Design and synthesis of isonucleosides constructed on a 2-Oxa-6-thiabicyclo[3.2.0]heptane Scaffold (1)

Article abstract of DOI:10.1021/jo100556u

A novel method for the design and synthesis of an isonucleoside containing a 2-oxa-6-thiobicyclo[3.2.0]heptane skeleton is described. 2,2-Dimethyl-1,3- dioxan-5-one 13 was converted into a dioxabicyclohexane derivative in six steps. After cleavage of the

Full text of DOI:10.1021/jo100556u

pubs.acs.org/joc
Design and Synthesis of Isonucleosides Constructed on a
2
1
-Oxa-6-thiabicyclo[3.2.0]heptane Scaffold
,
Yuichi Yoshimura,* Kazuhiro Asami, Tomozumi Imamichi, Tomoko Okuda,
†
†
‡
§
§
Kimiyasu Shiraki, and Hiroki Takahata*
,†
†
Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan,
Laboratory of Human Retrovirology, Applied and Development Research Program,
‡
National Institute of Allergy and Infectious Diseases at Frederick, Science Applications International
Corporation-Frederick, Inc. Frederick, Maryland 21702, and Department of Virology, University of
Toyama, 2630 Sugitani, Toyama 930-0194, Japan
§
yoshimura@tohoku-pharm.ac.jp
Received March 25, 2010
A novel method for the design and synthesis of an isonucleoside containing a 2-oxa-6-thiobicyclo-
[
3.2.0]heptane skeleton is described. 2,2-Dimethyl-1,3-dioxan-5-one 13 was converted into a dioxa-
bicyclohexane derivative in six steps. After cleavage of the epoxide group with a thiol (thiophenol or
PMB mercaptan), the resulting product was subjected to the Mitsunobu reaction in the presence of a
nucleobase. The reaction proceeded via the migration of the thiosulfide groups and gave the desired
isonucleoside derivatives. In the case of a phenyl sulfide derivative, radical desulfurization followed
0
0
0
by deprotection gave 4 -substituted 2 ,3 -dideoxyisonucleosides. A PMB sulfide derivative, on the
other hand, was converted into the corresponding dimesylate, which was then treated with mercury
acetate and trifluoroacetic acid to remove the PMB group. The resulting thiol derivative was treated
with DBU to give the desired isonucleoside constructed on a 2-oxa-6-thiobicyclo[3.2.0]heptane
scaffold after deprotection. The optimized conformer of the isonucleoside was calculated using DFT
at the B3LYP/6-31G** level and was compared with that of lamivudine using model compounds.
Introduction
The most successful regimen for AIDS, referred to as HAART
highly active anti-retroviral therapy), is the use of a cocktail
(
0
Since the discovery of 3 -azidothymidine (AZT), the
search for more effective chemotherapeutic agents against
the human immunodeficiency virus (HIV), a causative agent
of anti-HIV drugs, including reverse nucleoside transcriptase
inhibitors (NRTIs), non-nucleoside reverse transcriptase inhi-
3
bitors (NNRTIs), and protease inhibitors (PIs). Although
2
for AIDS, has continued. To date, more than 20 anti-HIV
drugs have now been approved for the treatment of AIDS.
HAART is successful in controlling HIV replication and
greatly improves patient lifespan, the virus acquires resistance
4
to the drug under conditions of suboptimal treatment. There-
(
1) A part of this work has been reported: Yoshimura, Y.; Asami, K.;
Matsui, H.; Tanaka, H.; Takahata, H. Org. Lett. 2006, 8, 6015–6018.
2) (a) Cihlar, T.; Ray, A. S. Antiviral Res. 2010, 85, 39–58. and references
cited therein. (b) Yamada, K.; Sakata, S.; Yoshimura, Y. J. Org. Chem. 1998,
3, 6891–6899. (c) Yoshimura, Y.; Yamazaki, Y.; Kawahata, M.; Yamagu-
fore, the development of new drugs that are more effective in the
treatment of HIV is constantly in demand.
(
6
chi, K.; Takahata, H. Tetrahedron Lett. 2007, 48, 4519–4522. (d) Yoshimura,
Y.; Ohta, M.; Imahori, T.; Imamichi, T.; Takahata, H. Org. Lett. 2008, 10,
(3) Est ꢀe , J. A.; Cihlar, T. Antiviral Res. 2010, 85, 25–33.
(4) (a) Meadows, D. C.; Gervey-Hague, J. ChemMedChem 2006, 1,
16–29. (b) Imamichi, T. Curr. Pharm. Des. 2004, 10, 4039–4053.
3
449–3452.
DOI: 10.1021/jo100556u
r 2010 American Chemical Society
Published on Web 05/26/2010
J. Org. Chem. 2010, 75, 4161–4171 4161

Yoshimura et al.
JOCArticle
FIGURE 2. Structures of novel isonucleosides built on a 2-oxa-6-
thiobicyclo[3.2.0]heptane scaffold.
0
SCHEME 1. Strategy for the Synthesis of 4 -Substituted
Isonucleosides 6 and Bicycloisonucleosides 7
FIGURE 1. Structures of some anti-HIV nucleosides.
One simple and efficient route to obtain novel NRTIs is to
design and synthesize nucleoside analogues by structural
transformation of known anti-HIV drug based on structure-
activity relationship (SAR) studies of NRTIs. For example,
5
dideoxynucleosides, e.g., didanosine (ddI, 1) and zalcitabine
5
ddC, 2), are NRTIs and are critical components ofHAART.
(
The transposition of a nucleobase moiety of a dideoxynucleo-
0
side from the anomeric to the 2 -position creates isoadenosine
3
6
, which preserves anti-HIV activity. In addition, the trans-
,7
formation could significantly improve the stability of the
glycoside bond of dideoxynucleosides, allowing the bond to
8
be resistant to both acidic and enzymatic hydrolysis. Simi-
0
larly, a report regarding the potent anti-HIV-1 activity of 4 -
9
ethynyl nucleosides such as 4 stimulated the synthesis of the
corresponding D4T derivative 5 which proved to have anti-
1
0
0
0
0
HIV activity. From these results, 4 -substituted 2 ,3 -dideoxy-
isonucleosides 6 are generally considered to be an interesting
target as a potential anti-HIV agent (Figure 1).
exception of a report by Nair et al. concerning the synthesis
0
0
0
of the D- and L-enantiomers of 2 ,3 -dideoxy-4 -hydroxymethyl
11
derivatives of 6. However, the synthesis is time-consuming
0
To our knowledge, attempts to synthesize 4 -substituted
0
and complex, a fact that discourages further attempts to pro-
0
0
2
,3 -dideoxyisonucleosides have been quite limited, with the
duce 4 -substituted isonucleoside derivatives. As a result,
0
SARs for the 4 -substituted isonucleosides have not been
(
5) Mitsuya, H.; Broder, S. Proc. Natl. Acad. Sci. U.S.A. 1986, 83, 1911–
915.
6) (a) Nair, V.; Nuesca, Z. M. J. Am. Chem. Soc. 1992, 114, 7951–7953.
b) Huryn, D. M.; Sluboski, B. C.; Tam, S. Y.; Weigele, M.; Sim, I.;
Anderson, B. D.; Mitsuya, H.; Border, S. J. Med. Chem. 1992, 35, 2347–
354. (c) Nair, V. In Recent Advances in Nucleosides; Chu, C. K., Eds.; Elsevier
Science B.V.: Amsterdam, 2002; pp 149-166 and references cited therein.
7) Recent reports regarding isonucleosides: (a) Est ꢀe vez, L.; Besada, P.;
explored in any detail. To overcome these problems, a more
efficient and straightforward methodology for the synthesis
of isonucleosides that is applicable to the preparation of the
1
(
(
0
4
fore, we focused on addressing these problems and developed a
-substituted derivatives would be highly desirable. There-
2
0
(
strategy for the synthesis of 4 -hydroxymethylisonucleosides
which could serve as an intermediate in the synthesis of a variety
Fall, Y.; Teijeira, M.; Ter ꢀa n, C. Synthesis 2010, 425–430. (b) D’Alonzo, D.;
Van Aerschot, A.; Guaragna, A.; Palumbo, G.; Schepers, G.; Capone, S.;
Rozenski, J.; Herdewijn, P. Chem.;Eur. J. 2009, 15, 10121–31. (c) Sanki,
A. K.; Bhattacharya, R.; Atta, A. K.; Suresh, C. G.; Pathak, T. Tetrahedron
008, 64, 10406–10416. (d) Bouisset, T.; Gosselin, G.; Griffe, L.; Meillon,
J.-C.; Storer, R. Tetrahedron 2008, 64, 6657–6661. (e) Nair, V.; Piotrowska,
D. G.; Okello, M.; Vadakkan, J. Nucleosides, Nucleotides Nucleic Acids 2007,
0
0
of 4 -substituted isonucleosides, including a 4 -ethynyl deriva-
tive. In addition, using this strategy, we also attempted to
synthesize novel isonucleosides 7, constructed on a 2-oxa-6-
thiobicyclo[3.2.0]heptane scaffold. Compound 7 was designed
2
2
6, 687–690. (f) Jiang, C.; Li, B.; Guan, Z.; Yang, Z.; Zhang, L.; Zhang, L.
12
on the basis of lamivudine 8 and the known anti-HIV nucleo-
Bioorg. Med. Chem. 2007, 15, 3019–3025. (g) Chun, B.-K.; Wang, P.; Hassan,
A.; Du, J.; Tharnish, P. M.; Murakami, E.; Stuyver, L.; Otto, M. J.; Schinazi,
R. F.; Watanabe, K. A. Nucleosides, Nucleotides Nucleic Acids 2007, 26,
3–97. (h) Wang, F.; Yang, Z.-J.; Jin, H.-W.; Zhang, L.-R.; Zhang, L.-H.
Tetrahedron: Asymmetry 2007, 18, 2139–2146. (i) Yoo, S. J.; Kim, H. O.;
Lim, Y.; Kim, J.; Jeong, L. S. Bioorg. Med. Chem. 2002, 10, 215–226.
13
side 9. As can be seen in Figure 2, it is clear that the synth-
esis and evaluation of the anti-HIV activity of racemic 7 would
be efficient because of the structural similarity of the L- and
8
(
8) Nair, V.; Jahnke, T. S. Antimicrob. Agents Chemother. 1995, 39, 1017–
029.
9) Ohrui, H.; Kohgo, S.; Kitano, K.; Sakata, S.; Kodama, E.; Yoshi-
mura, K.; Matsuoka, M.; Shigeta, S.; Mitsuya, H. J. Med. Chem. 2000, 43,
516–4525.
10) (a) Dutschman, G. E.; Grill, S. P.; Gullen, E. A.; Haraguchi, K.;
(11) (a) Zintek, L. B.; Jeon, G. S.; Nair, V. Heterocycles 1994, 37, 1853–
1864. (b) Nair, V.; Zintek, L. B.; Jeon, G. S. Nucleosides Nucleotides 1995, 14,
389–391.
(12) (a) Coates, J. A.; Cammack, N.; Jenkinson, H. J.; Mutton, I. M.;
Pearson, B. A.; Storer, R.; Cameron, J. M.; Penn, C. R. Antimicrob. Agents
Chemother. 1992, 36, 202–5. (b) Coates, J. A.; Cammack, N.; Jenkinson,
H. J.; Jowett, A. J.; Jowett, M. I.; Pearson, B. A.; Penn, C. R.; Rouse, P. L.;
Viner, K. C.; Cameron, J. M. Antimicrob. Agents Chemother. 1992, 36, 733–9.
(13) O-yang, C.; Kurz, W.; Eugui, E. M.; McRoberts, M. J.; Verheyden,
J. P. H.; Kurz., L. J.; Walker, K. A. M. Tetrahedron Lett. 1992, 33, 41–44.
1
(
4
(
Takeda, S.; Tanaka, H.; Baba, M.; Cheng, Y.-C. Antimicrob. Agents Chem-
other. 2004, 48, 1640–1646. (b) Nitada, T.; Wang, X.; Kumamoto, H.;
Haraguchi, K.; Tanaka, H.; Cheng, Y.-C.; Baba, M. Antimicrob. Agents
Chemother. 2005, 49, 3355–3360.
4
162 J. Org. Chem. Vol. 75, No. 12, 2010

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SCHEME 2. Synthesis of the Dioxabicyclohexane Derivative 19
D-enatiomers of 7 with 8 and 9, respectively. This is also the case
0
SCHEME 3. Synthesis of Isonucleosides Using the Mitsunobu
Reaction
for 4 -substituted isonucleosides, since the L-enantiomers of
nucleoside derivatives have occasionally been found to have
12,14
anti-HIV activity with lesser toxicity than the D-isomers.
In
addition, synthesizing new compounds in racemic form would
have the advantage that the anitiviral activities of both enatio-
mers could be assayed in one procedure. To address this issue,
we attempted to synthesize racemic mixture of the target
compounds 6 and 7 by a method that could potentially be
applied to a chiral synthesis.
Following this concept, we attempted to synthesize 6 and 7
from a common intermediate 12, the desulfurization of
0
which would give the 4 -substituted isonucleoside 6. The
0
0
formation of a thietane ring around 3 - and 4 -positions, on
the other hand, would afford bicycloisonucleoside 7. A key
to the success of the synthesis is the development of a
nucleophilic glycosylation reaction accompanying the sul-
fide migration, by which the product 10 could serve as an
acceptor for a nucleobase to give the desired intermediate 12
(Scheme 1).
Results and Discussion
The known ketone 13, readily obtained from tris-
trihydroxyethyl)amine hydrochloride as described in the
(
1
5
literature, was treated with the lithium or magnesium salt
of the propargyl alcohol dianion. The addition of this di-
anion to 13 gave diol 14 in moderate yields (30-40% yield).
The reaction was greatly improved when an organocerium
the dihydrofuran derivative 16 under the oxidative condi-
tions used in the reaction (data not shown).
1
6
reagent, prepared from the magnesium salt of the dianion
of propargyl alcohol and anhydrous cerium chloride, was
used and gave the allyl alcohol 14 in 84% yield. The
semihydrogenation of 14 in the presence of a Lindlar catalyst
gave the (Z)-allyl alcohol derivative 15 in 91% yield. We
hypothesized that the cyclization of the allyl alcohol to the
dihydrofuran derivative 16 and subsequent epoxidation
would give the dioxabicyclohexane derivative 18. However,
this procedure failed because of the unexpected instability of
Failure to obtain the dioxabicyclohexane derivative
prompted us to employ an epoxy alcohol 18 as a precursor
in constructing a tetrahydrofuran skeleton. Silylation of
the primary alcohol of 14 and subsequent treatment with
m-chloroperoxybenzoic acid (m-CPBA) gave epoxide 17 in
good yield. Desilylation of the epoxide 17 by treatment with
TBAF gave the epoxy alcohol 18, which was subjected to
intramolecular S 2 cyclization via Mitsunobu reaction con-
N
ditions. The intramolecular etherification of 18 was carried
out by treatment with PPh and DEAD in THF to give the
3
(
14) (a) Lin, T. S.; Luo, M. Z.; Liu, M. C.; Pai, S. B.; Dutschman, G. E.;
desired dioxabicyclohexane derivative 19 in excellent yield. It
is obvious that the oxirane ring of 18, which remained intact
under the reaction conditions used, could restrict its con-
formation suitable for cyclization (Scheme 2).
Our next effort was to cleave the oxirane ring of 19 with an
appropriate thiol derivative, followed by the introduction of
Cheng, Y. C. J. Med. Chem. 1994, 37, 798–803. (b) Lin, T. S.; Luo, M. Z.; Liu,
M. C.; Zhu, Y. L.; Gullen, E.; Dutschman, G. E.; Cheng, Y. C. J. Med. Chem.
1
6
2
996, 39, 1757–9.
15) Hoppe, D.; Schmincke, H.; Kleeman, H.-W. Tetrahedron 1989, 45,
87–694.
(
(16) Inamoto, T.; Takiyama, N.; Nakamura, K. Tetrahedron Lett. 1985,
6, 4763–4766.
J. Org. Chem. Vol. 75, No. 12, 2010 4163

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0
0
0
SCHEME 4. Synthesis of 2 ,3 -Dideoxy-4 -hydroxymethylisoadenosine
0
0
SCHEME 5. Synthesis of 3 -Deoxy-4 -hydroxymethylisothymidine
the nucleobase moiety. As mentioned above, our strategy
assumed that the introduced sulfide group would play the
following roles: (1) provide assistance in the next coupling
with nucleobases by forming an episulfonium ion, (2) serve
a doublet peak. Therefore, the results strongly suggest that
the nucleobases are attacked at the less hindered 2-position,
accompanied by the migration of the thiophenol moiety
after an intramolecular nucleophilic substitution by the
phenyl sulfide group, with the subsequent formation of an
episulfonium intermediate 21, as expected (Scheme 3).
The purine isonucleoside derivative 22 was treated with
methanolic ammonia at 100 °C in a sealed tube to give the
isoadenosine derivative 24. Desulfurization of 24 by treat-
ment with tributyltin hydride in the presence of AIBN in
refluxing toluene gave 25, which was deprotected under
0
as a convertible group to hydrogen for the synthesis of the 4 -
substituted isonucleoside, and (3) provide a unit for construc-
ting a thietane ring for a 2-oxa-6-thiobicyclo[3.2.0]heptane
skeleton of novel isonucleosides. We initially attempted the
reaction of 19 with thiophenol, the product of which was
intended for use in examining the nucleophilic glycosylation
0
reaction and conversion to the 4 -substituted isonucleosides.
0
0
0
Cleavage of the oxirane moiety of 19 was achieved by
treatment with sodium thiophenoxide to give the phenyl sulfide
derivative 20 as the sole product in 95% yield. The struc-
acidic conditions to give the 2 ,3 -dideoxy-4 -hydroxymethyl-
isoadenosine 26 in 94% yield. In the same manner, the
pyrimidine derivative 23 was debenzoylated followed by
1
0
ture of 20 was confirmed on the basis of H NMR spectral
data, which showed a triplet signal, corresponding to H-3 at
radical desulfurization to give the 3 -deoxy derivative 28.
0
Finally, deprotection of the acetal group of 28 gave 3 -deoxy-
0
4
D O. It is clear that the nucleophilic attack of the phenyl
.32 ppm, but which collapsed to a doublet on the addition of
4 -hydroxymethylisothymidine 29 in 98% yield. Spectros-
copic data for 26 and 29 were consistent with previously
2
1
reported data (Schemes 4 and 5).
1
sulfide occurred from the less hindered side of 19 as would be
expected. With the phenyl sulfide derivative 20 in hand, the
nucleophilic glycosylation reaction was next examined. Our
first choice for the reaction was the Mitsunobu reaction
The success of the sulfur-assisted Mitsunobu reaction for
introducing a nucleobase prompted us to start a second pro-
ject, with the goal of synthesizing isonucleosides constructed
on a 2-oxa-6-thiobicyclo[3.2.0]heptane skeleton. As descri-
bed for the synthesis of 20, the oxirane ring of 19 was cleaved
by treatment with the sodium salt of PMB mercaptan to give
the PMB sulfide 30 as the sole product in 85% yield. The
sulfur-assisted Mitsunobu reaction of 30 in the presence of
6-chloropurine proceeded efficiently, similar to the case of
20, to give the purine isonucleoside 31 in 80% yield. On the
1
7
conditions in the presence of a nucleobase. Fortunately,
9 coupled with 6-chloropurine under Mitsunobu conditions
to give the purine isonucleoside derivative 22 in 83% yield.
1
3
Similarly, the reaction of 19 with N -benzoylthymine gave
the pyrimidine isonucleoside derivative 23 in 52% yield. In
2
the reaction mixture, an O -alkylated thymine derivative was
not found. Both reactions proceeded in a regiospecific man-
ner, and no traces of regioisomers were detected in the
reaction mixtures. The structures of 22 and 23 were unambi-
1
basis of H NMR analyses, there is no doubt that the re-
action occurred via the formation of an episulfonium ion
followed by migration and substitution at the 2-position (see
the Experimental Section). After removal of the acetal group
of 31 by acid treatment, the resulting free isonucleoside 32
was converted to dimesylate 33 in good yield. The PMB
group of 33 was deprotected by treatment with mercury(II)
1
guously determined from spectroscopic data. The H NMR
spectra of 22 and 23 show the signals corresponding to
protons connected to the carbon to which the nucleobase
was bound as quartets at 5.06 and 4.88 ppm, respectively.
These data provide clear proof that C-N bond formation
occurred at the 2-position since it is predictable that the cor-
responding proton of 3-substituted product would appear as
1
8
acetate and phenol in TFA to give a mixture of thiol 34 and
1
thietane 35 in 63 and 25% yields, respectively. The H NMR
(17) For example, see: Yoshimura, Y.; Moon, H. R.; Choi, Y.; Marquez,
V. E. J. Org. Chem. 2002, 67, 5938–5945.
(18) Narayan, R. S.; VanNieuwenhze, M. S. Org. Lett. 2005, 7, 2655–
2658.
4
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SCHEME 6. Construction of a 2-Oxa-6-thiobicyclo-
SCHEME 7. Synthesis of Isoadenosine Constructed on the
2-Oxa-6-thiobicyclo[3.2.0]heptane Scaffold
[
3.2.0]heptane Scaffold
1
evidenced by H NMR (vide supra). Similar to the case for
1
5, in the H NMR spectrum of 42, the H-3 proton signal
0
3
0
appeared as a singlet at 3.81 ppm. In addition, the H-2 pro-
ton appeared as a doublet at 4.93 ppm due to the loss of
0
coupling with one of the H-1 protons as well as the H-3 pro-
ton. Needless to say, this tendency for coupling constants
was maintained in all of the compounds that contain a thi-
0
0
etane ring fused at the 3 and 4 -positions (see the Experi-
mental Section). To determine the preferred conformation of
isonucleosides constructed on a 2-oxa-6-thiobicyclo[3.2.0]-
heptane skeleton, theoretical calculations using an isodeoxy-
uridine derivative 45 as a model compound were perfor-
med. Possible conformers of 45 were surveyed by molecular
mechanics (MM) calculations and were optimized by theo-
retical calculations using density functional theory (DFT)
quantum mechanical calculations at the B3LYP/6-31G**
spectrum of 35, showing loss of one mesylate and a singlet
0
peak corresponding to H-3 at 3.94 ppm, was consistent with
the assigned structure (vide infra). Additionally, the mass
spectrum of the compound showed a molecular ion peak
2
0
level. The resulting 3D structure of 45 with the lowest
energy showed that the dihedral angles between one of the
0
0
0
0
(
m/z) at 376, thus further supporting the structure assign-
H-1 and H-2 and between H-2 and H-3 were 93.2 and
99.4°, respectively (Figure 3). The results adequately account
for the H NMR data reported above and revealed that the
ment. It is interesting to note that thietane 35 was sponta-
neously formed even under the acidic conditions used for
deprotecting the PMB group. The major thiol derivative 34
was also converted to 35 in moderate yield by treatment with
DBU in acetonitrile at 70 °C (Scheme 6).
1
simulated structure was in good agreement with the con-
formation adapted in solution.
The conformations of nucleosides are defined by the
0
Compound 35 was treated with benzoic acid in the pre-
glycosyl torsion angle, the conformation around the C4 -
1
sence of cesium fluoride in an S 2 reaction to give the 5 -
9
0
0
21
N
C5 bond, and sugar puckering. Among these, sugar puck-
ering of nucleosides is important for recognition by enzymes
utilizing nucleosides and nucleotides. NRTIs need to be acti-
vated by being transformed into their corresponding triphos-
phate forms which inhibit the reverse transcriptase encoded
by HIV. The first step in this transformation is catalyzed by
deoxynucleoside kinase, which is reported to preferentially
benzoate derivative 36. Finally, deprotection and conversion
to the adenine were achieved by the treatment of 36 with
methanolic ammonia in a sealed tube at 100 °C to give
desired bicycloisoadenosine 37 in 72% yield (Scheme 7).
The isothymidine analogue of compound 37 was con-
structed. The common intermediate 30 was subjected to the
3
0
22
sulfur-assisted Mitsunobu reaction in the presence of N -
benzoylthymine to give the isothymidine derivative 38 in
recognize an S-form of sugar puckering (C2 -endo). Thus,
we calculated the optimized conformer of 3TU 46, a uracil
congener of lamivudine, and compared the findings with the
calculated conformer of 45. Since our compounds, including
45, are members of a class of isonucleosides in which the
5
9% yield. After removal of the acetal group followed by
mesylation, the PMB group of dimesylate 40 was removed by
1
treatment with mercury(II) acetate and phenol in TFA to
9
1
give the thiol derivative 41 in quantitative yield. The H
0
0
base moiety is transposed from the 1 - to the 2 position, it is
difficult to make a direct comparison of sugar puckering.
Therefore, we evaluated these structures with a focus on the
NMR spectrum of 41 revealed that deprotection of the
benzoyl group also occurred under the reaction conditions.
In contrast to the results for isoadenosine, a thietane deri-
vative was not formed in this reaction. Thus, the intramole-
cular nucleophilic substitution of the thiol derivative 41 was
achieved by treatment with DBU in acetonitrile to give the
thietane 42 in 60% yield. The synthesis of the desired
isothymidine 44 was successfully achieved by conversion of
0
dispositions of the base, the 5 -hydroxymethyl group, and
hetero atoms in a pseudosugar ring. An optimized conformer
of 46 was obtained by the same method as described above
(DFT calculations using B3LYP/6-31G**). As depicted in
(20) Yoshimura, Y.; Yamazaki, Y.; Saito, Y.; Takahata, H. Tetrahedron
2
009, 65, 9091–9102.
21) Saenger, W. Principles in Nucleic Acid Structure; Springer-Verlag:
New York, 1984.
the mesylate to a benzoate by an S 2 reaction of 42, followed
N
by treatment with aqueous NH OH (Scheme 8).
4
(
The formation of a thietane ring resulted in a confor-
mational change (sugar puckering) of isonuclceosides, as
(22) (a) Marquez, V. E.; Ben-Kasus, T.; Barchi, J. J., Jr.; Green, K. M.;
Nicklaus, M. C.; Agbaria, R. J. Am. Chem. Soc. 2004, 126, 543–549.
(b) Sabini, E.; Hazra, S.; Konrad, M.; Lavie., A. J. Med. Chem. 2007, 50,
3004–3014. (c) Russ, P. L.; Gonzalez-Moa, M. J.; Vu, B. C.; Sigano, D. M.;
Kelley, J. A.; Lai, C. C.; Deschamps, J. R.; Hughes, S. H.; Marquez, V. E.
ChemMedChem. 2009, 4, 1354–1363.
(19) Otera, J.; Nakazawa, K.; Sekoguchi, K.; Orita, A. Tetrahedron 1997,
3, 13633–13640.
5
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SCHEME 8. Synthesis of Isothymidine Constructed on the 2-Oxa-6-thiobicyclo[3.2.0]heptane Scaffold
FIGURE 4. Structure of 3TU 46: (a) the structural formula of 46;
b) 3D-structure of optimized 46 shown as a ball-and-stick model.
(
pseudosugar ring are similar as originally expected. On the
other hand, the positions of the hydroxymethyl groups are
slightly different. In the case of isonucleoside 45, the distance
FIGURE 3. Structure of model compound 45: (a) structural for-
mula of 45; (b) 3D-structure of optimized 45 shown as a ball-and-
stick model.
0
between H-6 of the uracil ring and the 5 -oxygen atom is
0
Figure 4, the conformer, the sugar puckering of which had
0
˚
.197 A, while the 5 -oxygen atom of 3TU 46 occupies a
2
position 0.25 A away from that of 45. The distance discussed
above should be important for considering antiviral acti-
a C2 -endo configuration, is consistent with a previous
report regarding the calculation results for lamivudine
˚
2
3
(
Figure 4).
With information on the optimized conformer of 46 in
24
vity because the total conformational differences of nucleo-
side analogues directly influence it. Therefore, even this
small difference might make an impact on antiviral activity
since enzymes, e.g., deoxynucleoside kinase, recognize their
substrate conformations strictly as mentioned above. Indeed,
the antiviral evaluation revealed that neither isonucleosides 37
hand, the findings were compared with those for 45 described
above. To estimate the difference in the positions of func-
tional groups between 45 and 46, we overlaid the uracil
ring of the model compounds, and the results are shown in
Figure 5. The positions of oxygen and sulfur atoms in the
(24) Van Roey, P.; Salerno, J. M.; Chu, C. K.; Schinazi, R. F. Proc. Natl.
(
23) Yekeler, H. THEOCHEM 2004, 684, 223–230.
Acad. Sci. U.S.A. 1989, 86, 3929–3933.
4
166 J. Org. Chem. Vol. 75, No. 12, 2010

Yoshimura et al.
JOCArticle
chromatography was Fuji Silysia PSQ 100B. All of the reactions
described below were performed under argon atmosphere.
5-(3-Hydroxyprop-1-ynyl)-2,2-dimethyl-1,3-dioxan-5-ol (14).
To a solution of n-BuMgCl (39.5 mL, 35.4 mmol, 0.90 M THF
solution) in THF was slowly added propargyl alcohol (1.03 mL,
1
7.7 mmol) at 0 °C. After the mixture was stirred at °C for 80 min,
the whole mixture was added to an anhydrous suspension of
CeCl in THF (24 mL), which was prepared from CeCl 7H O
3
3
3
2
(6.70 g, 18.0 mmol) by the reported method. After the mixture was
stirred for 1.5 h at 0 °C, a THF solution (6 mL) of 2,2-dimethyl-
1
4
1
0
,3-dioxan-5-one 13 (1.53 g, 11.8 mmol) was added dropwise at
°C by cannula. The mixture was stirred at 0 °C for 1.5 h. After
4
being neutralized with satd NH Cl, the mixture was vigorously
stirred for 15 min. The resulting gummy residue was removed by
decantation and filtration through Celite. The filtrate was con-
centrated under reduced pressure, and the residual solids were
3
washed and extracted with CHCl . The combined organic layer
was dried over Na SO . After filtration, the filtrate was concen-
2
4
trated under reduced pressure, and the residue was purified by
silica gel column chromatography (33-50% AcOEt in hexane) to
give 14 (1.86 g, 84%) as a white solid: H NMR (400 MHz,
1
CDCl ) δ 1.45 (3H, s), 1.48 (3H, s), 2.16 (1H, t, J = 6.0 Hz), 3.50
3
(
(
1H, s), 3.77 (2H, d, J = 11.6 Hz), 4.03 (2H, d, J = 11.6 Hz), 4.30
1
2H, d, J = 5.8 Hz); C NMR (100 MHz, CDCl
3
3
) δ 18.7, 27.9,
5
1
C
0.7, 63.2, 68.3, 82.3, 85.5, 98.6; IR (KBr) 3402.4, 1638.0, 1377.5,
-
1
þ
082.8, 1058.8 cm ; EI-MS (m/z) 187 (M þ 1). Anal. Calcd for
0.1H O: C, 57.50; H, 7.61. Found: C, 57.58; H, 7.69.
5-((Z)-3-tert-Butyldimethylsilyloxyprop-1-enyl)-2,2-dimethyl-
FIGURE 5. Comparison of the optimized conformers of isonucleo-
side 45 (green) and 3TU 46 (blue). The overlay is based on the atoms
in the uracil ring. Oxygen atoms in a sugar portion are shown in red
H O
9 14 4
2
3
1,3-dioxan-5-ol (15). A mixture of 14 (2.0 g, 10.8 mmol), Pd-
0
0
and sulfur atoms in yellow: (a) view from the 2 - and 3 -side; (b) view
0
BaSO (456 mg), and quinoline (10 drops) was stirred at room
4
from the 4 -side.
2
temperature for 7 h under H atmosphere. After the catalyst was
removed by Celite filtration, the filtrate was concentrated under
reduced pressure and the residue was purified by silica gel col-
umn chromatography (60% AcOEt in hexane) to give 15 (1.84 g,
nor 44 showed antiviral activities against HIV-1 or herpes virus
(HSV-1).
25
0
0
In conclusion, we describe a new synthesis of 2 ,3 -dide-
0
1
9
1
1%) as a syrup: H NMR (400 MHz, CDCl
.48 (3H, s), 3.37 (1H, s), 3.67 (2H, d, J = 12.1 Hz), 3.90 (2H, d,
3
) δ 1.46 (3H, s),
oxy-4 -hydoxymethylisonucleosides, which can serve as in-
0
0
0
termediates in the synthesis of various 4 -substituted 2 ,3 -
dideoxyisonucleosides. The synthesis was achieved by using
the sulfur-assisted Mitsunobu reaction for introducing a
nucleobase onto the sugar portion. In addition, the synthetic
intermediates, e.g., 22 and 23, represent potentially good
precursors for preparing isonucleosides containing substitu-
J = 11.6 Hz), 4.30 (2H, s), 5.23 (1H, d, J = 12.6 Hz), 5.89-5.95
13
(1H, m); C NMR (100 MHz, CDCl
68.7, 98.2, 127.8, 134.5; IR (neat) 3390.4, 2993.7, 1651.0, 1374.9,
) δ 19.0, 27.9, 59.1, 68.2,
3
-
1
þ
1199.6, 829.9 cm ; EI-MS (m/z) 189 (M þ 1); HRMS calcd for
C H O 189.1127, found 189.1133.
9
17
4
5-((2R*,3R*)-3-((tert-Butyldimethylsilyloxy)methyloxiran-2-
yl)-2,2-dimethyl-1,3-dioxan-5-ol (17). A mixture of 15 (1.59 g,
0
0
ents at the C-3 as well as the 4 -positions. Thus, by applying
the developed method, we synthesized novel isonucleo-
side analogues constructed on a 2-oxa-6-thiobicyclo[3.2.0]-
heptane scaffold. Although the isonucleosides that were
designed were inactive against HIV-1 and HSV-1, theoretical
calculations using model compounds revealed that the iso-
nucleoside built on the 2-oxa-6-thiobicyclo[3.2.0]heptane scaf-
8
2
.40 mmol), TBSCl (2.54 g, 16.8 mmol), and imidazole (1.36 g,
0.2 mmol) in CH Cl (30 mL) was stirred at room temperature
Cl , washed with H
and brine, and then dried over Na SO . After filtration, the
2
2
for 1 h. The mixture was diluted with CH
2
2
2
O
2
4
solvents were removed under reduced pressure to give crude 15,
which was used for epoxidation without further purification.
A solution of m-CPBA (6.20 g, 22.2 mmol) in CH
was added to a solution of crude mixture of TBS ether in CH
30 mL) at room temperature. The mixture was stirred at the
same temperature overnight. The reaction mixture was washed
with satd NaHCO , 10% Na , and brine and then dried
over Na SO . After filtration, the solvents were removed under
Cl
2
(50 mL)
2
0
2
Cl
2
fold was a good mimic of the C2 -endo conformer (S-form)
(
of lamivudine. Therefore, such new isonucleosides may be
useful as biological tools for investigating steric interactions
of enzymes that recognize lamivudine with its analogues as a
substrate.
3
2 2 3
S O
2
4
reduced pressure, and the residue was purified by silica gel
column chromatography (10% AcOEt in hexane) to give 17
1
2.41 g, 90%, two steps) as a syrup: H NMR (400 MHz, CDCl
Experimental Section
(
3
)
δ 0.00 (6H, d, J = 2.9 Hz), 0.81 (9H, s), 1.35 (3H, s), 1.39 (3H, s),
.03 (1H, s), 3.12 (1H, dd, J = 9.7, 4.4 Hz), 3.26 (1H, d, J = 4.4
Hz), 3.65-3.73 (3H, m), 3.80 (1H, d, J = 12.1 Hz), 3.92-3.93
General Methods. All of the reactions described were per-
formed under argon atmosphere unless other conditions are
described. Melting points are uncorrected. NMR spectra were
3
1
3
1
13
(2H, m); C NMR (100 MHz, CDCl ) δ 18.3, 22.5, 24.3, 25.6,
3
recorded at 400 MHz ( H) and 100 MHz ( C) using CDCl
DMSO-d with tetramethylsilane as internal standard. Mass
spectra were obtained by EI or FAB mode. Silica gel used for
3
or
2
3
5.7, 25.8, 57.6, 58.1, 61.1, 64.3, 66.7, 67.3, 98.5; IR (neat)
444.8, 2955.9, 1373.6, 1256.2, 1079.1, 835.4 cm ; EI-MS (m/z)
6
-
1
þ
319 (M þ 1). Anal. Calcd for C H O Si: C, 56.57; H, 9.49.
Found: C, 56.39; H, 9.87.
1
5
30 5
(
25) Compounds 37 and 44 did not show any inhibitory activity against
(2R*,3R*)-5-(3-(Hydroxymethyl)oxiran-2-yl)-2,2-dimethyl-1,3-
dioxan-5-ol (18). To a solution of 17 (2.37 g, 7.40 mmol) in THF
HIV-1 at concentrations up to 100 μM. They excibit no inhibitory activity
against HSV-1 at concentrations less than 30 μg/mL.
J. Org. Chem. Vol. 75, No. 12, 2010 4167

Yoshimura et al.
JOCArticle
(
20 mL) was added a THF solution of TBAF (14.8 mL, 14.8 mmol)
3-Benzoyl-1-[(3R*,4S*)-8,8-dimethyl-4-(phenylthio)-1,7,9-tri-
oxaspiro[4.5]dec-3-yl]thymine (23). To a solution of 20 (250 mg,
0.840 mmol), PPh
at room temperature. The mixture was stirred at the same tem-
perature for 1 h. After the solvents were removed under reduced
pressure, the residue was purified by silica gel column chromato-
3
(240 mg, 0.920 mmol), and N -benzoylthy-
3
mine (288 mg, 1.26 mmol) in THF (20 mL) was dropwise added
DEAD (417 μL, 1.26 mmol) at 0 °C. After the mixture was stir-
red at room temperature for 3 h, the solvents were removed
under reduced pressure. The residue was purified by silica gel
column chromatography (60% AcOEt in hexane) to give 23
graphy (1% MeOH in CHCl
3
) to give 18 (1.49 g, 99%) as a white
solid: mp 69-70 °C; H NMR (400 MHz, CDCl ) δ 1.47 (3H, d),
.48 (3H, s), 2.66 (1H, t, J=6.5 Hz), 3.15 (1H, d, J=4.4 Hz), 3.28
1H, q, J=5.3 Hz), 3.33 (1H, s), 3.71-3.76 (2H, m), 3.86 (1H, dd,
J=12.6, 5.3 Hz), 3.91 (1H, d, J=11.6 Hz), 3.96 (1H, d, J=11.6
1
3
1
(
1
(223 mg, 52%) as a white solid: mp 94-96 °C; H NMR (400 MHz,
13
Hz), 4.06-4.12 (1H, m); C NMR (100 MHz, CDCl
2
1
3
) δ 22.1,
CDCl ) δ 1.38 (1H, s), 1.44 (1H, s), 1.82 (1H, s), 3.71 (1H, d, J=
3
4.7, 57.4, 57.5, 60.4, 65.1, 67.1, 98.7; IR (KBr) 3449.3, 3276.2,
8.7 Hz), 3.76-3.84 (2H, m), 3.96 (1H, d, J=12.6 Hz), 4.04 (1H, dd,
-
1
372.7, 1202.51, 1074.3, 1018.7, 831.5 cm ; EI-MS (m/z); 205
J=9.7, 7.2 Hz), 4.17-4.22 (2H, m), 4.88 (1H, q, J=7.7 Hz), 6.89
(1H, s), 7.30-7.37 (3H, m), 7.46-7.50 (4H, m), 7.63 (1H, m),
þ
(M
C, 52.84; H, 7.95.
þ 1). Anal. Calcd for C
9 16 5
H O : C, 52.93; H, 7.90. Found:
1
3
7.82-7.85 (2H, m); C NMR (100 MHz, CDCl ) δ12.5, 20.0, 26.8,
3
0
(
1R*,5R*)-2,2 -Dimethyl-3,6-dioxaspiro[bicyclo[3.1.0]hexane-
(555 mg, 2.22 mmol)
63.2, 65.8, 66.2, 79.4, 98.7, 111.8, 128.6, 129.1, 129.7, 130.4, 131.4,
132.3, 132.9, 135.1, 137.1, 149.4, 162.2, 168.4; UV (MeOH) λ 254
0
2
,5 -[1,3]dioxane] (19). A mixture of PPh
3
max
-
1
nm; IR (KBr) 1749.0, 1696.3, 1657.6 cm ; EI-MS (m/z) 508 (M );
þ
and DEAD (2.2 M solution in toluene, 1.01 mL, 2.22 mmol) was
stirred for 5 min at room temperature. To thismixture was added
a solution of 18 (227 mg, 1.11 mmol) in THF (5 mL), and the
mixture was stirred at room temperature for 1.5 h. After the sol-
vents were removed under reduced pressure, the residue was puri-
fied by silica gel column chromatography (5% AcOEt in hexane)
HRMS calcd for C H N O S 508.1668, found 508.1664
28
27
2 6
9-[(3R*,4S*)-8,8-Dimethyl-4-(phenylthio)-1,7,9-trioxaspiro[4.5]
dec-3-yl]adenine (24). A mixture of 22 (350 mg, 0.810 mol) in 8 M
ammonia in MeOH (25 mL) was kept at 80 °C overnight in a
sealed tube. After the mixturewas allowed to cool to room temper-
ature, the solvents were removed under reduced pressure. The
residue was purified by silica gel column chromatography (6%
1
to give 19 (193 mg, 94%) as a syrup: mp 75-76 °C; H NMR
(
3
400 MHz, CDCl ) δ 1.44 (3H, s), 1,48 (3H, s), 3.68 (1H, dd, J=
1
4
5
1
1.6, 1.9 Hz), 3.69-3.81 (4H, m), 3.91 (1H, dd, J=11.6, 1.5 Hz),
MeOH in CHCl ) to give 24 (301 mg, 90%) as a white solid: mp
3
1
1
3
.01-4.04 (2H, m); C NMR (100 MHz, CDCl ) δ 19.9, 27.0,
198-200 °C; H NMR (400 MHz, CDCl ) δ 1.39 (3H, s), 1,47
3
3
6.3, 58.5, 62.2, 63.8, 67.0, 75.0, 98.6; IR (KBr) 2875.7, 1374.1,
(3H, s), 3.90 (1H, d, J = 12.6 Hz), 3.99 (2H, s), 4.25 (1H, d, J =
7.3 Hz), 4.28 (1H, d, J=10.6 Hz), 4.31 (1H, dd, J=8.7, 7.3 Hz),
4.41 (1H, t, J = 9.2 Hz), 4.94 (1H, q, J = 8.4 Hz), 5.57 (2H, s),
-1
þ
202.5, 1079.8, 864.5 cm ; EI-MS (m/z) 186 (M ). Anal. Calcd
: C, 58.05; H, 7.58. Found: C, 58.08; H, 7.65.
3S*,4S*)-8,8-Dimethyl-3-(phenylthio)-1,7,9-trioxaspiro[4.5]-
9 14 4
for C H O
1
3
(
7.06-7.20 (5H, m), 7.67 (1H, s), 8,25 (1H, s); C NMR (100 MHz,
decan-4-ol (20). To a solution of thiophenol (2.3 mL, 21.5 mmol)
in dry methanol (10 mL) was added sodium methoxide (620 mg,
CDCl ) δ 20.5, 26.3, 55.1, 63.8, 64.0, 65.9, 66.9, 79.2, 98.8, 128,4,
3
129.0, 131.2, 132.1, 132.6, 144.2, 151.0, 151.3, 151.5; UV (MeOH)
-
1
1
0.7 mmol), and the mixture was stirred at room temperature
for 20 min. To this mixture was added a solution of 19 (774 mg,
.15 mmol) in dry methanol (5 mL). After being kept under
λmax 259 nm; IR (KBr) 3150.8, 1645.2, 1601.4, 1091.3 cm ;EI-MS
þ
(m/z) 413 (M ). Anal. Calcd for C H N O S: C, 58.09; H, 5.61;
5 3
2
0
23
4
N, 16.94. Found: C, 58.28; H, 5.57; N, 16.61.
(S*)-9-[8,8-Dimethyl-1,7,9-trioxaspiro[4.5]dec-3-yl]adenine (25).
To a solution of 24 (250 mg, 0.610 mmol) in toluene (10 mL)
reflux for 1 h, the mixture was allowed to cool to room temper-
ature. After the solvents were removed under reduced pressure,
the residue was purified by silica gel column chromatography
were added Bu SnH (320 μL, 1.22 mmol) and AIBN (103 mg,
3
(
10% AcOEt in hexane) to give 20 (1.09 g, 95%) as a white solid:
0.610 mmol). The mixture was kept under reflux for 10 h. After the
solvents were removed under reduced pressure, the residue was
purified by silica gel column chromatography (1% MeOH in
1
mp 100-102 °C; H NMR (400 MHz, CDCl ) δ 1.40 (3H, s),
3
1
1
1
7
5
,48 (3H, s), 2.75 (1H, brs), 3.68-3.76 (3H, m), 3.81 (1H, dd, J=
1.6, 1.9 Hz), 3.87 (1H, d, J=11.6 Hz), 4.08 (1H, dd, J=11.6,
.9 Hz), 4.25 (1H, dd, J=8.7, 5.8 Hz), 4.32 (1H, d, J=3.9 Hz),
CHCl ) to give 25 (162 mg, 87%) as a white solid: mp 252-
3
1
254 °C; H NMR (400 MHz, DMSO-d ) δ 1.31 (3H, s), 1.33 (3H,
6
1
3
.23-7.44 (5H, m); C NMR (100 MHz, CDCl
2.9, 62.7, 66.5, 70.6, 78.1, 80.5, 98.5, 127.1, 129.2, 130.8, 134.3;
3
) δ 20.3, 26.7,
s), 2.17 (1H, dd, J=13.5, 6.3 Hz), 2.37 (1H, dd, J=13.5, 7.7 Hz),
3.66-3.78 (4H, m), 4.16 (2H, m), 5.06-5.12 (1H, m), 7.24 (1H, s),
-
1
13
8,13 (1H, s), 8.18 (1H, s); C NMR (100 MHz, DMSO-d ) δ 22.3,
24.8, 37.5, 53.5, 65.6, 66.3, 69.4, 77.0, 97.3, 119.0, 139.0, 149.9,
IR (KBr) 3439.2, 1200.8, 1139.0, 1078.0, 1059.0, cm ; EI-MS
(
6
þ
m/z) 296 (M ). Anal. Calcd for C15
H
20
O
4
S: C, 60.79; H, 6.80.
Found: C, 60.84; H, 6.74.
-Chloro-9-[(3R*,4S*)-8,8-dimethyl-4-(phenylthio)-1,7,9-tri-
oxaspiro[4.5]dec-3-yl]purine (22). To a solution of 20 (350 mg,
.18 mmol), PPh (618 mg, 2.36 mmol), and 6-chloropurine
555 mg, 3.54 mmol) in THF (30 mL) was dropwise added
DEAD (1.07 mL, 2.36 mmol) at 0 °C. After the mixture was
stirred at room temperature for 1 h, the solvents were removed
under reduced pressure. The residue was purified by silica gel
152.4, 156.0; UV (MeOH) λmax 261 nm; IR (KBr) 3388.7, 1664.2,
1599.5, 1081.4 cm ; EI-MS (m/z) 305 (M ); HRMS calcd for
-
1
þ
6
C H N O 305.1488, found 305.1484.
19
14
5 3
1
(
3
(S*)-4-[(Adenin-9-yl)-tetrahydrofuran-2,2-diyl]dimethanol ((()-
0
0
0
2 ,3 -Dideoxy-4 -hydroxymethylisoadenosine, 26). A mixture of 25
(50 mg, 0.16 mmol) in 80% aq AcOH was stirred at room temp-
erature for 5 h. After the solvents were removed under reduced
pressure, the residual solvents were further removed by repeating
coevaporation with EtOH five times. The residue was purified by
column chromatography (60% AcOEt in hexane) to give 22
1
(
(
1
1
426 mg, 83%) as a white solid: mp 159-161 °C; H NMR
silica gel column chromatography (5% MeOH in CHCl ) to give
3
1
400 MHz, CDCl
3
) δ 1.44 (3H, s), 1,49 (3H, s), 3.91 (1H, dd, J=
2.3, 1.7 Hz), 3.99 (1H, dd, J = 12.1, 1.9 Hz), 4.08 (1H, d, J =
2.1 Hz), 4.21 (1H, d, J=8.7 Hz), 4.25 (1H, d, J=12.6 Hz), 4.36
26 (39 mg, 94%) as a white solid: mp 230-232 °C; H NMR
6
(400 MHz, DMSO-d ) δ 2.22 (1H, dd, J=13.0, 6.8 Hz), 2.41 (1H,
dd, J=13.0, 8.2 Hz), 3.37-3.45 (4H, m), 4.05 (1H, dd, J=9.2, 6.3
(
8
1H, dd, J=9.2, 7.7 Hz), 4.41 (1H, t, J=8.9 Hz), 5.06 (1H, q, J=
Hz), 4.21 (1H, J=8.7, 6.3 Hz), 4.82-4.86 (2H, m), 5.09-5.16 (1H,
m), 7.22 (2H, s), 8.12 (1H, s), 8.26 (1H, s); C NMR (100 MHz,
13
13
.4 Hz), 7.00-7.28 (5H, m), 8.00 (1H, s), 8,26 (1H, s); C NMR
) δ 20.5, 26.3, 55.1, 63.8, 64.0, 65.9, 66.9, 79.2,
8.8, 128,4, 129.0, 131.2, 132.1, 132.6, 144.2, 151.0, 151.3, 151.5;
(
100 MHz, CDCl
3
6
DMSO-d ) δ 35.2, 54.2, 63.8, 63.9, 86.4, 118.8, 139.0, 149.4, 152.3,
9
156.0; UV (MeOH) λmax 261 nm; IR (KBr) 3369.5, 3195.1, 1656.2,
-
1
þ
UV (MeOH) λmax 261 nm; IR (KBr) 1596.1, 1560.0, 1340.6,
1612.1, 1312.9, 1050.7 cm ; FAB-MS (m/z) 266 (M þ 1); HRMS
-1
þ
1
201.6, 1062.4, 828.2 cm ; EI-MS (m/z) 432 (M ). Anal. Calcd
for C20 21ClN S: C, 55.49; H, 4.89; N, 12.94. Found: C,
5.59; H, 4.81; N, 12.87.
15 5 3
calcd for C11H N O 266.1253, found 266.1252.
H
O
4 3
1-[(3R*,4S*)-8,8-Dimethyl-4-(phenylthio)-1,7,9-trioxaspiro-
[4.5]dec-3-yl]thymine (27). A mixture of 23 (214 mg, 0.420 mol)
5
4
168 J. Org. Chem. Vol. 75, No. 12, 2010

Yoshimura et al.
JOCArticle
in concd aq ammonia (10 mL) and MeOH (10 mL) was stirred at
room temperature for 2 h. After the solvents were removed under
reduced pressure, the residue was purified by silica gel column
6-Chloro-9-((3R*,4S*)-4-(4-methoxybenzylthio)-8,8-dimethyl-
1,7,9-trioxaspiro[4.5]dec-3-yl)-9H-purine (31). To a solution of 30
(170 mg, 0.50 mmol), PPh (196 mg, 0.75 mmol), and 6-chloropur-
3
chromatography (50% AcOEt in hexane) to give 27 (160 mg,
9
ine (117 mg, 0.75 mmol) in THF (30 mL) was dropwise added
DEAD (340 μL, 0.75 mmol) at 0 °C. After the mixture was stirred at
room temperature for 1 h, the solvents were removed under reduced
pressure. The residue was purified by silica gel column chromato-
1
5%) as a white solid: mp 165-167 °C; H NMR (400 MHz,
CDCl
.7 Hz), 3.81-3.87 (2H, m), 3.95-4.01 (2H, m), 4.16-4.23 (2H,
m), 4.95 (1H, q, J = 7.9 Hz), 6.83 (1H, s), 7.26-7.29 (3H, m),
3
) δ 1.39 (1H, s), 1.45 (1H, s), 1.80 (1H, s), 3.68 (1H, d, J=
8
graphy (66% AcOEt in hexane) to give 31 (203 mg, 80%) as a white
1
3
1
7
.44-7.46 (2H, m), 9.63 (1H, s); C NMR (100 MHz, CDCl
3
)
solid: mp 137-138 °C; H NMR (400 MHz, CDCl
3
) δ1.49 (3H, s),
δ 12.3, 19.9, 26.7, 54.8, 63.0, 64.7, 65.8, 66.3, 79.4, 98.6, 111.7,
1,51 (3H, s), 3.40 (1H, d, J=8.7 Hz), 3.56 (1H, d, J=13.5 Hz), 3.66
(1H, d, J=13.5 Hz), 3.74 (3H, s), 3.84 (1H, d, J=12.1 Hz), 3.93
(2H, s),4.20(1H,dd,J=9.4, 7.5 Hz), 4.26 (1H, d, J=12.6 Hz), 4.44
(1H, t, J = 8.9 Hz), 4.70 (1H, q, J = 8.1 Hz), 6.48 (2H, d, J =
1
2
28.4, 129.3, 132.2, 132.9, 137.0, 150.5, 163.5; UV (MeOH) λ
max
1
-
61 nm; IR (KBr) 3455.6, 1695.1, 1090.5, 1056.0 cm ; EI-MS
þ
(
m/z) 404 (M ); HRMS calcd for C20
24 2 5
H N O S 404.1406, found
1
3
4
04.1410.
S*)-1-[8,8-Dimethyl-1,7,9-trioxaspiro[4.5]dec-3-yl]thymine (28).
To a solution of 27 (154 mg, 0.380 mmol) and Bu SnH (298 μL,
.14 mmol) in toluene (10 mL) was added a solution of AIBN
64 mg, 0.380 mmol) in toluene (5 mL) over 1 h. The mixture was
8.7 Hz), 6,82 (2H, d, J = 8.7 Hz), 8.00 (1H, s), 8.60 (1H, s); C
NMR (100 MHz, CDCl ) δ 22.7, 24.4, 36.4, 51.0, 55.1, 63.8, 64.3,
(
3
3
66.1, 66.4, 78.6, 98.6, 113.3, 128.1, 129.6, 132.3, 144.6, 150.8, 151.2,
151.4, 158.6; UV (MeOH) λmax 267 nm; IR (KBr) 1594.5, 1561.2,
1
(
-1
þ
1513.2, 1250.1, 1191.2, 1084.9, 830.0 cm ; EI-MS (m/z) 476 (M ).
Anal. Calcd for C22 25ClN S: C, 55.4; H, 5.28; N, 11.75. Found:
C, 55.46; H, 5.14; N, 11.59.
kept under reflux for 2 h. After the solvents were removed under
reduced pressure, the residue was purified by silica gel column
chromatography (70% AcOEt in hexane) to give 28 (82 mg,
H
O
4 4
((3S*,4R*)-4-(6-Chloro-9H-purin-9-yl)-3-(4-methoxybenzylthio)-
tetrahydrofuran-2,2-diyl)dimethanol (32). A mixture of 31 (225 mg,
0.47 mmol) in 80% aq AcOH (20 mL) was stirred at room tem-
perature for 4 h. After the solvents were removed under reduced
pressure, the residual solvents were further removed by repeating
coevaporation with EtOH five times. The residue was purified by
1
7
4%) as a white solid: mp 252-253 °C; H NMR (400 MHz,
DMSO-d
5
3
6
) δ 1.29 (3H, s), 1.32 (3H, s), 1.73 (1H, dd, J = 13.5,
.8 Hz), 1.78 (1H, s), 2.16 (1H, dd, J=14.0, 8.7 Hz), 3.62 (2H, s),
.69 (1H, d, J=12.1 Hz), 3.79 (1H, d, J=12.1 Hz), 3.87 (1H, dd,
J=10.1, 5.3 Hz), 3.96 (1H, dd, J=9.7, 6.8 Hz), 4.91-4.98 (1H,
1
m), 7.47 (1H, s), 11.26 (1H, s); C NMR (100 MHz, DMSO-d )
3
silica gel column chromatography (10% MeOH in CHCl ) to give
3
6
1
26 (206 mg, quant) as a white solid: H NMR (400 MHz, CDCl
δ 12.2, 22.0, 25.1, 37.0, 54.2, 65.1, 66.3, 68.4, 77.0, 97.2, 109.5,
3
)
1
3
37.3, 150.9, 163.7; UV (MeOH) λmax 271 nm; IR (KBr)
175.8, 1689.5, 1672.4, 1282.5, 1089.9, 1050.6 cm ; EI-MS
δ1.77 (1H, s), 2.21 (1H, s), 3.43 (1H, d, J=14.0Hz), 3.49(1H, d,J=
14.0 Hz), 3.67 (1H, d, J=11.6 Hz), 3.78 (1H, d, J=11.6 Hz), 3.80
(1H, d, J=11.6 Hz), 3.95 (1H, d, J=10.1 Hz), 3.99 (1H, d, J=11.6
Hz), 4.34 (1H, t, J=8.7 Hz), 4.47 (1H, t, J=8.2 Hz), 4.99 (1H, dd,
-1
þ
(
2
m/z) 296 (M ); HRMS calcd for C14
96.1378
H
20
N
2
O
5
296.1372, found
(
S*)-4-[(Thymin-1-yl)tetrahydrofuran-2,2-diyl]dimethanol ((()-
-Deoxy-4 -hydroxymethylisothymidine, 29). A mixture of 28
J=17.9, 8.2 Hz), 6.41 (2H, d, J=8.7 Hz), 6.78 (2H, d, J=8.7 Hz),
7.94 (1H, s), 8.61 (1H, s); C NMR (100 MHz, CDCl ) δ36.3, 48.0,
3
0
0
13
3
(
47 mg, 0.16 mmol) in 80% aq AcOH was stirred at room temper-
55.0, 63.5, 64.1, 65.1, 68.0, 87.8, 113.1, 128.6, 129.5, 132.4, 145.0,
150.6, 151.1, 151.2, 158.4; UV (MeOH) λmax 268 nm; IR (KBr)
3423.6, 1594.8, 1562.9, 1511.7, 1341.2, 1253.4, 1033.3 cm 1; EI-MS
ature for 6 h. After the solvents were removed under reduced
pressure, the residual solvents were further removed by repeating
coevaporation with EtOH 5 times. The residue was purified by
silica gel column chromatography (5% MeOH in CHCl ) to give
3
2
-
þ
(m/z) 436 (M ); HRMS calcd for C19
436.0974.
H
21ClN
O
S 436.0972, found
4
4
1
9 (40 mg, 98%) as a white solid: mp 195-198 °C; H NMR
((3S*,4R*)-4-(6-Chloro-9H-purin-9-yl)-3-(4-methoxybenzylthio)-
tetrahydrofuran-2,2-diyl)bis(methylene) Dimethanesulfonate (33).
To a solution of 32 (175 mg, 0.4 mmol) in CH Cl (10 mL) were
(
6
400 MHz, DMSO-d ) δ 1.76 (3H, s), 1.87 (1H, dd, J = 13.5,
6
3
.3 Hz), 2.20 (1H, dd, J = 13.5, 9.2 Hz), 3.24-3.30 (2H, m),
.38-3.50 (2H, m), 3.78 (1H, dd, J= 9.4, 5.1 Hz), 4.00 (1H, dd,
2
2
added MsCl (104 μL, 1.2 mmol), Et
DMAP (2 mg). After the mixture was stirred at room tempera-
ture for 1 h, the mixture was diluted with CH Cl and washed
with 5% HCl, satd NaHCO , and brine and then dried over
3
N (163 μL, 1.2 mmol), and
J=9.7, 7.3 Hz), 4.76 (1H, t, J=5.8 Hz), 4.89 (1H, t, J=5.8 Hz),
5
DMSO-d ) δ 12.2, 34.3, 54.6, 63.4, 70.1, 86.6, 109.1, 137.7, 150.9,
1
3
.04-5.11(1H,m),7.64(1H,s),11.22(1H,s); C NMR (100 MHz,
2
2
6
3
1
63.7; UV (MeOH) λmax 271 nm; IR (KBr) 3390.0, 1681.6, 1473.6,
2 4
Na SO . After filtration, the filtrated was concentrated under
-
1
þ
1
062.1, 1040.2 cm ; FAB-MS (m/z) 257 (M þ 1); HRMS calcd
reduced pressure. The residue was purified by silica gel column
chromatography (10% MeOH in CHCl ) to give 33 (221 mg,
for C H N O 257.1131, found 257.1137.
2
11
16
5
3
1
(
3S*,4S*)-3-(4-Methoxybenzylthio)-8,8-dimethyl-1,7,9-tri-
oxaspiro[4.5]decan-4-ol (30). To a solution of PMBSH (1.65 mL,
2 mmol) in dry methanol (15 mL) was added sodium methoxide
336 mg, 6.0 mmol), and the mixture was stirred at room
93%) as a white solid: mp 193-194 °C; H NMR (400 MHz,
3
CDCl ) δ3.16 (3H, s), 3.21 (3H, s), 3.41 (1H, d, J=14.0 Hz), 3.50
1
(
(1H, d, J=14.5 Hz), 3.74 (2H, s), 3.97 (1H, d, J=10.1 Hz), 4.28
(1H, t, J=8.7 Hz), 4.32 (3H, s), 4.48 (1H, d, J=11.1 Hz), 4.53
(1H, d, J=10.6 Hz), 4.57 (1H, t, J=8.7 Hz), 4.82 (1H, q, J=9.3
Hz), 6.4 (2H, d, J=8.2 Hz), 6.76 (2H, d, J=8.7 Hz), 7.98 (1H, s),
temperature for 20 min. To this mixture was added a solution
of 19 (559 mg, 3.0 mmol) in dry methanol (20 mL). After being
kept under reflux for 2 h, the mixture was allowed to cool to
room temperature. After the solvents were removed under redu-
ced pressure, the residue was purified by silica gel column chro-
1
3
3
8.57 (1H, s); C NMR (100 MHz, CDCl ) δ36.3, 37.8, 37.9,
48.7, 55.0, 63.7, 66.9, 68.6, 70.7, 83.7, 113.2, 127.9, 129.4, 132.6,
145.2, 150.4, 151.1, 151.4, 158.6; UV (MeOH) λmax 266 nm; IR
(KBr) 1511.8, 1368.6, 1335.2, 1173.3, 962.6, 816.3 cm 1; FAB-
-
matography (20% AcOEt in hexane) to give 30 (867 mg, 85%) as
1
þ
a white solid: mp 108-109 °C; H NMR (400 MHz, CDCl
δ1.41 (3H, s), 1,47 (3H, s), 2.59 (1H, d, J=2.9 Hz), 3.13 (1H, td,
J=7.0, 4.8 Hz), 3.53 (1H, dd, J=9.7, 7.2 Hz), 3.69 (1H, d, J=
3
)
MS (m/z) 593 (M ); HRMS calcd for C21
593.0606, found 593.0592.
H26ClN
4
O
S
8 3
((3S*,4R*)-4-(6-Chloro-9H-purin-9-yl)-3-mercaptotetrahydro-
furan-2,2-diyl)bis(methylene) Dimethanesulfonate (34) and ((1S*,
4R*,5S*)-4-(6-Chloro-9H-purin-9-yl)-2-oxa-6-thiabicyclo[3.2.0]-
hept-1-yl)methyl methanesulfonate (35). To a solution of 33
(90 mg, 0.15 mmol) in TFA (20 mL) were added PhOH (69 mg,
1
4
2.1 Hz), 3.74-3.85 (7H, m), 3.99-4.01 (1H, m), 4.03 (1H, s),
13
.23 (1H, dd, J = 4.6, 2.7 Hz); C NMR (100 MHz, CDCl )
3
δ 20.6, 26.5, 35.8, 49.8, 55.3, 62.9, 66.4, 70.7, 77.6, 81.6, 98.5,
1
1
for C H O S: C, 59.98; H, 7.11. Found: C, 59.92; H, 7.04
14.0, 129.9, 130.0, 158.8; IR (KBr) 3489.5, 1512.5, 1250.5,
076.8, 1030.2, 830.3 cm ; EI-MS (m/z) 340 (M ), Anal. Calcd
-
1
þ
2
0.75 mmol) and Hg(OAc) (113 mg, 0.3 mmol) at room tempera-
ture. After the mixture was stirred at room temperature for 1 h,
17
24
5
J. Org. Chem. Vol. 75, No. 12, 2010 4169

Yoshimura et al.
JOCArticle
the solvents were removed under reduced pressure. The residue was
-
1
260 nm; IR (KBr) 3423.7, 1683.4, 1208.3, 1142.7 cm ; EI-MS
þ
dissolved in CH
solution, andthen dried over Na
was concentrated under reduced pressure. The residue was puri-
fied by silica gel column chromatography (2% MeOH in CHCl
to give 35 (14 mg, 25%) as a less polar product and 34 (45 mg,
3%).
Data for 34: mp 155-157 °C; H NMR (400 MHz, CDCl )
2 2
Cl , washed with 0.1 M potassium thioacetate
(m/z) 279 (M ); HRMS calcd for C11
279.0782.
H
13
N
5
O
2
S 279.0790, found
2
SO . After filtration, the filtrated
4
3-Benzoyl-1-((3R*,4S*)-4-(4-methoxybenzylthio)-8,8-dimethyl-
1,7,9-trioxaspiro[4.5]dec-3-yl)-5-methylpyrimidine-2,4(1H,3H)-
dione (38). To a solution of 30 (340 mg, 1.0 mmol), PPh (392 mg,
3
1.5 mmol), and N -benzoylthymine (251 mg, 1.5 mmol) in THF
(30 mL) was dropwise added DEAD (680 μL, 1.5 mmol) at 0 °C.
After the mixture was stirred at room temperature for 1 h, the
solvents were removed under reduced pressure. The residue was
3
)
3
6
1
3
δ3.14 (3H, s), 3.17 (3H, s), 4.32 (1H, d, J=11.6 Hz), 4.38-4.52
(
7
5H, m), 4.62 (1H, d, J=11.6 Hz), 4.72 (1H, s), 5.04 (1H, q, J=
1
.9 Hz), 8.25 (1H, s), 8.67 (1H, s); C NMR (100 MHz, CDCl3)
3
purified by silica gel column chromatography (66% AcOEt in
hexane) to give 38 (326 mg, 59%): H NMR (400 MHz, CDCl )
1
δ37.9, 38.1, 46.8, 66.3, 68.0, 68.2, 68.9, 84.6, 132.4, 144.5, 151.4,
3
1
1
51.9, 152.1; UV (MeOH) λmax 267 nm; IR (KBr) 3621.0,
δ 1.45 (6H, s), 1.87 (3H, s), 2.77 (1H, s), 3.63 (1H, dd, J=12.3,
1.7 Hz), 3.73-3.83 (4H, m), 3.78 (3H, s), 3.97 (1H, dd, J=10.6,
4.4 Hz), 4.14 (1H, d, J=13.0 Hz), 4.20 (1H, dd, J=10.6, 7.2 Hz),
4.94 (1H, s), 6.83 (2H, d, J=8.7), 6.99 (1H, s), 7.19(2H, d, J=
8.7 Hz), 7.50 (2H, t, J = 7.7 Hz), 7.66 (1H, t, J = 7.5 Hz), 7.92
-
1
593.8, 1561.1, 1340.1, 1175.4, 964.2 cm ; FAB-MS (m/z)
þ
4
found 470.9814.
71 (M - 1); HRMS calcd for C H ClN O S 470.9870,
1
3
16
4
7 3
1
Data for 35: mp 167-168 °C; H NMR (400 MHz, CDCl
3
)
1
3
δ3.01 (3H, s), 3.24 (1H, d, J=11.6 Hz), 3.34 (1H, J=11.1 Hz),
3
(2H, d, J=7.7 Hz); C NMR (100 MHz, CDCl ) δ 12.5, 20.2,
3
4
(
.94 (1H, s), 4.35 (1H, d, J=11.1 Hz), 4.54 (1H, d, J=11.6 Hz),
.75 (1H, d, J = 11.1 Hz), 5.13 (1H, dd, J = 11.1, 4.4 Hz), 5.37
1H, d, J = 4.4 Hz), 8.38 (1H, s), 8.75 (1H, s); C NMR (100
26.7, 36.0, 52.0, 55.2, 62.4, 63.9, 65.9, 67.2, 79.4, 98.5, 112.2,
114.1, 128.4, 129.1, 130.1, 130.4, 131.4, 135.1, 135.6, 149.6,
159.0, 162.3, 168.6; UV (MeOH) λmax 277 nm; IR (KBr)
1
3
-
1
þ
MHz, CDCl ) δ31.6, 37.9, 50.6, 60.7, 66.8, 71.4, 87.9, 131.4,
1748.5, 1698.3, 1655.1, 1252.3 cm ; EI-MS (m/z) 552 (M );
HRMS calcd for C H N O S 552.1930, found 552.1931.
3
1 265 nm; IR (KBr)
1595.1, 1359.8, 1336.2, 1173.8, 957.0 cm ; EI-MS (m/z) 376
43.1, 151.1, 151.3, 152.1; UV (MeOH) λ
max
-
29 32
2
7
1
3-Benzoyl-1-((3R*,4S*)-5,5-bis(hydroxymethyl)-4-(4-methoxy-
benzylthio)tetrahydrofuran-3-yl)-5-methylpyrimidine-2,4(1H,3H)-
dione (39). A mixture of 38 (270 mg, 0.49 mmol) in 80% aq AcOH
(30 mL) was stirred at room temperature for 9 h. After the solv-
ents were removed under reduced pressure, the residual solvents
were further removed by repeating coevaporation with EtOH five
þ
(
M ); HRMS calcd for C12
H13ClN
4
O
4
S
2
376.0067, found
3
76.0068.
Conversion of Dimesylate 34 to Thietane 35. To a solution of
4 (56 mg, 0.12 mmol) in CH CN (5 mL) was added DBU (45 μL,
.36 mmol) at room temperature. The mixture was stirred at the
3
0
3
same temperature for 6 h. After the solvents were removed under
reduced pressure, the residue was dissolved in CH Cl , washed
with satd NH Cl and brine, and then dried over Na SO . After
times. The residue was purified by silica gel column chromato-
1
) to give 39 (216 mg, 86%): H NMR
graphy (1% MeOH in CHCl
(400 MHz, CDCl
3
2
2
3
) δ 1.79 (1H, s), 2.25 (2H, s), 3.51-3.62(2H, m),
4
2
4
filtration, the filtrated was concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
3.65-3.73 (4H, m), 3.76 (3H, s), 3.81 (1H, d, J = 8.2 Hz), 3.84
(1H, d, J = 6.8 Hz), 4.22 (1H, t, J = 8.7 Hz), 5.06 (1H, q, J =
7.6 Hz), 6.76 (1H, s), 6,84 (2H, d, J=8.2 Hz), 7.21 (2H, d, J=8.7
Hz), 7.50 (2H, t, J=7.7 Hz), 7.65 (1H, t, J=7.5 Hz), 7.91 (2H, d,
(
5% MeOH in CHCl ) to give 35 (29 mg, 65%) as a white solid.
3
(
(1S*,4R*,5S*)-4-(6-Chloro-9H-purin-9-yl)-2-oxa-6-thiabicyclo-
3.2.0]hept-1-yl)methyl Benzoate (36). A mixture of CsF (33 mg,
.22 mmol) and PhCOOH (27 mg, 0.22 mmol) in DMF (4 mL) was
1
3
[
0
J=7.7 Hz); C NMR (100 MHz, CDCl ) δ 12.5, 36.3, 48.0, 55.1,
3
63.4, 64.4, 68.3, 77.2, 87.2, 111.7, 114.1, 129.1, 129.5, 130.2, 131.6,
135.1, 136.0, 149.8, 159.0, 162.4, 168.7; UV (MeOH) λm-ax 279 nm;
stirred at room temperature for 20 min. To this mixture was added a
solution of 35 (28 mg, 0.074 mmol) in DMF (2 mL). After being
stirred at 60 °C for 36 h, the mixture was partitioned between
1
IR (KBr) 3441.4, 1747.9, 1697.1, 1654.1, 1252.5 cm ; EI-MS
þ
(m/z) 512 (M ); HRMS calcd for C26
512.1614.
H N O S 512.1617, found
28 2 7
AcOEt and H O. The separated water layer was extracted with
2
AcOEt ꢀ 4, and the combined organic layer was washed with satd
((3S*,4R*)-4-(3-Benzoyl-5-methyl-2,4-dioxo-3,4-dihydropyri-
midin-1(2H)-yl)-3-(4-methoxybenzylthio)tetrahydrofuran-2,2-
diyl)bis(methylene) Dimethanesulfonate (40). To a solution of 39
3 2 4
NaHCO and brine and then dried (Na SO ). After filtration, the
filtrated was concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (50% AcOEt in
(180 mg, 0.35 mmol) in CH
1.1 mmol), Et N (142 μL, 1.1 mmol), and DMAP (2 mg). After
the mixture was stirred at room temperature for 1 h, the mixture
was diluted with CH Cl , washed with 5% HCl, satd NaHCO
and brine, and then dried over Na SO . After filtration, the filt-
2 2
Cl (10 mL) were added MsCl (91 μL,
hexane) to give 36 (21 mg,70%) as a white solid: mp 151-152 °C;
3
1
3
H NMR (400 MHz, CDCl ) δ 3.40 (2H, s), 4.03 (1H, s), 4.53 (1H,
d, J=12.1 Hz), 4.60 (1H, d, J=12.1 Hz), 4.78 (1H, d, J=11.6 Hz),
.13 (1H, dd, J=11.1, 4.4 Hz), 5.33(1H, d, J=4.4 Hz), 7.41 (2H, t,
J=7.7 Hz), 7.59 (1H, t, J=7.24Hz), 7.79(2H, d,J=7.24Hz), 8,32
2
2
,
3
5
2
4
rate was concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (2% MeOH in
1
3
(
6
1
7
1H, s), 8.73 (1H, s); C NMR (100 MHz, CDCl
1.1, 65.0, 71.0, 88.7, 128.5, 128.7, 129.6, 133.7, 151.3, 151.3, 152.1,
66.1; UV (MeOH) λ 266 nm; IR (KBr) 1717.8, 1593.0, 1268.4,
3
) δ 32.5, 51.1,
1
) to give 40 (260 mg, quant): H NMR (400 MHz, CDCl
CHCl
3
3
)
δ1.84 (3H, s), 3.03 (3H, s), 3.09 (3H, s), 3.52 (1H, d, J=9.2 Hz),
3.68 (2H, s), 3.77 (3H, s), 3.97 (1H, dd, J=9.4, 7.5 Hz), 4.11 (2H,
s), 4.22 (1H, t, J=9.4 Hz), 4.34 (1H, d, J=11.1 Hz), 4.41 (1H, d,
J=11.1 Hz), 4.88 (1H, s), 6.84 (2H, d, J=8.7 Hz), 6.86 (1H, s),
7.19 (2H, d, J=8.7 Hz), 7.51 (2H, t, J=7.7 Hz), 7.66 (1H, t, J=
max
-
1
þ
13.2 cm
;
EI-MS (m/z) 402 (M ); HRMS calcd for
S 402.0553, found 402.0560.
(1S*,4R*,5S*)-4-(6-Amino-9H-purin-9-yl)-2-oxa-6-thiabicyclo-
18 4 3
C H15ClN O
(
[
in 8 N NH
3.2.0]hept-1-yl)methanol (37). A solution of 36 (26 mg, 0.65 mmol)
in MeOH (5 mL) was kept at 100 °C for 24 h in a glass-
13
7.5 Hz), 7.91 (2H, d, J=7.7 Hz); C NMR (100 MHz, CDCl )
3
3
sealed tube. After the solvents were removed under reduced
pressure, the residue was purified by silica gel column chromato-
δ12.1, 36.4, 37.5, 37.6, 48.7, 54.9, 63.8, 67.3, 68.8, 69.5, 83.4, 111.7,
114.0, 128.8, 129.1, 130.0, 130.2, 131.3, 135.1, 136.6, 149.5, 158.9,
162.2, 168.7; UV (MeOH) λmax 281 nm; IR (KBr) 1748.2, 1698.4,
graphy (5% MeOH in CHCl
3
) to give 37 (13 mg, 72%) as a white
solid: mp 223-224 °C; H NMR (400 MHz, CD OD) δ 3.04 (1H,
d, J=10.6 Hz), 3.15(1H, d, J=10.6Hz), 3.59 (1H, d, J=12.1 Hz),
1
-1
þ
1658.2, 1361.7, 1174.8 cm ; FAB-MS (m/z) 669 (M þ 1);
3
HRMS calcd for C H N O S 669.1246, found 669.1252.
2 11 3
2
8
32
3
4
8
6
.72 (1H, d, J=12.1 Hz), 3.80 (1H, s), 4.54 (1H, d, J=11.1 Hz),
.93 (1H, dd, J=11.1, 4.4 Hz), 5.10 (1H, d, 4.4 Hz), 8.10 (1H, s),
((3S*,4R*)-3-Mercapto-4-(5-methyl-2,4-dioxo-3,4-dihydro-
pyrimidin-1(2H)-yl)tetrahydrofuran-2,2-diyl)bis(methylene) Di-
methanesulfonate (41). To a solution of 40 (67 mg, 0.1 mmol)
in TFA (20 mL) were added PhOH (48 mg, 0.5 mmol) and
13
3
.29 (1H, s); C NMR (100 MHz, CD OD) δ 32.3, 52.1, 62.5,
4.5, 72.5, 92.1, 119.6, 141.1, 150.3, 152.9, 156.7; UV (MeOH) λmax
4
170 J. Org. Chem. Vol. 75, No. 12, 2010

Yoshimura et al.
JOCArticle
Hg(OAc) (64 mg, 0.2 mmol) at room temperature. After the
2
(1H, d, J=12.1 Hz), 4.66 (1H, d, J=12.1 Hz), 4.90 (1H, dd, J=
11.6, 5.3 Hz), 5.12 (1H, d, J=4.8 Hz), 7.42 (2H, t, J=7.7 Hz), 7.59
mixture was stirred at room temperature for 1 h, the solvents
were removed under reduced pressure. The residue was dissolved
in CH Cl , washed with 0.1 M potassium thioacetate solution,
13
(1H, t, J=7.5 Hz), 7.93 (2H, dd, J=8.2, 1.5 Hz), 8.14 (1H, s);
C
NMR (100 MHz, CDCl ) δ 12.2, 32.1, 51.5, 62.3, 65.0, 69.9, 88.5,
2
2
3
and then dried over Na
concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (2% MeOH in CHCl ) to
give 41 (46 mg, quant) as a white solid: mp 155-156 °C; H NMR
2
SO
4
. After filtration, the filtrated was
111.6, 128.6, 129.1, 129.6, 133.7, 135.9, 150.7, 163.0, 166.1; UV
(MeOH) λmax 272 nm; IR (KBr) 3440.3, 1723.7, 1683.8, 1280.1
cm ; EI-MS (m/z) 374 (M ); HRMS calcd for C18H N O S
18 2 5
-
1
þ
3
1
374.0937, found 374.0937.
(
(
4
400 MHz, CDCl
1H, m), 4.09 (1H, d, J=8.2 Hz), 4.14 (1H, dd, J=10.1, 4.4 Hz),
.31 (1H, d, J=11.1 Hz), 4.38 (1H, d, J=10.6 Hz), 4.39 (1H, d,
J=11.1 Hz), 4.58 (1H, dd, J=11.1, 3.9 Hz), 4.96 (1H, q, J=7.7
3
) δ 1.76 (1H, s), 3.23 (3H, s), 3.24 (3H, s), 3.83
1-((1S*,4R*,5S*)-1-(Hydroxymethyl)-2-oxa-6-thiabicyclo[3.2.0]-
hept-4-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (44). A solution of
43 (3 mg, 0.0080 mmol) in 8 N NH in MeOH (3 mL) was stirred at
3
room temperature for 6 h. After the solvents were removed under
reduced pressure, the residue was purified by silica gel column
1
3
Hz), 7.50 (1H, s), 11.39 (1H, s); C NMR (100 MHz, DMSO-d
6
)
δ 12.2, 36.6, 37.0, 37.1, 50.4, 67.0, 69.2, 69.8, 87.2, 137.0, 150.9,
3
chromatography (9% MeOH in CHCl ) togive44 (2 mg, 93%) as a
1
1
1
51.6, 163.6; UV (MeOH) λ
271 nm; IR (KBr) 3456.2, 1687.9,
white solid: H NMR (400 MHz, CD OD) δ 1.75 (3H, s), 2.94 (1H,
max
3
-
1
þ
351.5, 1174.0 cm ; FAB-MS (m/z) 443 (M - 1); HRMS calcd
d, J=10.6 Hz), 3.11 (1H, d, J=10.6 Hz), 3.58 (1H, d, J=12.1 Hz),
3.64(1H, s), 3.75(1H, d, J=12.6Hz), 4.34(1H, d,J=11.6Hz), 4.73
for C13
(1S*,4R*,5S*)-4-(5-Methyl-2,4-dioxo-3,4-dihydropyrimidin-
(2H)-yl)-2-oxa-6-thiabicyclo[3.2.0]hept-1-yl)methyl Methane-
sulfonate (42). To a solution of 41 (30 mg, 0.067 mmol) in
CH CN (5 mL) was added DBU (26 μL, 0.20 mmol) at room
19 2 9 3
H N O S 443.0253, found 443.0209.
1
3
(
(1H, d, J=5.3 Hz), 4.99 (1H, d, J=5.3 Hz), 7.65 (1H, s); C NMR
(100 MHz, CD OD) δ 12.3, 30.8, 32.1, 52.3, 63.9, 64.4, 71.6, 92.1,
1
3
111.0, 139.9, 153.4; UV (MeOH) λmax 271 nm; IR (KBr) 3440.2,
1678.5, 1138.1 cm .
-
1
3
temperature. The mixture was stirred at the same temperature
for 24 h. After the solvents were removed under reduced
Theoretical Calculations. The theoretical calculations were
performed by using SPARTAN (Wavefunction, Inc.). Confor-
mers of model compounds were surveyed by molecular me-
chanics (MM) calculations. The structures of the conformers
obtained by MM were further optimized by theoretical calcula-
tions using density functional theory (DFT) quantum mechan-
pressure, the residue was dissolved in CH
2
Cl
satd NH Cl and brine, and then dried over Na
2
, washed with
SO . After
4
2
4
filtration, the filtrate was concentrated under reduced pres-
sure. The residue was purified by silica gel column chromato-
graphy (5% MeOH in CHCl ) to give 42 (14 mg, 60%) as a
2
0
3
ical calculations at the B3LYP/6-31G** level.
1
white solid: mp 239-240 °C; H NMR (400 MHz, DMSO-d
6
)
Evaluation for Antiviral Activities. Anti-HIV-1 activities of
isonucleosides were assayed by inhibition of HIV replication in
peripheral blood mononuclear cells (PBMC). Anti-HIV effect
δ1.73 (3H, s), 3.17 (1H, d, J=11.1 Hz), 3.20 (3H, s), 3.29 (1H,
d, J=6.3 Hz), 3.81 (1H, s), 4.37 (1H, d, J=11.6 Hz), 4.52 (2H,
d, J=11.1 Hz), 4.74 (1H, dd, J=11.6, 5.3 Hz), 4.93 (1H, d, J=
2
6
was determined by p24 HIV antigen assay. Anti-HSV-1
activities of isonucleosides were evaluated by a plaque reduction
method.
1
3
5
.3 Hz), 7.26 (1H, s), 11.30 (1H, s); C NMR (100 MHz,
2
7
DMSO-d ) δ12.2, 31.0, 36.6, 50.4, 61.9, 69.2, 69.8, 87.2, 108.9,
6
1
3
37.0, 150.9, 163.7; UV (MeOH) λmax 270 nm; IR (KBr)
664.3, 1687.5, 1348.0, 1172.3 cm ; EI-MS (m/z) 348 (M );
-
1
þ
Acknowledgment. This work was supported in part by a
Grant-in-Aid for Scientific Research (Nos. 18590103, 21590119),
JSPS (Y.Y.), by Research for Promoting Technological Seeds,
JST (Y.Y.), and by the High Technology Research Program
from Ministry of Education, Culture, Sports, Science and Tech-
nology of Japan.
HRMS calcd for C H N O S 348.0450, found 348.0437.
1
2
16
2
6 2
(
(1S*,4R*,5S*)-4-(5-Methyl-2,4-dioxo-3,4-dihydropyrimidin-
(2H)-yl)-2-oxa-6-thiabicyclo[3.2.0]hept-1-yl)methyl Benzoate (43).
A mixture of CsF (23 mg, 0.16 mmol) and PhCOOH (21 mg,
.16 mmol) in DMF (4 mL) was stirred at room temperature for
0 min. To this mixture was added a solution of 42 (18 mg,
.052 mmol) in DMF (2 mL). After being stirred at 60 °C for
6 h, the mixture was partitioned between AcOEt and H O. The
separated water layer was extracted with AcOEt ꢀ 4, and the
combined organic layer was washed with satd NaHCO and brine
and then dried (Na SO ). After filtration, the filtrated was concen-
1
0
2
0
3
1
Supporting Information Available: Data for H and
13
C
2
NMR of compounds 14-44 except 16 and DFT calculation
results for compounds 45 and 46. This material is available free
of charge via the Internet at http://pubs.acs.org.
3
2
4
trated under reduced pressure. The residue was purified by silica gel
column chromatography (50% AcOEt in hexane) to give 36 (8 mg,
(
26) Brann, T. W.; Dewar, R. L.; Jiang, M.-K.; Shah, A.; Nagashima, K.;
Metcalf, J. A.; Falloon, J.; Lane, H. C.; Imamichi, T. J. Virol. 2006, 80, 6136–
145.
27) Okuda, T.; Kurokawa, K.; Matsuo, K.; Honda, M.; Niimura, M.;
Shiraki, K. J. Med. Virol. 2004, 72, 112–120.
1
4
0%) as a white solid: mp 181-182 °C; H NMR (400 MHz,
6
CDCl
(
3
) δ1.50 (3H, s), 1.57 (3H, s), 3.28 (1H, d, J= 11.1 Hz), 3.32
(
1H, d, J= 11.1 Hz), 3.87 (1H, s), 4.43 (1H, d, J= 11.6 Hz), 4.51
J. Org. Chem. Vol. 75, No. 12, 2010 4171