Design and synthesis of a novel ring-expanded 4′-thio-apio-nucleoside derivatives

Article abstract of DOI:10.1016/j.tetlet.2007.04.139

The synthesis of a ring-expanded 4′-thio-apio-nucleoside derivative 4, designed to serve as a potential anti-HIV agent, is described. The epoxy alcohol derivative 10, prepared from 2-butene-1,4-diol, was converted to an allylsulfide derivative 13 in 3 ste

Full text of DOI:10.1016/j.tetlet.2007.04.139

Tetrahedron Letters 48 (2007) 4519–4522
Design and synthesis of a novel ring-expanded
40-thio-apio-nucleoside derivatives
Yuichi Yoshimura,a,* Yoshiko Yamazaki,a Masatoshi Kawahata,b
Kentaro Yamaguchib and Hiroki Takahataa,*
aTohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan
bFaculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, 1314-1 Shido, Sanuki-shi,
Kagawa 769-2193, Japan
Received 2 April 2007; revised 24 April 2007; accepted 27 April 2007
Available online 1 May 2007
Abstract—The synthesis of a ring-expanded 40-thio-apio-nucleoside derivative 4, designed to serve as a potential anti-HIV agent, is
described. The epoxy alcohol derivative 10, prepared from 2-butene-1,4-diol, was converted to an allylsulfide derivative 13 in 3 steps.
Ring-closing-metathesis of 13 gave the dihydrothiopyran derivative 20, which was further converted into sulphoxide 24. A Pum-
merer-type thioglycosylation reaction of 24 with a persilylated uracil derivative, followed by conversion to a cytosine derivative
and deprotection, gave a racemic mixture of the ring-expanded 40-thio-apio-nucleoside derivative 4 in good yield.
Ó 2007 Elsevier Ltd. All rights reserved.
C
C
C
C
In recent AIDS treatment, referred to as HAART
(highly active anti-retroviral therapy), nucleoside reverse
transcriptase inhibitors (NRTIs) play a critical role.1
Nucleoside derivatives containing a sulfur atom in a
sugar or a pseudosugar skeleton, for example, 40-thio-
nucleosides, are of particular interest: Lamivudine2
(3TC, 1, Chart 1), an NRTI used in the clinical treat-
ment of AIDS, may formally belong to a category of
D-iso-40-thionucleosides.
S
HO
HO
HO
HO
S
O
2
1
S
S
OH
3
4
In addition, it was recently reported that L-20,30-di-
deoxydidehydrocytidine (L-D4C, 2) has anti-HIV-1
activity.3 We previously reported on the design and
synthesis of iso-40-thiocytidine 3, but, no activity against
HIV was observed.4 In our continuous attempts to de-
sign and synthesize novel nucleoside derivatives,4,5 we
designed a dihydrothiopyranylcytosine derivative 4 as
a potential anti-HIV agent. Compound 4 can be consid-
ered to be a ring-expanded 40-thio-apio-nucleoside deriv-
ative designed from L-D4C. The apio-nucleoside is
another novel class of nucleoside derivatives,6 some of
which are known to have anti-HCMV activity and cyto-
toxicity.6b,c To the best of our knowledge, dihydrothio-
pyranylcytosine derivatives similar to 4 as well as its 40-
B
B
HO
HO
O
X
6: X = H
7: X = OH
5
Chart 1.
oxy congener 5 have not been reported. From the stand-
point of nucleosides built on a cyclohexene scaffold, the
ring-expanded 40-thio-apio-nucleoside derivative 4 is un-
ique. The synthesis of cyclohexenyl nucleosides 6 and 7
were recently reported7 and the latter was proven to
have anti-herpes virus activity.7b,c Herein, we report
on the racemic synthesis of 4 starting from 2-butene-
1,4-diol (Chart 1).
*
Corresponding authors. Tel.: +81 22 727 0145 (Y.Y.); e-mail:
yoshimura@tohoku-pharm.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.139

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Y. Yoshimura et al. / Tetrahedron Letters 48 (2007) 4519–4522
The monosilylation of 2-butene-1,4-diol by a known
method8a,c gave an allyl alcohol 9 in 99% yield. It has
already been reported that the Sharpless asymmetric
epoxidation of 9 gives the corresponding epoxy alcohol
with high enatiomeric excess.8b,c However, we did not
attempt to synthesize the target compound in an enatio-
merically pure form, because the antiviral evaluation of
the racemic target compounds would give results regard-
ing both enatiomers in one procedure. We intended to
synthesize a racemic mixture of 4 and treated allyl alco-
hol 9 with mCPBA in CH2Cl2 to give ( )-10 in 95%
yield. Cleavage of the epoxy ring of 10 was achieved
by a known method8b,c,9 with minor modifications to
give the vinyl diol 11 in good yield. Selective mono-
tosylation at the primary hydroxyl group of 11 was
attempted. However, all efforts were unsuccessful: the
typical reaction for tosylation (TsCl, Et3N, DMAP,
CH2Cl2) gave a ditosylated derivative as the major prod-
uct (data not shown).10 Instead of the tosyl group, a
more bulky 2,4,6-triisopropylbenzenesulfonyl (TPS)
group was next employed. The reaction of 11 with
TPSCl, triethylamine, and DMAP in CH2Cl2 gave the
desired mono-TPS derivative 12 in 97% yield. It is note-
worthy that no di-TPS derivative was detected in the
reaction mixture. A nucleophilic substitution reaction
of 12 with allyl mercaptan (10 equiv) and DBU (2 equiv)
in Et2O gave an allyl sulfide and oxetane derivatives in
51% and 16%, respectively, after acetylation (see sup-
porting information). To suppress the formation of the
oxetane derivative which was formed via an intramolec-
ular SN2 reaction, the substitution reaction was per-
formed using allyl mercaptan as the solvent.11 As a
result, the allyl sulfide 13 was obtained in 77% yield with
only trace amounts of the oxetane derivative 14. The
fact that the reaction of 14 with allyl mercaptan and
DBU did not proceed at all, suggests that the substitu-
tion of the TPS group occurs via a direct SN2 reaction
(Scheme 1).
mCPBA
CH2Cl2
O
rt, overnight
RO
OH
RO
OH
10 (95%)
TBDPSCl
NaH, THF
rt, 1h
8 : R = H
9 : R = TBDPS (99%)
ArSO2Cl
DMAP, Et3N
CH2Cl2, rt, 5h
CH2=CHMgCl
CuI, Et2O
OH
−10 oC, 45 min
RO
OH
11: R = TBDPS (79%)
OH
DBU
allyl mercaptan
TBDPSO
rt, 6h
OSO2Ar
12 : Ar = 2,4,6-tri-iso-propylphenyl (97%)
OH
O
TBDPSO
S
TBDPSO
+
13 (77%)
14 (trace)
Scheme 1. Synthesis of ally sulfide derivative 13.
(1:1, v/v) at ꢀ40 °C gave the dihydorothiopyranyluracil
derivatives 17 and 18 in 41% and 29% yields, respec-
tively (Scheme 2). It is noteworthy that the adducts
reacted at the 30-position, formed via the c-alkylation
of an allylic sulfonium intermediate, were not observed.
The stereochemistry of the dihydorothiopyranyluracil
derivative 17 was elucidated by NOE experiments and
In order to construct a dihydrothiopyran skeleton,
RCM reaction of 13 was attempted. The reaction of
13 with 1st Grubbs catalyst, after the acetylation of
the hydroxyl group, gave dihydrothiopyran 15 in poor
yield (data not shown). In contrast, the use of the 2nd
Grubbs catalyst in refluxing benzene11 resulted in a
more efficient reaction, giving the desired 15 in 92%
yield.
1) Ac2O, Et3N
DMAP
CH2Cl2
OAc
rt, overnight
(99%)
TBDPSO
X
13
2) 2nd Grubbs cat.
PhH, reflux, 12h
(92%)
15 : X = S
16 : X =
S
O
3) NaIO4
EtOH, H2O
rt, overnight
(90%)
To achieve the synthesis of a thionucleoside, the forma-
tion of a thioglycosyl bond is a key reaction. The Pum-
merer-type thioglycosylation reaction, developed by
us,12 appeared to be the most suitable for the synthesis
of our target compound. Prior to the synthesis of the
ring-expanded 40-thio-apio-D4C 4, the Pummerer-type
thioglycosylation reaction of 16 derived from 15 was
examined as a model reaction. Upon treatment with
NaIO4 in EtOH/H2O overnight, compound 15 was oxi-
dized to give a diastereomeric mixture of the corre-
sponding sulphoxide 16 in 90% yield.
Bis(TMS)uracil
TMSOTf
DIPEA
PhCH3, CH2Cl2
−40oC, 50 min
AcO
H
TBDPSO
S
O
N
NH
17 : cis-isomer (41%)
18 : trans-isomer (29%)
O
We found that the Pummerer-type thioglycosylation of
the sulphoxide 16 by treatment with bis(trimethylsi-
lyl)uracil, TMSOTf, and DIPEA in toluene and CH2Cl2
Scheme 2. Synthesis of dihydrothiopyran derivative 16 and its
Pummerer-type thioglycosylation.

Y. Yoshimura et al. / Tetrahedron Letters 48 (2007) 4519–4522
1) 2nd Grubbs cat.
4521
1) NaOMe
MeOH
rt, overnight
(74%)
HO
PhH, reflux, 12h
(85%)
2) TBAF, THF, rt
overnight (97%)
H
HO
OH
S
H
O
RO
18
S
N
NH
2) TBAF
THF
rt, 6h
13
R = TBDPS
O
19 (99%)
20 : R = TBDPS
21 : R = H
Scheme 3. Synthesis of dihydrothiopyranyluracils 19.
1) NaIO4
EtOH, H2O
0 oC, 1h
2) NaBH4, rt, 3.5h
(57%, 2 steps)
was determined to be the cis-isomer (data not shown).
On the other hand, compound 18, after deprotection
with sodium methoxide and subsequent treatment with
TBAF, gave dihydrothiopyranyluracil 19 (Scheme 3).
RO
X
22 : R = H, X = S
23 : R = TBDPS, X = S
24 : R = TBDPS, X = S
3) TBDPSCl, imidazole
CH2Cl2, rt, 2h (99%)
4) NaIO4, EtOH, H2O
rt, overnight (94%)
Based on the X-ray crystallographic analysis of 19 as
depicted in Figure 1, its relative stereochemistry could
be unambiguously confirmed as ‘trans’.
O
Scheme 4. Synthesis of dihydrothiopyran derivative 24.
We next attempted the synthesis of the ring-expanded
40-thio-apio-nucleoside 4. As in the case of the acetylated
derivative mentioned above, the RCM-reaction of 13,
without protection of the secondary hydroxyl group,
catalyzed by 2nd Grubbs catalyst effectively gave rise
to the dihydrothiopyran derivative 20 in 85% yield.
The oxidative cleavage of the side-chain of 20 appeared
problematic since the reaction needed to proceed with-
out oxidation of the sulfur in the dihydrothiopyran ring.
Fortunately, the conversion of 15 to the sulphoxide 16
required long periods of time for completion (vide
supra). This suggests that oxidative cleavage could be
carried out selectively if the cleavage were sufficiently
fast that the sulfur atom would not be oxidized. There-
fore, after deprotection of the TBDPS group by treat-
ment with TBAF, compound 21 thus obtained was
treated with NaIO4 followed by sodium borohydride.
The reaction gave 3-hydroxymethyl-3,6-dihydrothio-
pyran 22 in moderate yield, as expected. Compound
22 was protected by introducing a TBDPS group at
the primary hydroxyl group, then, oxidized with NaIO4
to give the sulphoxide 24 in good yield (Scheme 4).
Bis(TMS)uracil
TMSOTf
DIPEA
TBDPSO
S
O
PhCH3, CH2Cl2
N
NH
−40 oC, 50 min
24
O
25 : cis-isomer (45%)
26 : trans-isomer (22%)
Scheme 5. Pummerer-type thioglycosylation of 24.
40-thio-apio-nucleoside derivatives 25 and 26 in 45%
and 22% yields, respectively (Scheme 5).
NOE experiments of a ring-expanded 40-thio-D4U 27
obtained by the deprotection of 25 showed that the ma-
jor procuct 25 was the cis-isomer. It is interesting to note
that the Pummerer-type thioglycosylation of 24 as well
as 16 both gave cis-isomers as major products. However,
the reason for the predominant formation of these cis-
isomers is not clear at present.
Using conditions similar to those described above, the
Pummerer-type thioglycosylation reaction of 24 with
bis(trimethylsilyl)uracil gave the desired ring-expanded
Finally, the conversion of the uracil moiety of 25 to
cytosine was achieved by treatment with TPSCl and
DMAP followed by conc. NH4OH13 to give 28, which
was further treated with TBAF to give the desired
ring-expanded 40-thio-D4C 4 in 98% yield (Scheme 6).
In summary, we report on the design of a novel ring-
expanded 40-thio-apio-D4C derivative 4 as a potential
antiviral agent including anti-HIV. 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 intro-
duction of vinyl and allyl sulfide moieties. The dihydro-
thiopyran 23 was converted to the corresponding
sulphoxide, the Pummerer-type thioglycosylation of
which gave the desired 40-thio-apio-D4C derivative.
The evaluation of anti-HIV activity of 4 is currently in
progress and will be reported elsewhere.
Figure 1. ORTEP diagram of compound 19.

4522
Y. Yoshimura et al. / Tetrahedron Letters 48 (2007) 4519–4522
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Acknowledgments
This work was supported, in part, by a Grant-in-Aid for
Scientific Research (No. 18590103), JSPS (Y.Y.) and by
the High Technology Research Program from the Min-
istry of Education, Culture, Sports, Science and Tech-
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Supplementary data
Experimental procedures and characterization data for
compounds 9–27, and 4. Supplementary data associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2007.04.139.
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