2.63 (dd,
Data for 29 (less polar): 1H NMR (400 MHz, CDCl3)
d
1.06 (s, 9H),
J¼5.3, 13.5 Hz, 1H), 3.56 (d, J¼5.8 Hz, 2H), 5.59 (d, J¼8.2 Hz, 1H),
5.75 (ddd, J¼2.4, 4.8, 10.6 Hz, 1H), 5.84–5.86 (m, 1H), 6.18 (d,
J¼10.6 Hz, 1H), 7.62 (d, J¼8.2 Hz, 1H). 13C NMR (100 MHz, CD3OD)
2.80–2.90 (m, 2H), 3.22–3.27 (m, 1H), 3.40–3.42 (m, 1H), 3.61 (dd,
J¼6.3, 10.1 Hz, 1H), 3.70–3.78 (m, 2H), 5.60–5.69 (m, 2H), 7.38–7.47
(m, 6H), 7.63–7.65 (m, 4H). 13C NMR (100 MHz, CDCl3)
d
19.3, 26.8,
d 24.2, 39.6, 51.9, 65.5, 102.7, 124.3, 138.5, 143.4, 152.1, 166.1. IR (KBr,
38.8, 49.6, 51.0, 66.3, 118.7, 127.8, 129.9, 130.7, 133.0, 135.5. IR (neat,
cmꢀ1): 1645, 1651. EIMS (m/z): 384 (Mþ). HRMS calcd for
C22H28O2SSi: 384.1579, found 384.1570.
cmꢀ1): 559, 1098, 1241, 1353, 1384, 1462, 1616, 1699, 3034. EIMS
(m/z): 240 (Mþ). HRMS calcd for C10H12N2O3S: 240.0569, found
240.056. Anal. Calcd for C10H12N2O3S: C, 49.99; H, 5.03; N, 11.66.
Found: C, 50.27; H, 5.00; N, 11.44.
Data for 29 (more polar): 1H NMR (400 MHz, CDCl3)
d 1.06 (s,
9H), 2.76 (dd, J¼8.7, 12.1 Hz, 1H), 3.05 (br s, 1H), 3.11 (dd, J¼4.8,
13.0 Hz, 1H), 3.25 (dq, J¼2.0, 17.0 Hz, 1H), 3.39 (d, J¼17.0 Hz, 1H),
3.68 (dd, J¼6.3, 9.7 Hz, 1H), 3.73 (dd, J¼5.3, 9.7 Hz, 1H), 5.66–5.69
(m, 1H), 5.85 (dd, J¼2.2, 10.6 Hz, 1H), 7.37–7.46 (m, 6H), 7.63–7.66
3.20. 1-((2R
*
,5R )-5,6-Dihydro-5-(hydroxymethyl)-2H-
*
thiopyran-2-yl)pyrimidine-2,4-(1H,3H)-dione (32)
(m, 4H). 13C NMR (100 MHz, CDCl3)
d
19.2, 26.8, 32.7, 46.2, 46.6,
By the same procedure described above, compound 32 (31 mg,
96%) was obtained from 31 (64 mg, 0.134 mmol). Mp 183–184 ꢁC.
66.3,117.6,127.7,129.8, 130.2, 133.1,135.5. IR (neat) cmꢀ1: 702,1040,
1112, 1428, 1651, 2857. EIMS (m/z): 385 (Mþþ1). HRMS calcd for
C22H28O2SSi: 384.1579, found 384.1563.
UV (MeOH): lmax 268 nm. 1H NMR (400 MHz, CD3OD)
d 2.60–2.62
(m, 1H), 2.83 (dd, J¼2.9, 14.0 Hz, 1H), 2.96 (dd, J¼3.9, 14.0 Hz, 1H),
3.59 (dd, J¼4.8, 10.6 Hz, 1H), 3.66 (dd, J¼9.1, 10.6 Hz, 1H), 5.68 (d,
J¼7.7 Hz,1H), 5.83–5.89 (m, 2H), 6.27 (dd, J¼5.3, 9.7 Hz,1H), 7.70 (d,
3.18. 1-((2S
dihydro)-2H-thiopyran-2-yl)-pyrimidine-2,4(1H,3H)-dione
(30), and 1-((2R ,5R )-5-(tert-butyldiphenylsilanyloxymethyl-
*
,5R
*
)-5-(tert-Butyldiphenylsilanyloxymethyl-5,6-
J¼7.7 Hz, 1H). 13C NMR (100 MHz, CD3OD)
d 23.8, 37.3, 51.6, 62.5,
*
*
102.9, 124.7, 136.9, 143.4, 152.1, 166.1 IR (KBr) cmꢀ1: 1047, 1236,
1351, 1386, 1419, 1452, 1699, 3316. EIMS (m/z): 240 (Mþ). HRMS
calcd for C10H12N2O3S: 240.0569, found 240.0564. Anal. Calcd for
C10H12N2O3S: C, 49.99; H, 5.03; N, 11.66. Found: C, 50.47; H, 5.14; N,
11.32.
5,6-dihydro)-2H-thiopyran-2-yl)pyrimidine-
2,4(1H,3H)-dione (31)
To a solution of 29 (2.37 g, 0.616 mmol) in PhCH3/CH2Cl2 (1:1,
30 mL) were added bis(trimethylsilyl)uracil (475 mL, 1.85 mmol)
and N,N-diisopropylethylamine (1.07 mL, 6.16 mmol). After cooled
3.21. 1-Allylthio-2-(tert-butyldimethylsilyloxy)-3-butene (36)
to ꢀ40 ꢁC, trimethylsilyl trifluoromethanesulfonate (3649
mL,
1.85 mmol) was added and the mixture was stirred at the same
temperature for 50 min. After the reaction was quenched with satd
NaHCO3, the resulting insoluble materials were removed by filtra-
tion. The filtrate was extracted with CHCl3 three times, and the
combined organic layer was dried over MgSO4. After filtration, the
filtrate was concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (n-hexane/ethyl
acetate¼1:1) to give 30 (137 mg, 46%) and 31 (64 mg, 22%) as
amorphous foam.
To a solution of 359 (3.64 g, 25.2 mmol) in CH2Cl2 (100 mL) were
added imidazole (2.58 g, 37.8 mmol), DMAP (612 mg, 5.05 mmol),
and tert-butyl-dimethylchlorosilane (5.70 g, 37.8 mmol). After be-
ing stirred at room temperature overnight, the mixture was diluted
with CH2Cl2. The diluted mixture was washed with satd NaCl and
dried over Na2SO4. After filtration, the filtrate was concentrated
under reduced pressure and the residue was purified by silica gel
column chromatography (n-hexane/ethyl acetate¼5:1) to give 36
(6.52 g, quant) as a syrup. 1H NMR (400 MHz, CDCl3)
d 0.04 (s, 3H),
Data for 30: 1H NMR (400 MHz, CDCl3)
d
1.08 (s, 9H), 2.62 (m,
0.08 (s, 3H), 0.89 (s, 9H), 2.47 (dd, J¼6.3, 13.0 Hz, 1H), 2.55 (dd,
J¼6.3, 13.0 Hz, 1H), 3.10 (d, J¼6.8 Hz, 2H), 4.17 (dd, J¼6.3, 12.6 Hz,
1H), 5.02–5.07 (m, 3H), 5.17 (d, J¼16.9 Hz, 1H), 5.68–5.86 (m, 2H).
1H), 2.68 (dd, J¼4.8, 13.5 Hz, 1H), 2.74 (dd, J¼10.6, 13.5 Hz, 1H), 3.75
(d, J¼4.3 Hz, 2H), 5.60 (dd, J¼1.9, 8.2 Hz, 1H), 5.78 (dd, J¼2.4,
11.1 Hz, 1H), 6.01–6.02 (m, 1H), 6.20 (d, J¼11.1 Hz, 1H), 7.41–7.46 (m,
13C NMR (100 MHz, CDCl3)
d
ꢀ4.73, ꢀ4.47, 18.2, 25.9, 35.6, 38.3,

Y. Yoshimura et al. / Tetrahedron 65 (2009) 9091–9102
9101
73.7, 115.0, 117.0, 134.6, 140.2. IR (neat, cmꢀ1): 777, 837, 1256, 2930.
EIMS (m/z): 258 (Mþ). HRMS calcd for C13H26OSSi: 258.1474, found
258.1485.
same temperature for 10 min. After the reaction was quenched
with satd NaHCO3, the resulting insoluble materials were removed
by filtration. The filtrate was extracted with CHCl3 three times, and
the combined organic layer was dried over MgSO4. After filtration,
the filtrate was concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (n-hexane/ethyl
acetate¼3:2) to give a mixture of 39, 40, and 41 (61 mg, 89%) as an
amorphous foam.
3.22. 3-(tert-Butyldimethylsilyloxy)-6H-
dihydrothiopyran (37)
To a solution of 36 (653 mg, 2.53 mmol) in dry benzene (150 mL)
was added tricyclohexylphosphine-[1,3-bis(2,4,6-trimethylphenyl)-
4,5-dihydroimidazol-2-yl-idene][benzylidine]ruthenium(IV) dichlo-
3.25. 1-((3S
*
,4R )-3-(tert-Butyldimethylsilyloxy)-3,4-dihydro-
*
ride (second Grubbs catalyst, 55 mg, 6.44 mmol, 3 mol %). After the
2H-thiopyran-4-yl)-pyrimidine-2,4(1H,3H)-dione (41)
mixture was kept under reflux for 5 h, second Grubbs catalyst (99 mg,
0.12 mmol, 3 mol %) was added. The mixture was kept under reflux
for 9.5 h. Another 68 mg (0.08 mmol, 2 mol %) of second Grubbs
catalyst was added. The mixture was kept under reflux for 13 h. The
solvents were removed under reduced pressure and the residue was
purified by silica gel column chromatography (n-hexane/ethyl
acetate¼99.9:0.1) to give 37 (537 mg, 92%) as a syrup. 1H NMR
By the same procedure described above, a mixture of 39, 40, and
41 (63.5 mg, 0.186 mmol) was retreated. Then, the mixture was
stirred at room temperature for 10 days. After the reaction was
quenched with satd NaHCO3, the resulting insoluble materials were
removed by filtration. The filtrate was extracted with CHCl3 three
times, and the combined organic layer was dried over MgSO4. After
filtration, the filtrate was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (CHCl3/
MeOH¼97:3) to give 41 (42.5 mg, 67%) as an amorphous foam. 1H
(400 MHz, CDCl3) d 0.00 (s, 6H), 0.80 (s, 9H), 2.50–2.60 (m, 2H), 2.69
(d, J¼2.3,17.7 Hz, 1H), 3.17 (dd, J¼2.3, 17.7 Hz, 1H), 4.29–4.33 (m, 1H),
5.58 (d, J¼11.6 Hz, 1H), 5.70–5.74 (m, 1H). 13C NMR (100 MHz, CDCl3)
d
ꢀ4.75, ꢀ4.56,18.1, 24.6, 25.8, 31.6, 65.8,125.0,133.3. IR (neat) cmꢀ1
:
NMR (600 MHz, CDCl3)
d
0.08 (s, 6H), 0.85 (s, 9H), 2.78 (ddd, J¼1.3,
776, 836, 871, 1074, 1256, 2857, 2929, 2956. EIMS (m/z): 230 (Mþ).
3.1, 12.9 Hz, 1H), 3.11 (dd, J¼9.4, 12.9 Hz, 1H), 4.13 (ddd, J¼3.1, 7.1,
9.4 Hz, 1H), 5.05–5.10 (m, 1H), 5.47 (dd, J¼3.2, 10.0 Hz, 1H), 5.74 (dd,
J¼2.6, 8.1 Hz, 1H), 6.33 (dd, J¼1.3, 2.1, 10.0 Hz, 1H), 7.20 (d, J¼8.1 Hz,
HRMS calcd for C11H22OSSi: 230.1161, found 230.1180.
1H), 8.07 (br s, 1H). 13C NMR (150 MHz, CDCl3)
20.20, 23.48, 25.44, 25.74, 31.30, 67.89, 102.45, 117.94, 150.58,
162.53. IR (neat, cmꢀ1): 1248, 1684, 3418. EIMS (m/z): 340 (Mþ).
HRMS calcd for C15H24N2O3SSi: 340.1277, found 340.1284.
d
ꢀ5.06, ꢀ4.57, 17.67,
3.23. 3-(tert-Butyldimethylsilyloxy)-6H-dihydrothiopyran-
1-oxide (38)
To a solution of 37 (1.21 g, 5.23 mmol) in EtOH/H2O (1:1, 15 mL)
was added NaIO4 (1.23 g, 5.75 mmol) was added at room temper-
ature and the mixture was stirred at the same temperature over-
night. The resulting insoluble materials were removed by suction.
After the filtrate was concentrated under reduced pressure, the
residue was purified by silica gel column chromatography (CHCl3/
MeOH¼97:3) to give 38 (1.20 g, 95%) as a mixture of diastereomers
(less polar/more polar¼1:2). A part of the mixture was separated by
repeating silica gel column chromatography.
3.26. 1-((2R
*
,5S )-5,6-Dihydro-5-hydroxy-2H-thiopyran-2-
*
yl)pyrimidine-2,4(1H,3H)-dione (42 (trans))
To a solution of 39 and 40 (852 mg, 2.5 mmol) in THF (100 mL)
was added a THF solution of TBAF (1 M, 3.75 mL, 3.75 mmol). The
mixture was stirred at room temperature overnight. After the sol-
vents were removed under reduced pressure, The residue was
purified by silica gel column chromatography (ethyl acetate/
EtOH¼10:1), then, crystallization from MeOH to give 42 (98 mg,
37%) as a crystal. Mp 199–201 ꢁC. UV (MeOH): lmax 210, 266 nm. 1H
Data for 38 (less polar): 1H NMR (600 MHz, CDCl3)
d 0.12 (s, 6H),
0.91 (s, 9H), 2.97 (t, J¼10.6 Hz,1H), 3.30 (dq, J¼2.9,12.5 Hz,1H), 3.51
(dddd, J¼1.5, 3.3, 5.9, 12.5 Hz, 1H), 3.73 (ddt, J¼3.7, 7.0, 10.6 Hz, 1H),
4.57–4.61 (m, 1H), 5.63 (ddt, J¼1.8, 7.0, 10.6 Hz, 1H), 5.77 (dt, J¼2.6,
10.6 Hz,1H). 13C NMR (150 MHz, CDCl3)
d
ꢀ4.8, ꢀ4.6,18.1, 25.7, 49.2,
NMR (600 MHz, CD3OD)
d
2.81 (dd, J¼5.9, 13.9 Hz, 1H), 3.02 (dd,
56.2, 65.3, 117.4, 134.1. IR (neat, cmꢀ1): 776, 838, 1007, 1081, 1259,
1474, 2858, 2954. EIMS (m/z): 247 (Mþþ1). Anal. Calcd for
C11H22O2SSi: C, 53.61; H, 9.00. Found: C, 53.50; H, 9.11.
J¼3.7, 13.9 Hz, 1H), 4.34–4.37 (m, 1H), 5.69 (d, J¼8.1 Hz, 1H), 5.84
(ddd, J¼1.5, 4.0, 10.6 Hz, 1H), 6.11 (dd, J¼1.8, 4.0 Hz, 1H), 6.28 (ddd,
J¼2.2, 4.0, 10.6 Hz, 1H), 7.58 (d, J¼8.1 Hz, 1H). 13C NMR (150 MHz,
Data for 38 (more polar): 1H NMR (600 MHz, CDCl3)
d 0.12 (d,
CD3OD)
d 32.0, 51.9, 62.1, 103.2, 125.8, 138.3, 143.4, 152.0, 166.0. IR
(KBr, cmꢀ1): 1034, 1247, 1395, 1427, 1629, 1701, 3373. EIMS (m/z):
J¼2.93 Hz, 6H), 0.91 (s, 9H), 2.85 (ddd, J¼1.5, 7.3, 12.8 Hz, 1H), 3.15–
3.31 (m, 2H), 3.55 (ddd, J¼1.5, 4.8, 13.5 Hz, 1H), 4.80 (dddd, J¼1.46,
5.9, 7.3, 11.7 Hz, 1H), 5.65 (ddt, J¼1.5, 3.7, 10.6 Hz, 1H), 5.92 (dddd,
226 (Mþ). HRMS calcd for C9H10N2O3S: 226.0412, found 226.0416.
J¼2.2, 4.8, 5.9, 10.6 Hz, 1H). 13C NMR (150 MHz, CDCl3)
d
ꢀ4.74,
3.27. 3-Benzoyl-1-((2R
*
,5R )-5,6-dihydro-5-(tert-butyl-
*
ꢀ4.66, 18.1, 25.7, 47.0, 52.1, 62.9, 117.7, 132.9. IR (neat, cmꢀ1): 471,
475, 492, 778, 837, 1042, 1078, 1254, 2929. EIMS (m/z): 246 (Mþ).
Anal. Calcd for C11H22O2SSi: C, 53.61; H, 9.00. Found: C, 53.24; H,
9.00.
dimethylsilyloxy)-2H-thiopyran-2-yl)pyrimidine-
2,4(1H,3H)-dione (45) and 3-benzoyl-1-((2S
5,6-dihydro-5-(tert-butyldimethylsilyloxy)-
2H-thiopyran-2-yl)pyrimidine-2,4(1H,3H)-
dione (43)
*
,5R )-
*
3.24. 1-((2R
2H-thiopyran-2-yl)-pyrimidine-2,4(1H,3H)-dione (39 (cis)), 1-
((2R ,5S )-5,6-dihydro-5-(tert-butyldimethylsilyloxy)-2H-
*
,5R )-5,6-Dihydro-5-(tert-butyldimethylsilyloxy)-
*
To a solution of 39 and 40 (348 mg, 1.02 mmol) in CH2Cl2
(10 mL) were added benzoyl chloride (237 L, 2.04 mmol), Et3N
(356 L, 2.56 mmol), and DMAP (12 mg, 0.102 mmol). The mixture
*
*
m
thiopyran-2-yl)pyrimidine-2,4(1H,3H)-dione (40 (trans))
m
(Table 1, entry 4)
was stirred at room temperature overnight. After the reaction was
quenched by adding MeOH (2 mL), the mixture was partitioned
between CHCl3 and H2O. The separated organic layer was dried
over MgSO4. After filtration, the filtrate was concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (n-hexane/ethyl acetate¼2:1) to give 45 (194 mg,
44%) and 43 (containing small amount of 44, 261 mg, 56%).
To a solution of 38 (less polar, 50 mg, 0.20 mmol) in PhCH3/
CH2Cl2 (1:1, 2 mL) were added bis(trimethylsilyl)uracil (156
m
L,
0.61 mmol) and N,N-diisopropylethylamine (353
mL, 2.03 mmol).
After cooled to ꢀ40 ꢁC, trimethylsilyl trifluoromethanesulfonate
(120 mL, 0.61 mmol) was added and the mixture was stirred at the

9102
Y. Yoshimura et al. / Tetrahedron 65 (2009) 9091–9102
Data for 45: 1H NMR (400 MHz, CDCl3)
d
0.00 (s, 6H), 0.80 (s, 9H),
the High Technology Research Program from the Ministry of Edu-
2.50–2.52 (m, 2H), 4.28 (dd, J¼4.4, 11.1 Hz, 1H), 5.54 (ddd, J¼1.9, 3.9,
cation, Culture, Sports, Science and Technology of Japan.
11.1 Hz,1H), 5.71–5.74 (m, 2H), 6.07 (d, J¼11.1 Hz,1H), 7.29–7.53 (m,
4H), 7.79–7.81 (m, 2H). 13C NMR (100 MHz, CDCl3)
d
ꢀ4.98, ꢀ4.95,
18.0, 25.6, 27.2, 49.8, 65.7, 102.7, 121.9, 129.1, 130.4, 131.2, 135.0,
140.5, 141.8, 149.2, 161.8, 168.4. IR (neat) cmꢀ1: 773, 1020, 1260,
1674, 1708, 1748, 2853, 2924, 2959. EIMS (m/z): 444 (Mþ). Anal.
Calcd for C22H28N2O4SSi: C, 59.43; H, 6.35; N, 6.30. Found: C, 59.38;
H, 6.44; N, 6.16.
References and notes
1. (a) Yoshimura, Y.; Iino, T.; Matsuda, A. Tetrahedron Lett. 1991, 32, 6003–6006; (b)
Iino, T.; Yoshimura, Y.; Matsuda, A. Tetrahedron 1994, 50, 10397–10406; (c)
Yoshimura, Y.; Saitoh, K.; Ashida, N.; Sakata, S.; Matsuda, A. Bioorg. Med. Chem.
Lett. 1994, 4, 721–724; (d) Yoshimura, Y.; Satoh, H.; Sakata, S.; Ashida, N.;
Miyazaki, S.; Matsuda, A. Nucleosides Nucleotides 1995, 14, 427–429; (e)
Yoshimura, Y.; Ohta, M.; Imahori, T.; Imamichi, T.; Takahata, H. Org. Lett. 2008,
10, 3449–3452.
Data for 43: 1H NMR (400 MHz, CDCl3)
d 0.13 (s, 3H), 0.14 (s, 3H),
0.92 (s, 9H), 2.84 (dd, J¼4.4, 14.0 Hz, 1H), 2.96 (dd, J¼8.2, 14.0 Hz,
1H), 4.51–4.54 (m, 1H), 5.71 (dd, J¼2.4, 10.6 Hz, 1H), 5.88 (d,
J¼8.2 Hz, 1H), 6.14 (d, J¼10.6 Hz, 1H), 6.36 (d, J¼2.4 Hz, 1H), 7.44 (d,
J¼8.2 Hz, 1H), 7.49–7.53 (m, 2H), 7.64–7.68 (m, 1H), 7.93–7.95 (m,
2. (a) Yoshimura, Y.; Kitano, K.; Satoh, H.; Watanabe, M.; Miura, S.; Sakata, S.;
Sasaki, T.; Matsuda, A. J. Org. Chem. 1996, 61, 822–823; (b) Yoshimura, Y.; Ki-
tano, K.; Yamada, K.; Satoh, H.; Watanabe, M.; Miura, S.; Sakata, S.; Sasaki, T.;
Matsuda, A. J. Org. Chem. 1997, 62, 3140–3152; (c) Yoshimura, Y.; Watanabe, M.;
Satoh, H.; Ashida, N.; Ijichi, K.; Sakata, S.; Machida, H.; Matsuda, A. J. Med. Chem.
1997, 40, 2177–2183; (d) Machida, H.; Ashida, N.; Miura, S.; Endo, M.; Yamada,
K.; Kitano, K.; Yoshimura, Y.; Sakata, S.; Ijichi, O.; Eizuru, Y. Antiviral Res. 1998,
39, 129–137; (e) Miura, S.; Yoshimura, Y.; Endo, M.; Machida, H.; Matsuda, A.;
Tanaka, M.; Sasaki, T. Cancer Lett. 1998, 129, 103–110; (f) Satoh, H.; Yoshimura,
Y.; Sakata, S.; Miura, S.; Machida, H.; Matsuda, A. Bioorg. Med. Chem. Lett. 1998,
8, 989–992; (g) Satoh, H.; Yoshimura, Y.; Watanabe, M.; Ashida, N.; Ijichi, K.;
Sakata, S.; Machida, H.; Matsuda, A. Nucleosides Nucleotides 1998, 17, 65–79; (h)
Yamada, K.; Sakata, S.; Yoshimura, Y. J. Org. Chem. 1998, 63, 6891–6899; (i)
Yoshimura, Y.; Endo, M.; Kitano, K.; Yamada, K.; Sakata, S.; Miura, S.; Machida,
H. Nucleosides Nucleotides 1999, 18, 815–820; (j) Yoshimura, Y.; Endo, M.; Miura,
S.; Sakata, S. J. Org. Chem. 1999, 64, 7912–7920; (k) Yoshimura, Y.; Endo, M.;
Sakata, S. Tetrahedron Lett. 1999, 40, 1937–1940; (l) Yoshimura, Y.; Kitano, K.;
Yamada, K.; Sakata, S.; Miura, S.; Ashida, N.; Machida, H. Bioorg. Med. Chem.
2000, 8, 1545–1558; (m) Miura, S.; Yamada, K.; Kano, F.; Yoshimura, Y. Biol.
Pharm. Bull. 2004, 27, 520–523.
3. A part of this work has been reported: Yoshimura, Y.; Yamazaki, Y.; Kawahata,
M.; Yamaguchi, K.; Takahata, H. Tetrahedron Lett. 2007, 48, 4519–4522.
4. Yoshimura, Y.; Kuze, T.; Ueno, M.; Komiya, F.; Haraguchi, K.; Tanaka, H.; Kano,
F.; Yamada, K.; Asami, K.; Kaneko, N.; Takahata, H. Tetrahedron Lett. 2006, 47,
591–594.
5. (a) Lim, M. H.; Kim, H. O.; Moon, H. R.; Chun, M. W.; Jeong, L. S. Org. Lett. 2002,
4, 529–531; (b) Naka, T.; Minakawa, N.; Abe, H.; Kaga, D.; Matsuda, A. J. Am.
Chem. Soc. 2000, 122, 7233–7243; (e) Paquette, L. A.; Dong, S. J. Org. Chem. 2005,
70, 5655–5664; (d) Choo, H.; Chen, X.; Yadav, V.; Wang, J.; Schinazi, R. F.; Chu,
C. K. J. Med. Chem. 2006, 49, 1635–1647.
2H). 13C NMR (100 MHz, CDCl3)
d
ꢀ4.54, ꢀ0.02, 18.1, 25.7, 33.3, 51.6,
64.0, 103.3, 124.7, 129.2, 130.5, 131.3, 135.2, 139.5, 140.7, 161.8, 168.4.
IR (neat, cmꢀ1): 773, 1029, 1258, 1668, 1704, 1747, 2927. EIMS (m/z):
444 (Mþ). HRMS calcd for C22H28N2O4SSi: 444.1539, found
444.1536.
3.28. 1-((2R
*
,5R )-5,6-Dihydro-5-hydroxy-2H-thiopyran-
*
2-yl)pyrimidine-2,4(1H,3H)-dione (46)
To a solution of 45 (194 mg, 0.436 mmol) in THF (15 mL) were
added acetic acid (75 mL, 1.31 mmol) and TBAF (1.09 mL, 1.09 mmol).
The mixture was stirred at room temperature overnight. After the
solvents were removed under reduced pressure, the residue was
purified by silica gel column chromatography (EtOAc) to give
desilylated product (143 mg, 99%). A part of desilylated product
(43 mg, 0.130 mmol) was dissolved in dry MeOH (5 mL). To this
solution was added NaOMe (27 mg, 0.5 mmol). The mixture was
stirred at room temperature overnight, then neutralized by addi-
tion of dry ice. After the solvents were removed under reduced
pressure, the residue was purified by silica gel column chroma-
tography (ethyl acetate/EtOH¼8:1) to give 46 (28 mg, 95%) as
a crystal. Mp 153–155 ꢁC. UV (MeOH): lmax 268 nm. 1H NMR
6. Feldman, K. S. Tetrahedron 2006, 62, 5003–5034.
7. (a) McDougal, P. G.; Rico, J. G.; Oh, Y.-I.; Condon, B. D. J. Org. Chem. 1986, 51,
3388–3390; (b) Escudier, J.-M.; Baltas, M.; Gorrichon, L. Tetrahedron 1993, 49,
(400 MHz, CD3OD)
d
2.65 (dd, J¼9.7, 13.0 Hz, 1H), 2.73 (dd, J¼5.3,
´
5253–5266; (c) Ayad, T.; Genisson, Y.; Baltas, M. Org. Biomol. Chem. 2005, 3,
13.0 Hz,1H), 4.30 (ddd, J¼2.4, 5.3, 9.7 Hz,1H), 5.70 (d, J¼8.2 Hz,1H),
5.76 (ddd, J¼2.4, 4.3,10.6 Hz,1H), 5.84–5.86 (m,1H), 6.25 (dd, J¼1.4,
10.6 Hz, 1H), 7.72 (d, J¼8.2 Hz, 1H). 13C NMR (100 MHz, CD3OD)
2626–2631.
8. (a) Ichikawa, E.; Yamamura, S.; Kato, K. Tetrahedron Lett. 1999, 40, 7385–7388;
(b) Schmidt, B.; Pohler, M.; Costisella, B. Tetrahedron 2002, 58, 7951–7958.
9. Evans, D. A.; Campos, K. R.; Tedrow, J. S.; Michael, F. E.; Gagne´, M. R. J. Am. Chem.
Soc. 2000, 122, 7905–7920.
10. Some examples of apio-nucleosides: (a) Nair, V.; Jahnke, T. S. Antimicrob. Agents
Chemother. 1995, 39, 1017–1029; (b) Jeong, L.-S.; Kim, H. O.; Moon, H. R.; Hong,
J. H.; Yoo, S. J.; Choi, W. J.; Chun, M. W.; Lee, C.-K. J. Med. Chem. 2001, 44, 806–
813; (c) Moon, H. R.; Kim, H. O.; Lee, S. K.; Choi, W. J.; Chun, M. W.; Jeong, L.-S.
Bioorg. Med. Chem. 2002, 10, 1499–1507; (d) Jin, Z. D.; Kwon, S. H.; Moon, H. R.;
Gunaga, P.; Kim, H. O.; Kim, D.-K.; Chun, M. W.; Jeong, L.-S. Bioorg. Med. Chem.
2004, 12, 1101–1109.
d
18.4, 27.8, 51.1, 58.3, 65.6, 103.0, 124.2, 141.3, 143.2. IR (KBr, cmꢀ1):
1042, 1246, 1615, 1665, 1699. EIMS (m/z): 226 (Mþ). HRMS calcd for
C9H10N2O3S: 226.0412, found 226.0416.
Acknowledgements
The authors greatly appreciate Dr. Yoshiyuki Tanaka, Graduate
School of Pharmaceutical Sciences, Tohoku University, for his
helpful advices. This work was supported, in part, by a Grant-in-Aid
for Scientific Research (No. 18590103, 00230813), JSPS (Y.Y.) and by
11. Holy, A. Current Protocols in Nucleic Acid Chemistry; John Wiley and Sons: New
York, NY, 2005; Chapter 14, Unit 14 2.
12. Denance´, M.; Legay, R.; Gaumont, A.-G.; Gulea, M. Tetrahedron Lett. 2008, 49,
4329–4332.