Synthesis of conformationally locked carbocyclic nucleosides built on a thiabicyclo[3.1.0]hexane system as a pseudosugar surrogate

Article abstract of DOI:10.1002/ejoc.200600488

The synthesis of prototype models of purine and pyrimidine carbanucleosides built on a 6-thiabicyclo[3.1.0]hexane system as pseudosugar moiety has been investigated. These pyrimidine carbanucleosides proved to be very stable compounds, in contrast to the parent epoxy analogs, which experienced epoxide ring-opening due to intramolecular enol base attack. In addition, as the synthesis of a thiirane moiety fused to a five-membered ring is not a trivial synthetic task, validation and optimization of the existing methods for episulfide preparation were required to access the committed synthetic precursor of the title compounds: (±)-(1RS,2RS,5SR)-6-thiabicyclo[3.1.0]hexan-2- ol, compound 28. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200600488

FULL PAPER
DOI: 10.1002/ejoc.200600488
Synthesis of Conformationally Locked Carbocyclic Nucleosides Built on a
Thiabicyclo[3.1.0]hexane System as a Pseudosugar Surrogate
Eleonora Elhalem,[a] María J. Comin,[a] and Juan B. Rodriguez*[a]
Keywords: 6-Thiabicyclo[3.1.0]hexane / Thiiranes / 2Ј,3Ј-Dideoxyneplanocin C / Nucleosides / Carbanucleosides
The synthesis of prototype models of purine and pyrimidine
carbanucleosides built on a 6-thiabicyclo[3.1.0]hexane sys-
tem as pseudosugar moiety has been investigated. These
pyrimidine carbanucleosides proved to be very stable com-
pounds, in contrast to the parent epoxy analogs, which expe-
rienced epoxide ring-opening due to intramolecular enol
base attack. In addition, as the synthesis of a thiirane moiety
fused to a five-membered ring is not a trivial synthetic task,
validation and optimization of the existing methods for epi-
sulfide preparation were required to access the committed
synthetic precursor of the title compounds: ( )-
(1RS,2RS,5SR)-6-thiabicyclo[3.1.0]hexan-2-ol, compound 28.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
fit molecular recognition as a result of the smaller size of
the epoxy group. In addition, many nucleoside derivatives
bearing an oxabicyclo[3.1.0]hexane system as sugar moiety
exhibit important pharmacological properties.[5–12] On the
basis of this idea, carbocyclic nucleosides 2–5 were de-
signed, motivated not only by the potential antiviral prop-
erties of the pyrimidine derivatives, but also to enable hetero-
duplex stabilization studies to be carried out (Figure 2).[13]
However, it was not possible to obtain the theoretical pyr-
imidine derivatives 4 and 5 as a consequence of intermo-
lecular enol base attack on the epoxy group present in their
synthetic intermediates 6 and 7, which form the tricyclic
structures 8 and 9, as illustrated in Scheme 1.
Introduction
Nucleosides have been demonstrated to be a profuse
source of lead drugs in the search for new antiviral and
antitumor agents. The isosteric replacement of the furanose
ring by a cyclopentyl moiety affords a new class of metabol-
ically more stable nucleoside analogs known as carbocyclic
nucleosides. The absence of the oxygen atom in the furanose
ring enhances potential structural variations at different
positions not possible with conventional nucleosides.[1,2]
The carbanucleoside analog N-methanocarbathymidine
[(1ЈS,2ЈS,4ЈS,5ЈR)-1-{4-hydroxy-5-(hydroxymethyl)bicyclo-
[3.1.0]hex-2-yl}-5-methylpyrimidine-2,4(1H,3H)-dione
(1)] has been found to exhibit potent antiherpetic activity
against the herpes simplex virus types 1 (HSV-1) and 2
(HSV-2) (Figure 1).[3,4] The efficacy of this carbocyclic nu-
cleoside is even greater than that exhibited by acyclovir, a
well-known antiherpetic agent.[3,4]
Figure 2. Chemical structures of carbanucleosides built on an oxa-
bicyclic[3.1.0]hexane system.
Figure 1. Chemical structure of N-methanocarbathymidine (1).
It had been considered that the isosteric replacement of
the cyclopropyl moiety of 1 by an epoxy group would bene-
[a] Departamento de Química Orgánica, Facultad de Ciencias Ex-
actas y Naturales, Universidad de Buenos Aires,
Pabellón 2, Ciudad Universitaria, C1428EHA, Buenos Aires,
Argentina
Scheme 1.
This spontaneous epoxide ring-opening reaction had
been quite unexpected bearing in mind that this epoxy
group proved to be a very stable functionality in similar
structurally related compounds even in harsh basic condi-
Fax: +54-11-4-576-3385
E-mail: jbr@qo.fcen.uba.ar
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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E. Elhalem, M. J. Comin, J. B. Rodriguez
FULL PAPER
tions such as methanolic ammonia.[13–16] Therefore, this in-
tramolecular reaction could be attributable to the relative
positions of the epoxy group and the pyrimidine base rather
than the lability of the epoxide.
Owing to the incompatibility of an epoxy group adjacent
to a pyrimidine base, it was thought that the isosteric re-
placement of the cyclopropyl moiety with a thiirane group
would be more appropriate. The preparation of carbanu-
cleosides, especially pyrimidine derivatives, built on a thiab-
icyclo[3.1.0]hexane system is not a trivial task for a number
of reasons: 1) the existing methods for the introduction of
an episulfide into a five-membered ring are associated with
extremely low reaction yields making them impractical
from a synthetic point of view;[17–36] 2) when an epoxy
group is present in the vicinity of a pyrimidine heterocyclic
base, an intramolecular attack by the enol of the base takes
place to produce epoxy ring-opening; 3) as epoxides and
thiiranes exhibit similar chemical properties, there is also a
risk of episulfide ring-opening.
Scheme 2. Reagents and conditions: (a) N3-benzoylthymine, PPh3,
DEAD, THF, –45 °C, 2 h Ǟroom temp., 16 h, 21% for 11; N3-ben-
zylthymine, PPh3, DEAD, THF, –45 °C, 30 minǞroom temp. 16 h,
26% for 13; (b) NH3/MeOH, 0 °C, 1 h 30 min, 84% from 11; H2,
1 atm, 10% Pd/C, MeOH, room temp., 48% from 13; (c) thymine,
PPh3, DEAD, THF, –45 °C, 2 h Ǟroom temp., 16 h, 20%.
Results and Discussion
ticeable at pH = 12.5. At this pH, a hydroxy ion from the
medium attacked the epoxide at C-5Ј to form irreversibly
compound 16.
In order to study the tendency for base O-2 nucleophilic
attack on any 6-oxabicyclo[3.1.0]hexane system, a very sim-
ple model of a carbocyclic thymidine derivative was pre-
pared, as shown in Scheme 2. ( )-cis-6-Oxabicyclo[3.1.0]-
hexan-2-ol (10)[14] was used as a rigid carbocyclic ring. This
compound was coupled with N3-benzoylthymine[37] to give
11, which, after ammonolysis, produced the tricyclic com-
pound 12. It was considered that the basic conditions em-
ployed could catalyze this transformation and, for this
reason, N3-benzylthymine[38] was used instead of N3-benzo-
ylthymine. The very mild conditions used for benzyl ether
cleavage would not catalyze any nucleophilic attack. There-
fore, epoxy alcohol 10 was treated with N3-benzylthymine
under Mitsunobu conditions to give 13. Surprisingly, cata-
lytic hydrogenation of 13 also produced 12. Moreover, when
10 was treated with free thymine under Mitsunobu-type
conditions 12 was isolated as the main product.
Molecular modelling studies of the optimized energy
conformers of compounds 12 (opened ring) and 14 (the
base built on the 6-oxabicyclic system) indicated that 12 is
2.88 kcal/mol more stable than the hypothetical compound
14. The ab initio energy calculations of the optimized con-
formers were performed with the Gaussian 98 program em-
ploying a HF/6-31Gdp basis set.[39] An equilibrium between
the open and intact epoxy group may be postulated to favor
the opened-ring structure, as shown in Scheme 3. Bearing
in mind that the O-bonded position of the base is a good
leaving group and that the free hydroxy group at C-4Ј can
Scheme 3.
Once this incompatibility was established, the isosteric
act as an intramolecular nucleophile, this equilibrium was replacement of the oxygen atom by a sulfur atom was envi-
1
studied by H NMR spectroscopy at different pHs starting sioned. The common precursor for the preparation of a
at neutral pH = 7.0 and ascending in order to pH = 14.0 particular thiirane ring may be either the corresponding ep-
in 0.5 pH-unit increments. Above pH = 9.0 it was possible oxide or the corresponding alkene, the former one being
to observe the signal corresponding to the epoxy group as favored. In order to validate a reliable method for the prep-
a singlet centered at δ = 3.28 ppm. This effect is more no- aration of an episulfide attached to a five-membered ring,
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Synthesis of Conformationally Locked Carbocyclic Nucleosides
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it was considered that epoxides 17–19 would be suitable ferent sulfur-containing reagents such as potassium thiocy-
models for the preparation of the corresponding thiirane anate in water/methanol,[17,18] thiourea,[19] N,N-dimethyl-
derivatives. Compound 19 is the synthetic intermediate in thioformamide,[20] ammonium thiocyanate with tert-butyl
the preparation of simple carbanucleosides built on a thia- alcohol as a solvent in the presence of ceric ammonium
bicyclo[3.1.0]hexane system bearing in mind that episulfide nitrate[21] and ammonium thiocyanate in acetonitrile in the
formation from an epoxide occurs with inversion of the presence of ruthenium trichloride.[22] Another interesting
configuration. The introduction of the silyl ether function- method was the preparation of thiiranes via the corre-
alities was motivated by the need to obtain aqueous hypos- sponding 2-chloroalkyl 2Ј,4Ј-dinitrophenyl sulfides, which
oluble compounds that would be easy to handle. Therefore, could be easily prepared from the corresponding alkene.[36]
on treatment with m-chloroperbenzoic acid, cyclohexenol This method was not satisfactory for the preparation of 22
20 was converted into 21 as a single diastereomer according starting from 25. In this case, when 25 was treated with 2,4-
to Henbest’s rule.[40] Compound 18 was prepared starting dinitrobenzenesulfenyl chloride a complex mixture of prod-
from the already described epoxy alcohol 10 by treatment ucts was obtained instead of the desired 2-chloroethyl 2Ј,4Ј-
with tert-butylchlorodiphenylsilane. Compound 19 was pre- dinitrophenyl sulfide. The best results were obtained by em-
pared from cyclopentenol 23. This compound, treated with ploying potassium thiocyanate or thiourea with good yields
tert-butylchlorodiphenylsilane, afforded the corresponding of 65 and 64%, respectively, while the use of either ammo-
silyl ether 24, which treated with m-chloroperbenzoic acid nium thiocyanate or N,N-dimethylthioformamide gave very
yielded 19 as the main product and a minor product, which low yields making these methods impractical from a syn-
turned out to be compound 18. The relative stereochemistry thetic point of view. In addition, N,N-dimethylformamide
of 19 was unambiguously established by analysis of the was an inappropriate solvent when used in combination
NMR spectra of this minor component, which matched the with potassium thiocyanate because epoxide 17 could not
spectroscopic data of 18 prepared from epoxy alcohol 10.[14] be transformed into thiirane 22 under these reactions condi-
As the tert-butyldiphenylsilyl moiety is a bulky group, the tions. Therefore, it was decided to employ potassium thiocy-
stereochemical course of the epoxidation reaction can be anate as the sulfur-introducing reagent using a mixture of
explained by electrophilic attack of the epoxidizing agent methanol and water as the solvent. Note that on treatment
on the less hindered side of the molecule (Scheme 4).
with potassium thiocyanate in methanol/water at room tem-
perature, 17 was readily converted into 22 in a highly dia-
stereoselective reaction. These results were in agreement
with the postulated reaction mechanism[18] and with some
experimental observations.[22] The introduction of an epi-
sulfide functionality into a five-membered ring required
stronger reaction conditions such as higher temperatures
and a longer reaction time, as expected.[18] Certainly, epox-
ides 18 and 19, in independent experiments, treated with
potassium thiocyanate in methanol/water under reflux for
15 h, gave the title compounds 26 and 27, respectively, with
high stereoselectivity. Once again, the reaction occurred
with inversion of the configuration at the positions where
the epoxy group was originally bonded (Scheme 4). The for-
mation of products with retention of configuration was not
observed in any case.
Purine carbanucleosides built on a thiabicyclo[3.1.0]hex-
ane system were readily synthesized from the thiirane pre-
cursor 27. Thus, this compound treated with a solution of
tetrabutylammonium fluoride in tetrahydrofuran afforded
the corresponding alcohol 28 in 92% yield. Analysis of the
1H NMR spectrum of 28 showed similar multiplicity pat-
terns to those in the spectrum of the epoxy alcohol 10. As
an example, the signal corresponding to 2-H of 28 appeared
as a doublet of triplets (J = 7.9 and 3.7 Hz) centered at δ =
4.49 ppm, while the signal corresponding to 2-H of 10 also
appeared as a doublet of triplets (J = 8.0 and 1.2 Hz). How-
ever, the signal arising from 2-H of the diastereoisomer 29
Scheme 4. Reagents and conditions: (a) MCPBA, CH2Cl2,
0 °CǞroom temp., 1 h, 83% for 21; 57% for 19; 32% for 18; (b)
imidazole, DMF, TBDPSCl, 0 °CǞroom temp., 6 h, 66% for 17;
20 h, 82% for 24; 20 h, 83% for 25; (c) KSCN, EtOH/H2O (1:1),
room temp., 72 h, 65% for 22; reflux, 15 h, 23% for 26; reflux, 15 h,
48% for 27.
Once these precursors for thiirane preparation were at was observed as a doublet (J = 4.8 Hz) centered at δ =
hand, the appropriate method to transform the epoxy 4.49 ppm. Once the relative stereochemistry was confirmed,
group into a thiirane ring was validated. Attempts to con- alcohol 28 was coupled with 6-chloropurine under Mitsu-
vert compound 17 into the thiirane 22 were made under a nobu-type conditions[40] to produce the desired carbocyclic
variety of conditions, for example, by treatment with dif- nucleoside derivative, yielding exclusively the N9-alkylated
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E. Elhalem, M. J. Comin, J. B. Rodriguez
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Scheme 5. Reagents and conditions: (a) 1.0  (nBu)4NF, THF, 0 °CǞroom temp., 2 h, 92% for 28; 95% for 29; (b) 6-chloropurine, Ph3P,
DEAD, THF, room temp., 24 h; (c) NH3/MeOH, 70 °C, 3 h, 38% from 28; (d) 2-amino-6-benzyloxypurine, Ph3P, DEAD, THF, room
temp., 24 h, 28%; (e) 1.0  BCl3 in CH2Cl2, CH2Cl2, –78 °C, 4 h, 63 %.
product 30. Treatment of 30 with methanolic ammonia gave these Mitsunobu-type reactions. The cytosine target 38 was
the sulfur-containing carbocyclic analog of adenosine 31. prepared from 37 via the formation of a triazole intermedi-
The presence of a thiirane group fused to a five-membered ate according to published methods (Scheme 6).[48]
ring produced a similar effect as a cyclopropyl[41–44] or ep-
oxy group,[13–16] fixing the pseudosugar conformation in the
northern hemisphere, as deduced from the analysis of the
1
relevant coupling constants of the H NMR spectrum. The
signal corresponding to the pseudoanomeric proton (2Ј-H)
was observed as a doublet centered at δ = 5.17 ppm with a
coupling constant of 6.6 Hz, indicating that the two torsion
angles between the pseudoanomeric proton and the three
adjacent hydrogen atoms were close to 90°. The sulfur-con-
taining carbocyclic analog of guanosine 33 was prepared
from 28 in a Mitsunobu coupling[45–47] reaction with 2-
amino-6-benzyloxypurine[41,42] to yield the carba-guanosine
precursor 32. As shown for the adenosine analog, the N7-
alkylated product was not detected. Benzyl ether cleavage
by treatment with boron trichloride afforded compound 33
in 63% yield without affecting the thiirane group
Scheme 6. Reagents and conditions: (a) N3-benzoylthymine, Ph3P,
DEAD, THF, –45 °C, 2 h, Ǟroom temp., 22 h, 38% or N3-benzo-
yluracil, Ph3P, DEAD, THF, –45 °C, 30 minǞroom temp., 48 h,
49%; (b) NH3/MeOH, 0 °C, 1 h, 41 % for 35 from 28, 95% for 37
from 28; (c) i. POCl3, 1,2,4-triazole, Et3N, CH3CN, room temp.,
36 h, ii. NH4OH, dioxane, room temp., 20 h, 43%.
(Scheme 5).
The corresponding pyrimidine derivatives were also syn-
thesized directly. The heterocyclic base was introduced by
treatment of 28 with N3-benzoylthymine[37] under Mitsu-
nobu-type conditions at –45 °C to form 34 as a single iso-
mer, which after benzoyl group cleavage by treatment with
methanolic ammonia at 0 °C for one hour afforded com-
pound 35. Contrary to what was observed for pyrimidine
Unexpectedly and in contrast to the antiviral activity ex-
derivatives built on the oxabicyclo[3.1.0]hexane system, hibited by the parent epoxy derivatives,[14] all title com-
which underwent epoxide ring-opening by intramolecular pounds were devoid of antiviral activity against herpes sim-
attack of the heterocyclic base, 35 was a stable carbanucleo- plex virus types 1 and 2, and human cytomegalovirus. Anti-
side. This is a very relevant result because it will enable the viral activity was evaluated following standard pro-
design of more complex carbanucleosides bearing a thia- cedures.[49]
bicyclo[3.1.0]hexane system as the pseudosugar moiety. The
In conclusion, the preparation of five-membered rings
uridine derivative 37 was prepared following a similar ap- bearing a thiirane group was successfully carried out. Lit-
proach: alcohol 28 treated with N3-benzoyluracil yielded 36, erature data indicated that the preparation of episulfides
which after treatment with methanolic ammonia afforded fused to a cyclopentane ring, although apparently a trivial
the desired carbocyclic nucleoside 37. This nucleoside ana- chemical transformation, was not a simple task. In ad-
log was also stable on standing. The usual competition, O- dition, with the above results at hand, it was possible to
versus N-alkylation,[41,42] was not observed in either of- synthesize simple models of carbanucleosides built on a 6-
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Synthesis of Conformationally Locked Carbocyclic Nucleosides
FULL PAPER
1.28 mmol) under argon. The resulting mixture was stirred at 0 °C
for 20 min. After cooling to –45 °C, a solution of N3-benzylthymine
(186 mg, 0.86 mmol) and ( )-cis-6-oxabicyclo[3.1.0]hexan-2-ol (10;
50 mg, 0.5 mmol) in tetrahydrofuran (8 mL) was added over a
period of 10 min. The reaction mixture was stirred at –45 °C for
30 min and then at room temperature overnight. The reaction was
quenched as described for 11 and the residue was purified by col-
umn chromatography (silica gel) eluting with hexane/EtOAc (4:1).
Compound 13 was repurified by column chromatography em-
ploying CH2Cl2/Et2O (99:1) as eluent to afford 38 mg (26% yield)
of pure compound 13 as a colorless oil. 1H NMR (200 MHz,
CDCl3): δ = 7.23–7.55 (m, 5 H, aromatic protons), 6.82 (d, J =
1.5 Hz, 1 H, 6-H), 5.00 (d, J = 7.3 Hz, 1 H, 2Ј-H), 3.76 (s, 1 H, 1Ј-
H), 3.50 (d, J = 1.8 Hz, 1 H, 5Ј-H), 1.94 (d, J = 1.1 Hz, 3 H, CH3),
1.64–2.20 (m, 4 H, 3Ј-H, 4Ј-H) ppm. 13C NMR (CDCl3): δ = 163.1
(C-4), 151.3 (C-2), 136.8 (C-6), 135.1 (Ph), 129.1 (Ph), 128.3 (Ph),
127.5 (Ph), 110.4 (C-5), 60.3 (C-5Ј), 57.9 (C-1Ј), 56.8 (C-2Ј), 44.7
(PhCH2), 27.9 (C-3Ј), 26.4 (C-4Ј), 13.3 (CH3) ppm.
thiabicyclo[3.1.0]hexane system as the pseudosugar unit.
The main finding of this study was the stability of these
sulfur-containing carbanucleosides, which was not observed
when an epoxy group was used to fix the sugar conforma-
tion. Finally, the smaller size of the thiirane moiety relative
to the cyclopropyl group present in other carbanucleosides
of pharmacological importance seems to be beneficial for
molecular recognition. These results provide new insights
into the design of new carbanucleosides.
Experimental Section
The glassware used in air- and/or moisture-sensitive reactions was
flame-dried and carried out under argon. Unless otherwise noted,
chemicals were commercially available and used without further
purification. NMR spectra were recorded with a Bruker AM-500
spectrometer. Chemical shifts are reported in parts per million (δ)
Tricyclic Compound 12
1
relative to tetramethylsilane. The H NMR spectra are referenced
Method A: Compound 11 (50 mg, 0.16 mmol) was treated with
methanolic ammonia (5 mL, saturated at –78 °C) and stirred in a
sealed tube at 0 °C for 30 min. The mixture was cooled to –70 °C,
the tube opened and nitrogen was bubbled through it to eliminate
the ammonia. The solvent was evaporated and the residue was
purified by column chromatography (silica gel) eluting with EtOAc/
hexane (4:1) to give 28 mg (84% yield) of pure compound 12 as a
white solid.
to the residual CHCl3 proton of the solvent CDCl3 (δ = 7.26 ppm).
Coupling constants are reported in Hertz (Hz). 13C NMR spectra
were fully decoupled and are referenced to the middle peak of the
solvent CDCl3 (δ = 77.0 ppm). Splitting patterns are designated as
follows: s, singlet; d, doublet; t, triplet; q, quartet. Low-resolution
mass spectra were obtained with a VG TRIO 2 instrument at 70 eV
(direct inlet). High-resolution mass spectra were recorded with a
Micromass Q-Tof Ultima apparatus, which is a hybrid quadrupole
time-of-flight mass spectrometer with MS/MS capability. Melting
points were determined using a Fisher-Johns apparatus and are
uncorrected. Column chromatography was performed with E.
Merck silica gel (Kieselgel 60, 230–400 mesh). Analytical thin-layer
chromatography was performed by employing 0.2 mm coated com-
mercial silica gel plates (E. Merck, DC-Aluminium sheets, Kieselgel
60 F254) which were visualized with 254 nm UV light or by immer-
sion in an ethanolic solution of 5% H2SO4. Elemental analyses
were performed by Atlantic Microlab, Norcross, Georgia. The re-
sults were within 0.4% of the theoretical values except where
otherwise stated.
Method B: A solution of compound 13 (35.1 mg, 0.12 mmol) in
methanol (10 mL) in the presence of 10% Pd/C was treated with
hydrogen at 1 atm. The solution was stirred at room temperature
for 3 h. The mixture was filtered off and the solvent evaporated.
The residue was purified by column chromatography (silica gel)
eluting with CH2Cl2/methanol (19:1) to give 12.0 mg (48% yield)
of pure compound 12 as a white solid.
Method C: A solution of triphenylphosphane (828 mg, 3.2 mmol)
in anhydrous tetrahydrofuran (20.0 mL) was treated with diethyl
azodicarboxylate (1.1 mL, 3.0 mmol) under argon. The resulting
mixture was stirred at 0 °C for 20 min. After cooling to –45 °C, a
solution of ( )-cis-6-oxabicyclo[3.1.0]hexan-2-ol (10; 126.3 mg,
1.3 mmol) in tetrahydrofuran (8 mL) and solid thymine (320 mg,
2.5 mmol) were added. The reaction mixture was stirred at –45 °C
for 2 h and at room temperature overnight. The reaction was
quenched as described in Method A. The product was purified by
column chromatography (silica gel) employing a mixture of
CH2Cl2/methanol (19:1) to produce 58 mg (21% yield) of pure 12
as white crystals: m.p. 149–152 °C. 1H NMR (200 MHz, CD3OD):
δ = 7.63 (d, J = 1.1 Hz, 1 H, 6-H), 5.09 (d, J = 7.1 Hz, 1 H, 1Ј-H),
5.01 (t, J = 6.7 Hz, 1 H, 2Ј-H), 4.34 (d, J = 3.6 Hz, 1 H, 5Ј-H),
2.29 (dt, J = 13.2, 6.6 Hz, 1 H, 3Јb-H), 2.06 (dd, J = 14.1, 6.6 Hz,
1 H, 3Јa-H), 1.93 (d, J = 1.1 Hz, 3 H, CH3), 1.86 (dd, J = 13.9,
6.4 Hz, 1 H, 4Јb-H), 1.70 (m, 1 H, 4Јa-H) ppm. 13C NMR
(CD3OD): δ = 175.4 (C-4), 161.9 (C-2), 135.1 (C-6), 119.2 (C-5),
90.5 (C-1Ј), 76.2 (C-5Ј), 64.5 (C-2Ј), 31.60 (C-4Ј), 31.59 (C-3Ј), 13.9
(CH3) ppm. C9H10N2O3: C 55.67, H 5.19; found C 55.97, H 5.32.
( )-3-Benzoyl-5-methyl-1-[(1RS,2SR,5SR)-6-oxabicyclo[3.1.0]-
hex-2-yl]pyrimidine-2,4(1H,3H)-dione (11): A solution of tri-
phenylphosphane (1.43 g, 5.45 mmol) in anhydrous tetra-
hydrofuran (20 mL) was treated with diethyl azodicarboxylate
(0.90 mL, 5.45 mmol) and stirred at 0 °C for 20 min. After cooling
to –45 °C, a solution of N3-benzoylthymine (1.00 g, 4.36 mmol) and
alcohol 10 (218 mg, 2.18 mmol) in tetrahydrofuran (8 mL) was
added via cannula over a period of 10 min. The reaction mixture
was stirred at –45 °C for 2 h and then at room temperature for 16 h.
The solvent was evaporated and the residue was purified by column
chromatography (silica gel) employing hexane/EtOAc (4:1) as elu-
ent to afford 59 mg (20% yield) of pure compound 11 as a colorless
oil. 1H NMR (200 MHz, CDCl3): δ = 7.60–7.72 (m, 5 H, aromatic
protons), 6.96 (d, J = 1.1 Hz, 1 H, 6-H), 4.90 (d, J = 7.3 Hz, 1 H,
2Ј-H), 3.77 (s, 1 H, 1Ј-H), 3.55 (d, J = 1.8 Hz, 1 H, 5Ј-H), 1.95 (d,
J = 0.9 Hz, 3 H, CH3 at C-5), 1.85–2.17 (m, 4 H, 3Ј-H, 4Ј-H) ppm.
13C NMR (50 MHz, CDCl3): δ = 168.8 (COPh), 162.5 (C-4), 149.7
(C-2), 139.7 (Ph), 137.3 (C-6), 135.0 (Ph), 130.4 (Ph), 129.1 (Ph),
111.3 (C-5), 59.0 (C-5Ј), 57.8 (C-1Ј), 57.1 (C-2Ј), 28.1 (C-3Ј), 26.5
(C-4Ј), 14.3 (CH3) ppm.
( )-5-Methyl-1-[2,3,4-trihydroxy-3-(hydroxymethyl)cyclopentyl]pyr-
imidine-2,4(1H,3H)-dione (16): A 40% solution of deuteriated po-
tassium hydroxide in deuteriated water was added to a solution of
compound 15 (3 mg) in deuteriated water (0.5 mL). The pH values
were increased in 0.5 units by addition of measurable volumes of
KOD. The reaction was monitored by 1H NMR spectroscopy.
( )-3-Benzyl-5-methyl-1-[(1RS,2SR,5SR)-6-oxabicyclo[3.1.0]hex-2-
yl]pyrimidine-2,4(1H,3H)-dione (13): A solution of triphenylphos-
phane (303 mg, 1.28 mmol) in anhydrous tetrahydrofuran
When the pH value reached 12.5, 15 was irreversibly converted into
1
(20.0 mL) was treated with diethyl azodicarboxylate (0.2 mL, 16 in an almost theoretical yield. H NMR (500.13 MHz, D2O): δ
Eur. J. Org. Chem. 2006, 4473–4482
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4477

E. Elhalem, M. J. Comin, J. B. Rodriguez
= 7.32 (s, 1 H, 6-H), 5.24 (m, 1 H, 1Ј-H), 4.22 (t, J = 7.7 Hz, 1 H), as a colorless oil. Rf 0.62 (hexane/EtOAc, 9:1). 1H NMR
FULL PAPER
4.06 (d, J = 4.8 Hz, 1 H, 2Ј-H), 3.81 (d, J = 12.0 Hz, 1 H, Hb-
CHOH), 3.61 (d, J = 12.0 Hz, 1 H, Ha-CHOH), 2.37 (m, 1 H, 5Јa-
H), 2.09 (ddd, J = 14.3, 10.5, 6.7 Hz, 1 H, 5Јb-H), 1.81 (s, 3 H,
CH3) ppm. 13C NMR (125.77 MHz, D2O): δ = 166.9 (C-4), 151.9
(C-2), 141.1 (C-6), 110.6 (C-5), 82.9 (C-3Ј), 76.1 (C-2Ј), 71.9 (C-
4Ј), 63.6 (CH2OH), 56.1 (C-1Ј), 34.1 (C-5Ј), 13.6 (CH3) ppm.
(500.13 MHz, CDCl3): δ = 7.72–7.66 (m, 4 H, aromatic protons),
7.44–7.35 (m, 6 H, aromatic protons), 4.32 (dt, J = 6.4, 1.0 Hz, 1
H, 2-H), 3.24 (ddd, J = 6.4, 3.8, 2.6 Hz, 1 H, 1-H), 3.07 (dd, J =
6.6, 1.1 Hz, 1 H, 6-H), 2.11 (m, 2 H, 3a-H, 5a-H), 1.75 (m, 1 H, 5b-
H), 1.48 (m, 1 H, 3b-H), 1.27 (m, 2 H, 4-H), 1.10 [s, 9 H,
C(CH3)3] ppm. 13C NMR (125.77 MHz, CDCl3): δ = 135.8 (Ph),
135.7 (Ph), 134.1 (Ph), 134.0 (Ph), 129.7 (Ph), 129.7 (Ph), 127.7
(Ph), 127.6 (Ph), 69.8 (C-2), 41.3 (C-1), 37.4 (C-6), 30.1 (C-3), 27.0
[C(CH3)3], 25.5 (C-5), 19.2 [C(CH3)3], 14.8 (C-4) ppm. MS: m/z (%)
= 368 (1) [M]+, 311 (19), 279 (33), 233 (36), 199 (100), 181 (11),
155 (6), 135 (5).
( )-(1SR,2RS,6SR)-7-Oxabicyclo[4.1.0]heptan-2-ol (21): A solution
of 60% m-chloroperbenzoic acid (6.00 g, 20.8 mmol) in dichloro-
methane (30 mL) was added to a solution of cyclohexenol (20;
1.70 g, 17.3 mmol) in dichloromethane (60 mL) at 0 °C. The mix-
ture was stirred at room temperature for 1 h. The solvent was evap-
orated and the residue purified by column chromatography (silica
gel) eluting with a mixture of hexane/EtOAc (9:1) to afford 1.65 g
(83% yield) of pure epoxy alcohol 21 as a colorless oil. Rf 0.38
( )-tert-Butyldiphenylsilyl Cyclopent-2-enyl Ether (24): Imidazole
(1.884 g, 27.7 mmol) was added to a solution of cyclopentenol 23
(1.164 g, 13.9 mmol) in anhydrous N,N-dimethylformamide
(10 mL) at 0 °C. The mixture was stirred at 0 °C for 10 min. Then
tert-butylchlorodiphenylsilane (4.0 mL, 15.3 mmol) was added
dropwise. The reaction mixture was stirred at room temperature for
20 h. The reaction was quenched by the addition of water (50 mL)
and extracted with dichloromethane (3×50 mL). The combined or-
ganic layers were washed with an aqueous saturated solution of
sodium chloride (5×50 mL), dried (MgSO4) and the solvent evapo-
rated. The residue was purified by column chromatography (silica
gel) employing a mixture of hexane/EtOAc (99.5:0.5) as eluent to
afford 3.654 g (82% yield) of pure compound 24 as a colorless oil:
1
(hexane/EtOAc, 4:6). H NMR (500.13 MHz, CDCl3): δ = 4.00
(ddd, J = 7.6, 4.9, 2.9 Hz, 1 H, 2-H), 3.34 (t, J = 3.9 Hz, 1 H, 6-
H), 3.30 (t, J = 3.5 Hz, 1 H, 1-H), 2.59 (br. s, 1 H, OH), 1.86 (ddd,
J = 15.2, 9.1, 5.9 Hz, 1 H, 5a-H), 1.78 (m, 1 H, 3a-H), 1.55 (m, 2
H, 4-H), 1.45 (m, 1 H, 5b-H), 1.25 (m, 1 H, 3b-H) ppm. 13C NMR
(125.77 MHz, CDCl3): δ = 67.0 (C-2), 55.4 (C-1), 55.3 (C-6), 28.9
(C-3), 23.1 (C-5), 18.1 (C-4) ppm.
tert-Butyl(7-oxabicyclo[4.1.0]hept-2-yloxy)diphenylsilane (17): Imid-
azole (2.08 g, 30.6 mmol) was added to a solution of 21 (1.74 g,
15.3 mmol) in anhydrous N,N-dimethylformamide (5.0 mL) at
0 °C. The mixture was stirred at this temperature for 10 min and
then tert-butylchlorodiphenylsilane (4.4 mL, 16.8 mmol) was added
and the mixture was stirred at room temperature for 6 h. The reac-
tion was quenched by addition of an aqueous saturated solution of
sodium chloride (50 mL). The mixture was extracted with dichloro-
methane (3×50 mL). The combined organic phases were washed
with brine (2×30 mL), dried (MgSO4) and the solvent evaporated.
The product was purified by column chromatography (silica gel)
eluting with hexane/EtOAc (99.5:0.5) to yield 3.56 g (66% yield) of
pure compound 17 as a colorless oil. Rf 0.65 (hexane/EtOAc, 4:1).
1H NMR (500.13 MHz, CDCl3): δ = 7.75 (m, 2 H, aromatic pro-
tons), 7.70 (m, 2 H, aromatic protons), 7.41 (m, 6 H, aromatic
protons), 3.98 (ddd, J = 9.8, 5.1, 1.9 Hz, 1 H, 2-H), 3.14 (dist. t, J
= 3.4 Hz, 1 H, 6-H), 3.01 (dd, J = 3.9, 1.9 Hz, 1 H, 1-H), 1.71 (m,
2 H, 3-H), 1.56 (m, 2 H, 4-H), 1.47 (m, 2 H, 5-H), 1.09 [s, 9 H,
C(CH3)3] ppm. 13C NMR (125.77 MHz, CDCl3), δ = 135.8 (Ph),
134.2 (Ph), 134.1 (Ph), 129.6 (Ph), 127.6 (Ph), 127.6 (Ph), 70.3 (C-
2), 55.9 (C-1), 54.6 (C-6), 27.9 (C-3), 26.9 (CH3), 22.6 (C-4), 20.2
(C-5), 19.2 [(CH3)3C] ppm. MS: m/z (%) = 352 (1) [M]+, 295 (15),
253 (25), 217 (55), 199 (100), 183 (20), 155 (17), 139 (97), 115 (28).
1
Rf 0.85 (hexane/EtOAc, 9:1). H NMR (500.13 MHz, CDCl3): δ =
7.69 (m, 4 H, aromatic protons), 7.37 (m, 6 H, aromatic protons),
5.84 (ddt, J = 5.7, 2.3, 1.2 Hz, 1 H, 2-H), 5.64 (dq, J = 5.8, 2.0 Hz,
1 H, 3-H), 4.90 (m, 1 H, 1-H), 2.45 (m, 1 H, 4b-H), 2.13 (m, 1 H,
4a-H), 2.05 (dddd, J = 13.1, 8.6, 7.4, 3.6 Hz, 1 H, 5b-H), 1.78 (dddd,
J = 13.3, 8.9, 5.4, 4.4 Hz, 1 H, 5a-H), 1.06 [s, 9 H, C(CH3)3] ppm.
13C NMR (125.77 MHz, CDCl3): δ = 135.79 (Ph), 135.77 (Ph),
134.7 (Ph), 134.6 (Ph), 133.7 (Ph), 133.5 (C-2), 129.5 (C-3), 127.50
(Ph), 127.51 (Ph), 79.0 (C-1), 33.5 (C-5), 30.9 (C-4), 27.0 [C-
(CH3)3], 19.0 [C(CH3)3] ppm. MS: m/z (%) = 265 (23) [M – tBu]+,
200 (24), 199 (100), 77 (14).
( )-tert-Butyldiphenylsilyl Cyclohex-2-enyl Ether (25): Imidazole
(710 mg, 10.4 mmol) was added to a solution of 2-cyclohexenol
(512 mg, 5.2 mmol) in anhydrous N,N-dimethylformamide (10 mL)
at 0 °C as described for the preparation of 24. The product was
purified by column chromatography (silica gel) eluting with hexane
to afford 1.45 g (83% yield) of pure 25 as a colorless oil: Rf 0.80
(hexane/EtOAc, 19:1). 1H NMR (500.13 MHz, CDCl3): δ = 7.69
(m, 4 H, aromatic protons), 7.34–7.42 (m, 6 H, aromatic protons),
5.69 (ddt, J = 10.0, 3.6, 1.1 Hz, 1 H, 3-H), 5.59 (dq, J = 10.1,
2.3 Hz, 1 H, 2-H), 4.23 (m, 1 H, 1-H), 2.02 (m, 1 H, 4b-H), 1.90
(m, 1 H, 4a-H), 1.77 (m, 1 H, 5b-H), 1.68 (m, 2 H, 5a-H, 6b-H),
1.46 (m, 1 H, 6a-H), 1.06 [s, 9 H, C(CH3)3] ppm. 13C NMR
(125.77 MHz, CDCl3): δ = 135.87 (Ph), 135.84 (Ph), 134.7 (Ph),
130.8 C-2), 129.47 (Ph), 129.46 (Ph), 129.2 (C-3), 127.5 (Ph), 67.2
(C-1), 32.2 (C-6), 27.0 [C(CH3)3], 25.0 (C-4), 19.4 (C-5), 19.2
[C(CH3)3] ppm.
tert-Butyldiphenyl(7-thiabicyclo[4.1.0]hept-2-yloxy)silane (22)
Method A: A solution of compound 17 (203 mg, 0.57 mmol) in
ethanol/water (1:1, 10 mL) was treated with potassium thiocyanate
(553 mg, 5.7 mmol) and the mixture was stirred at room tempera-
ture for 72 h. Then a saturated solution of sodium chloride (5 mL)
was added and the mixture was extracted with dichloromethane
(2×30 mL). The combined organic layers were washed with brine
(2×10 mL), dried (MgSO4), and the solvent was evaporated. The
product was purified by column chromatography (silica gel) eluting
with hexane to afford 135 mg (65% yield) of pure 22 as a colorless
oil.
( )-(1RS,2RS,3RS)-tert-Butyldiphenylsilyl 6-Oxabicyclo[3.1.0]-
hex-2-yl Ether (19) and ( )-(1RS,2SR,3RS)-tert-Butyldiphenyl-
silyl 6-Oxabicyclo[3.1.0]hex-2-yl Ether (18): A solution of 60% m-
chloroperbenzoic acid (3.63 g, 12.6 mmol) in dichloromethane
Method B: A solution of 17 (217 mg, 0.62 mmol) in anhydrous (50 mL) was added dropwise to a solution of compound 24 (3.39 g,
methanol (4 mL) was treated with thiourea (83 mg, 1.1 mmol) un-
der argon. The reaction mixture was stirred at room temperature
for 5 d. The solvent was evaporated and the residue was purified by
column chromatography (silica gel) employing a mixture of hexane/
EtOAc (95.5:0.5) as eluent to give 144 mg (64% yield) of pure 22
10.5 mmol) in dichloromethane (20 mL) at 0 °C. The reaction mix-
ture was stirred at room temperature for 24 h. Then the organic
phase was washed with an aqueous saturated solution of sodium
hydrogencarbonate (3×50 mL), water (2×50 mL) and then dried
(MgSO4). The solvent was evaporated and the residue was purified
4478
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Eur. J. Org. Chem. 2006, 4473–4482

Synthesis of Conformationally Locked Carbocyclic Nucleosides
FULL PAPER
by column chromatography (silica gel) eluting with a mixture of
hexane/EtOAc (99:1) to give 2.044 g (57% yield) of epoxide 19 and
1.130 g (32% yield) of 18 as white solids. Compound 19: Rf 0.65
(hexane/EtOAc, 9:1); m.p. 70–71 °C. 1H NMR (500.13 MHz,
CDCl3): δ = 7.66 (m, 4 H, aromatic protons), 7.40 (m, 6 H, aro-
matic protons), 4.36 (d, J = 5.2 Hz, 1 H, 2-H), 3.52 (d, J = 2.0 Hz,
1 H, 1-H), 3.27 (d, J = 2.4 Hz, 1 H, 5-H), 1.92 (m, 2 H, 4-H), 1.57
(ddd, J = 13.7, 7.6, 1.9 Hz, 1 H, 3b-H), 1.45 (m, 1 H, 3a-H), 1.08
[s, 9 H, C(CH3)3] ppm. 13C NMR (125.77 MHz, CDCl3): δ =
135.69 (Ph), 135.68 (Ph), 134.0 (Ph), 133.9 (Ph), 129.8 (Ph), 129.7
(Ph), 127.71 (Ph), 127.69 (Ph), 73.1 (C-2), 58.5 (C-1), 56.9 (C-6),
29.6 (C-3), 26.9 [C(CH3)3], 25.3 (C-4), 19.2 [C(CH3)3] ppm. MS:
m/z (%) = 338 (1) [M]+, 281 (100), 239 (16), 199 (87), 183 (34), 139
(14). Compound 18: Rf 0.48 (hexane/EtOAc, 9:1); m.p. 53–54 °C.
1H NMR (500.13 MHz, CDCl3): δ = 7.76 (m, 2 H, aromatic pro-
tons), 7.70 (m, 2 H, aromatic protons), 7.41 (m, 6 H, aromatic
protons), 4.22 (dt, J = 7.6, 1.4 Hz, 1 H, 2-H), 3.28 (d, J = 3.0 Hz,
1 H, 1-H), 3.18 (dd, J = 2.8, 1.4 Hz, 1 H, 5-H), 2.01 (m, 1 H, 4a-
H), 1.61 (m, 1 H, 4b-H), 1.47 (m, 2 H, 3-H), 1.08 [s, 9 H,
C(CH3)3] ppm. 13C NMR (125.77 MHz, CDCl3): δ = 135.7 (Ph),
135.7 (Ph), 134.0 (Ph), 133.9 (Ph), 129.7 (Ph), 129.7 (Ph), 127.7
(Ph), 127.6 (Ph), 74.8 (C-2), 58.4 (C-1), 54.9 (C-6), 26.8 [C(CH3)3],
26.2 (C-3), 25.5 (C-4), 19.2 [C(CH3)3] ppm. MS: m/z (%) = 281 (17)
135.7 (Ph), 134.12 (Ph), 134.06 (Ph), 129.7 (Ph), 129.6 (Ph), 127.7
(Ph), 127.6 (Ph), 74.2 (C-2), 44.9 (C-1), 39.5 (C-6), 26.9 [C(CH3)3],
26.3 (C-4), 26.2 (C-5), 19.2 [C(CH3)3] ppm. MS: m/z (%) = 355 (1)
[M + 1]+, 321 (21), 297 (70), 219 (100), 199 (45), 185 (26).
( )-(1RS,2RS,5SR)-6-Thiabicyclo[3.1.0]hexan-2-ol (28): A 1.0 
solution of tetrabutylammonium fluoride in tetrahydrofuran
(3.8 mL, 3.8 mmol) was added to a solution of 27 (0.69 g,
1.95 mmol) in anhydrous tetrahydrofuran (150 mL) at 0 °C under
argon. The reaction mixture was stirred at room temperature for
2 h. The solvent was evaporated and the residue was purified by
column chromatography (silica gel) eluting with a mixture of hex-
ane/CH2Cl2 (4:1) to afford 201 mg (92% yield) of pure compound
28 as a white solid: Rf 0.25 (CH2Cl2); m.p. 42–45 °C. 1H NMR
(500.13 MHz, CDCl3): δ = 4.49 (dt, J = 7.9, 3.7 Hz, 1 H, 2-H),
3.53 (t, J = 3.9 Hz, 1 H, 1-H), 3.36 (t, J = 3.9 Hz, 1 H, 5-H), 2.10
(dd, J = 13.6, 7.6 Hz, 1 H, 3b-H), 1.86 (m, 2 H, 3a-H, 4a-H), 1.44
(m, 1 H, 4b-H) ppm. 13C NMR (125.77 MHz, CDCl3): δ = 73.3 (C-
2), 46.7 (C-1), 41.5 (C-5), 27.0 (C-3), 26.7 (C-4) ppm. MS: m/z (%)
= 116 (94) [M]+, 98 (61), 97 (100), 83 (54), 72 (25), 71 (33).
( )-(1SR,2RS,5RS)-6-Thiabicyclo[3.1.0]hexan-2-ol (29): A solution
of 26 (270 mg, 0.58 mmol) in anhydrous tetrahydrofuran (15 mL)
was treated with a 1.0  solution of tetrabutylammonium fluoride
in tetrahydrofuran (1.2 mL, 1.2 mmol) under argon at 0 °C as de-
scribed for the preparation of 28. The residue was purified by col-
umn chromatography (silica gel) eluting with a mixture of hexane/
t
[M – Bu]+, 203 (100), 199 (35), 185 (21), 141 (31), 105 (21).
( )-(1SR,2RS,5RS)-tert-Butyldiphenylsilyl 6-Thiabicyclo[3.1.0]-
hex-2-yl Ether (26): A solution of potassium thiocyanate (2.70 g,
27.8 mmol) in water (5 mL) was added to a solution of 18 (940 mg, CH2Cl2 (1:4) to afford 67 mg (95% yield) of epi alcohol 29 as a
2.8 mmol) in ethanol (15 mL). The mixture was treated as de-
scribed for the preparation of 27. The product was purified by col-
umn chromatography (silica gel) eluting with hexane/EtOAc
(99.5:0.5) to yield 227 mg (23% yield) of pure 26 as a colorless oil
colorless oil: Rf 0.25 (hexane/EtOAc, 4:1). 1H NMR (500.13 MHz,
CDCl3): δ = 4.49 (d, J = 4.8 Hz, 1 H, 2-H), 3.42 (t, J = 3.9 Hz, 1
H, 1-H), 3.20 (d, J = 4.3 Hz, 1 H, 5-H), 2.19 (dddd, J = 13.9, 10.8,
7.6, 3.3 Hz, 1 H, 3b-H), 2.04 (dd, J = 13.8, 7.6 Hz, 1 H, 3a-H), 1.93
(dddd, J = 14.0, 10.9, 7.7, 4.8 Hz, 1 H, 4b-H), 1.54 (dd, J = 14.0,
and 220 mg of unreacted starting material: Rf 0.75 (hexane/EtOAc,
1
9:1). H NMR (500.13 MHz, CDCl3): δ = 7.68 (m, 4 H, aromatic 7.6 Hz, 1 H, 4a-H) ppm. 13C NMR (125.77 MHz, CDCl3): δ = 74.5
protons), 7.42 (m, 6 H, aromatic protons), 4.51 (d, J = 4.6 Hz, 1
H, 2-H), 3.41 (t, J = 3.8 Hz, 1 H, 1-H), 3.13 (d, J = 4.3 Hz, 1 H,
5-H), 2.27 (dddd, J = 13.8, 10.7, 7.5, 3.4 Hz, 1 H, 3b-H), 1.99 (dd,
J = 13.4, 7.3 Hz, 1 H, 4b-H), 1.77 (dddd, J = 13.7, 11.0, 7.3, 4.6 Hz,
1 H, 3a-H), 1.54 (dd, J = 13.4, 7.7 Hz, 1 H, 4a-H), 1.09 [s, 9 H,
C(CH3)3] ppm. 13C NMR (125.77 MHz, CDCl3): δ = 135.8 (Ph),
135.7 (Ph), 134.1 (Ph), 134.1 (Ph), 129.7 (Ph), 129.6 (Ph), 127.7
(Ph), 127.6 (Ph), 74.2 (C-2), 44.9 (C-1), 39.5 (C-6), 26.9 [C(CH3)3],
26.3 (C-4), 26.2 (C-5), 19.2 [C(CH3)3] ppm. MS: m/z (%) = 354 (2)
[M]+, 297 (44), 200 (18), 199 (100), 99 (24).
(C-2), 43.0 (C-1), 40.8 (C-5), 28.6 (C-3), 26.8 (C-4) ppm.
(
)-6-Chloro-9-[(1RS,2SR,5SR)-6-thiabicyclo[3.1.0]hex-2-yl]-
purine (30): A suspension of 6-chloropurine (247 mg, 1.6 mmol)
and triphenylphosphane (603 mg, 2.3 mmol) in anhydrous tetra-
hydrofuran (2.0 mL) was treated with diethyl azodicarboxylate
(DEAD; 0.18 mL, 1.13 mmol) at 0 °C under argon. The mixture
was stirred at 0 °C for 10 min. Then a solution of 28 (116 mg
1.0 mmol) in tetrahydrofuran (2.0 mL) was added and the reaction
mixture was stirred at room temperature for 24 h. The solvent was
evaporated and the residue was purified by column chromatog-
raphy (silica gel) employing a mixture of hexane/EtOAc (17:3) as
eluent to afford 41 mg of pure compound 30 as a white solid and
313 mg of the same compound with traces of reduced DEAD: Rf
0.74 (EtOAc/methanol, 19:1); m.p. 145–148 °C. UV (methanol):
( )-(1SR,2SR,5RS)-tert-Butyldiphenylsilyl 6-Thiabicyclo[3.1.0]-
hex-2-yl Ether (27): A solution of potassium thiocyanate (3.94 g,
40.6 mmol) in water (7 mL) was added to a solution of compound
19 (1.35 g, 4.06 mmol) in ethanol (20 mL) and the reaction mixture
was refluxed for 15 h. The solvent was evaporated almost to dry-
ness and the mixture was partitioned between an aqueous saturated
solution of sodium chloride (20 mL) and dichloromethane (30 mL).
The aqueous phase was extracted with dichloromethane
(2×30 mL). The combined organic layers were washed with brine
(2×10 mL), dried (MgSO4) and the solvent evaporated. The resi-
due was purified by column chromatography (silica gel) eluting
with hexane/EtOAc (99.5:0.5) to afford 690 mg (48% yield) of pure
compound 27 as a colorless oil: Rf 0.8 (hexane/EtOAc, 9:1). 1H
NMR (500.13 MHz, CDCl3): δ = 7.77 (m, 2 H, aromatic protons),
7.70 (m, 2 H, aromatic protons), 7.42 (m, 6 H, aromatic protons),
4.45 (ddt, J = 7.5, 3.5, 0.8 Hz, 1 H, 2-H), 3.13 (dd, J = 4.5, 3.2 Hz,
1
λmax = 265 nm. H NMR (500.13 MHz, CDCl3): δ = 8.76 (s, 1 H,
2-H), 8.11 (s, 1 H, 8-H), 5.38 (d, J = 6.2 Hz, 1 H, 2Ј-H), 3.69 (t, J
= 3.5 Hz, 1 H, 5Ј-H), 3.48 (d, J = 4.1 Hz, 1 H, 1Ј-H), 2.48 (m, 2
H, 3Ј-H), 2.35 (dt, J = 13.0, 6.0 Hz, 1 H, 4Јb-H), 1.91 (dt, J = 12.2,
6.7 Hz, 1 H, 4Јa-H) ppm. 13C NMR (125.77 MHz, CDCl3): δ =
152.0 (C-2), 151.4 (C-4), 151.3 (C-6), 142.9 (C-8), 131.8 (C-5), 58.2
(C-2Ј), 41.5 (C-1Ј), 41.1 (C-5Ј), 28.2 (C-4Ј), 27.3 (C-3Ј) ppm. MS:
m/z (%) = 253 (9) [M + 1]+, 219 (54), 155 (100), 119 (10), 97 (51).
C10H9ClN4S: C 47.52, H 3.59, Cl 14.03, N 22.17, S 12.69; found C
47.65, H 3.83, Cl 14.05, N 21.63, S 12.16.
(
) 9-[(1RS,2SR,5SR)-6-thiabicyclo[3.1.0]hex-2-yl]purin-6-yl-
1 H, 1-H), 3.08 (t, J = 4.1 Hz, 1 H, 5-H), 1.99 (m, 1 H, 3b-H), 1.71 amine (31): Compound 30 (310 g, mmol) was treated with a satu-
(m, 2 H, 3a -H, 4b -H), 1.57 (m, 1 H, 4a -H), 1.09 [s, 9 H, rated solution of methanolic ammonia (5 mL) in a sealed tube at
C(CH3)3] ppm. 13C NMR (125.77 MHz, CDCl3): δ = 135.8 (Ph),
70 °C for 4 h. The mixture was cooled to –78 °C, the tube was
Eur. J. Org. Chem. 2006, 4473–4482
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4479

E. Elhalem, M. J. Comin, J. B. Rodriguez
FULL PAPER
opened and nitrogen was bubbled through it to eliminate the am-
monia. The product was purified by column chromatography (silica
gel) eluting with EtOAc/methanol (19:1) to give 77 mg (38% yield
from 28) of pure 31 as a white solid: Rf 0.27 (EtOAc/methanol,
ate (0.44 mL, 2.8 mmol) was added to a solution of triphenylphos-
phane (735 mg, 2.8 mmol) in anhydrous tetrahydrofuran (5 mL) at
0 °C under argon. The resulting mixture was stirred at 0 °C for
10 min. Then the mixture was cooled to –45 °C and a suspension
of N3-benzoylthymine (515 mg, 2.24 mmol) and 28 (130 mg,
1
19:1); m.p. 194–196 °C. UV (methanol): λmax = 261 nm. H NMR
(500.13 MHz, [D6]DMSO): δ = 8.17 (s, 1 H, 2-H), 8.15 (s, 1 H, 8- 1.12 mmol) in tetrahydrofuran (8 mL) was added dropwise through
H), 7.21 (br. s, 2 H, NH2), 5.17 (d, J = 6.6 Hz, 1 H, 2Ј-H), 3.72 a cannula over a 10 min period. The reaction mixture was stirred
(dist. t, J = 3.6 Hz, 1 H, 5Ј-H), 3.62 (d, J = 3.9 Hz, 1 H, 1Ј-H), at –45 °C for 2 h and at room temperature for 22 h. The solvent
2.51 (m, 1 H, 3Јb-H), 2.20 (m, 1 H, 3Јa-H), 2.13 (dd, J = 13.6,
7.9 Hz, 1 H, 4Јb-H), 1.85 (dd, J = 13.6, 8.0 Hz, 1 H, 4Јa-H) ppm.
13C NMR (125.77 MHz, [D6]DMSO): δ = 156.2 (C-6), 152.6 (C-
was evaporated and the residual was purified by column
chromatography (silica gel) eluting with a mixture of hexane/
EtOAc (3:1) to afford the desired product, which was further puri-
2), 149.3 (C-4), 138.9 (C-8), 119.0 (C-5), 56.6 (C-2Ј), 42.9 (C-1Ј), fied by column chromatography (silica gel) employing hexane/
42.3 (C-5Ј), 27.8 (C-4Ј), 26.3 (C-3Ј) ppm. MS: m/z (%) = 233 (15) CH2Cl2 (2:3) to afford 138.6 mg (38% yield) of compound 34 as a
[M]+, 200 (30), 136 (100), 99 (31). HRMS (ESI): calcd. for
C10H12N5S [MH+]: 234.0810; found 234.0813. C10H11N5S: C 51.48,
H 4.75, N 30.02, S 13.74; found C 51.45, H 4.67, N 30.17, S 13.65.
white solid: Rf 0.87 (AcOEt); m.p. 185–186 °C. UV (methanol):
λmax = 280 nm. H NMR (500.13 MHz, CDCl3): δ = 7.92 (dq, J =
1
4.2, 1.2 Hz, 2 H, aromatic protons), 7.65 (dist. t, J = 7.7 Hz, 1 H,
aromatic proton), 7.50 (dist. t, J = 7.7 Hz, 2 H, aromatic protons),
7.05 (d, J = 1.1 Hz, 1 H, 6-H), 5.09 (d, J = 7.2 Hz, 1 H, 2Ј-H), 3.63
(t, J = 3.5 Hz, 1 H, 5Ј-H), 3.33 (d, J = 4.0 Hz, 1 H, 1Ј-H), 2.35 (m,
2 H, 4Ј-H), 2.25 (m, 1 H, 3Јb-H), 1.97 (d, J = 1.1 Hz, 3 H, CH3 at
C-5), 1.78 (q, J = 6.7 Hz, 1 H, 3Јa -H) ppm. 1 3 C NMR
(125.77 MHz, CDCl3): δ = 168.9 (C-4), 162.6 (COPh), 149.6 (C-2),
137.0 (C-6), 135.0 (Ph), 131.7 (Ph), 130.4 (Ph), 129.1 (Ph), 111.2
(C-5), 60.1 (C-2Ј), 42.3 (C-5Ј), 41.7 (C-1Ј), 28.9 (C-4Ј), 27.3 (C-3Ј),
12.7 (CH3 at C-5) ppm. MS: m/z (%) = 328 (16) [M]+, 295 (17),
231 (17), 105 (100), 77 (60). C17H16N2O3S: C 62.18, H 4.91, N 8.53,
S 9.76; found C 61.85, H 5.34, N 8.11, S 9.17.
( )-9-[(1RS,2SR,5SR)-6-Thiabicyclo[3.1.0]hex-2-yl]-6-(benzyl-
oxy)purin-2-ylamine (32): A suspension of 2-amino-6-(benzyloxy)-
purine (873 mg, 3.6 mmol) and triphenylphosphane (1.18 g,
4.5 mmol) in anhydrous tetrahydrofuran (10 mL) cooled to 0 °C
was treated with diethyl azodicarboxylate (0.71 mL, 4.5 mmol) un-
der argon. The mixture was stirred at 0 °C for 10 min. Then a solu-
tion of 28 (210 mg, 1.8 mmol) in tetrahydrofuran (2.0 mL) was
added and the reaction mixture was stirred at room temperature
for 24 h. The solvent was evaporated and the residue was purified
by column chromatography (silica gel) eluting with a mixture of
hexane/EtOAc (3:1) to afford 174 mg (28% yield) of pure 32 as a
white solid: Rf 0.74 (hexane/EtOAc, 1:9); m.p. 165–167 °C. 1H
NMR (500.13 MHz, CDCl3): δ = 7.59 (s, 1 H, 8-H), 7.50 (d, J =
7.4 Hz, 2 H, aromatic protons), 7.35 (dist. t, J = 7.3 Hz, 2 H, aro-
matic protons), 7.30 (dist. t, J = 7.3 Hz, 1 H, aromatic proton),
5.57 (s, 2 H, OCH2Ph), 5.14 (d, J = 6.3 Hz, 1 H, 2Ј-H), 4.88 (s, 2
H, NH2), 3.59 (t, J = 3.2 Hz, 1 H, 5Ј-H), 3.42 (d, J = 4.1 Hz, 1 H,
1Ј-H), 2.37 (m, 2 H, 4Ј-H), 2.28 (m, 1 H, 3Јb-H), 1.83 (m, 1 H, 3Јa-
H) ppm. 13C NMR (125.77 MHz, CDCl3): δ = 161.1 (C-6), 159.2
(C-2), 153.8 (C-4), 136.7 (Ph), 136.4 (C-8), 128.4 (Ph), 128.3 (Ph),
128.0 (Ph), 115.7 (C-5), 68.0 (OCH2Ph), 56.6 (C-2Ј), 41.6 (C-1Ј),
41.4 (C-5Ј), 28.1 (C-4Ј), 26.9 (C-3Ј) ppm. MS: m/z (%) = 339 (8)
[M]+, 240 (9), 135 (7), 99 (65), 91 (100). C17H17N5OS·¼H2O: C
59.37, H 5.13, N 20.36, S 9.32; found C 59.40, H 5.02, N 20.46, S
9.27.
( )-5-Methyl-1-[(1RS,2SR,5SR)-6-thiabicyclo[3.1.0]hex-2-yl]pyrim-
idine-2,4(1H,3H)-dione (35): Compound 34 (123 mg, mmol) was
treated with methanolic ammonia (5 mL, saturated at –78 °C) and
stirred in a pressure vessel at 0 °C for 1 h. The solvent was evapo-
rated and the residue was purified by column chromatography (sil-
ica gel) using hexane/EtOAc (7:3) as eluent to afford 92.4 mg (41%
from 28) of 35 as a white solid: Rf 0.67 (AcOEt); m.p. 197–198 °C.
UV (methanol): λmax = 272 nm. 1H NMR (500.13 MHz, [D6]-
DMSO): δ = 11.27 (s, 1 H, NH), 7.29 (d, J = 1.1 Hz, 1 H, 6-H),
4.94 (d, J = 7.4 Hz, 1 H, 2Ј-H), 3.70 (t, J = 3.8 Hz, 1 H, 5Ј-H),
3.47 (d, J = 4.3 Hz, 1 H, 1Ј-H), 2.38 (m, 1 H, 4Јb-H), 2.07 (m, 2
H, 3Јb-H, 4Јa-H), 1.79 (d, J = 0.9 Hz, 3 H, CH3 at C-5), 1.68 (dd,
J = 14.1, 8.1 Hz, 1 H, 3Јa-H) ppm. 13C NMR (125.77 MHz, [D6]-
DMSO): δ = 163.9 (C-4), 150.9 (C-2), 138.0 (C-6), 109.3 (C-5), 58.6
(C-2Ј), 43.8 (C-5Ј), 42.6 (C-1Ј), 28.5 (C-4Ј), 26.5 (C-3Ј), 12.2 (CH3
at C-5) ppm. MS: m/z (%) = 224 (23) [M]+, 191 (9), 148 (8), 127
(38), 99 (100). HRMS (ESI): calcd. for C10H13N2O2S [MH+]:
225.0700; found 225.0698. C10H12N2O2S: C 53.55, H 5.39, N 12.49,
S 14.30; found C 53.52, H 5.51, N 12.21, S 14.08.
( )-2-Amino-9-[(1RS,2SR,5SR)-6-thiabicyclo[3.1.0]hex-2-yl]-1,9-
dihydropurin-6-one (33): A solution of 32 (32 mg, 0.1 mmol) in an-
hydrous dichloromethane (10 mL) was cooled to –78 °C under ar-
gon and treated with boron trichloride (1.0  in dichloromethane,
0.75 mL). The reaction mixture was stirred at –78 °C for 4 h, after
which time methanol (4.0 mL) was added while maintaining the
same temperature. The mixture was then warm to room tempera-
ture and the solvent was evaporated to dryness. Methanol
(6×4 mL) was added and evaporated after each addition. The resi-
due was purified by column chromatography (silica gel) employing
a mixture of CHCl3/methanol (9:1) as eluent to afford 16 mg (63%
yield) of pure compound 33 as a white solid: Rf 0.30 (CHCl3/meth-
anol, 9:1); m.p. Ͼ280 °C. 1H NMR (500.17 MHz, [D6]DMSO): δ
= 10.63 (s, 1 H, NH), 7.73 (s, 1 H, 8-H), 6.54 (s, 2 H, NH2), 4.92
(d, J = 6.5 Hz, 1 H, 2Ј-H), 3.70 (t, J = 3.8 Hz, 1 H, 5Ј-H), 3.55 (d,
J = 4.3 Hz, 1 H, 1Ј-H), 2.42 (m, 1 H, 4Јb-H), 2.12 (m, 2 H, 3Јb-H,
4Јa-H), 1.82 (m, 1 H, 3Јa-H) ppm. 13C NMR (125.77 MHz, [D6]-
DMSO): δ = 156.7 (C-6), 153.5 (C-2), 150.8 (C-4), 134.9 (C-8),
116.6 (C-5), 55.9 (C-2Ј), 42.6 (C-1Ј), 42.2 (C-5Ј), 27.6 (C-4Ј), 26.2
(C-3Ј) ppm.
( )-3-Benzoyl-1-[(1RS,2SR,5SR)-6-thiabicyclo[3.1.0]hex-2-yl]pyrim-
idine-2,4(1H,3H)-dione (36): Diethyl azodicarboxylate (0.40 mL,
2,5 mmol) was added to a solution of triphenylphosphane (656 mg,
2.5 mmol) in anhydrous tetrahydrofuran (5 mL) at 0 °C under ar-
gon. The resulting mixture was stirred at 0 °C for 10 min. Then the
mixture was cooled to –45 °C and a suspension of N3-benzoyluracil
(432 mg, 2 mmol) and 28 (116 mg, 1 mmol) in tetrahydrofuran
(8 mL) was added dropwise through a cannula over a 10 min
period. The reaction mixture was stirred at –45 °C for 30 min and
at room temperature for 2 d. The solvent was evaporated and the
residue was purified by column chromatography (silica gel) eluting
with a mixture of hexane/EtOAc (3:1). The product was repurified
by column chromatography (silica gel) eluting with hexane/CH2Cl2
(1:1) to afford 154 mg (49% yield) of pure 36 as a white solid: Rf
0.50 (hexane/EtOAc, 3:7); m.p. 151–153 °C. UV (methanol): λmax
( )-3-Benzoyl-5-methyl-1-[(1RS,2SR,5SR)-6-thiabicyclo[3.1.0]- = 256 nm. 1H NMR (500.13 MHz, CDCl3): δ = 7.94 (dd, J =
hex-2-yl]pyrimidine-2,4(1H,3H)-dione (34): Diethyl azodicarboxyl- 8.4 Hz, 1.2 Hz, 2 H, aromatic protons), 7.66 (tt, J = 7.5, 1.2 Hz, 1
4480
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 4473–4482

Synthesis of Conformationally Locked Carbocyclic Nucleosides
FULL PAPER
H, aromatic proton), 7.51 (m, 2 H, aromatic protons), 7.24 (d, J =
8.1 Hz, 1 H, 6-H), 5.84 (d, J = 8.1 Hz, 1 H, 5-H), 5.11 (d, J =
7.3 Hz, 1 H, 2Ј-H), 3.61 (t, J = 3.6 Hz, 1 H, 5Ј-H), 3.33 (d, J =
4.1 Hz, 1 H, 1Ј-H), 2.38 (m, 1 H, 4Јb-H), 2.28 (m, 2 H, 3Јb-H,
4Јa-H), 1.79 (dd, J = 14.4, 7.1 Hz, 1 H, 3Јa-H) ppm. 13C NMR
(125.77 MHz, CDCl3): δ = 168.6 (CO), 161.8 (C-4), 149.6 (C-2),
141.0 (C-6), 135.2 (Ph), 131.4 (Ph), 130.5 (Ph), 129.2 (Ph), 102.6
(C-5), 60.3 (C-2Ј), 42.0 (C-5Ј), 41.4 (C-1Ј), 28.7 (C-4Ј), 27.3 (C-
3Ј) ppm. MS: m/z (%) = 314 (14) [M]+, 281 (18), 103 (100), 77 (50).
Acknowledgments
This work was supported in part by grants from the National Re-
search Council of Argentina, CONICET (PIP 5508), and the Uni-
versidad de Buenos Aires (X-252).
[1] S. W. Schneller, Curr. Top. Med. Chem. 2002, 2, 1087–1092.
[2] J. B. Rodriguez, M. J. Comin, Mini-Rev. Med. Chem. 2003, 3,
95–114.
[3] V. E. Marquez, M. A. Siddiqui, A. Ezzitouni, P. Russ, J. Wang,
R. W. Wagner, M. Matteucci, J. Med. Chem. 1996, 39, 3739–
3747.
[4] L. Zalah, M. Huleihel, E. Manor, A. Konson, H. Ford Jr, V. E.
Marquez, D. G. Johns, R. Agbaria, Antiviral Res. 2002, 55, 63–
75.
[5] M. L. Paoli, S. Piccini, M. Rodriquez, A. Sega, J. Org. Chem.
2004, 69, 2881–2883.
( )-1-[(1RS,2SR,5SR)-6-Thiabicyclo[3.1.0]hex-2-yl]pyrimidine-
2,4(1H,3H)-dione (37): Compound 36 (104 mg, 0.33 mmol) was
treated with methanolic ammonia (5 mL, saturated at –78 °C) and
stirred in a pressure vessel at 0 °C for 1 h. The solvent was evapo-
rated and the product was purified by column chromatography (sil-
ica gel) employing a mixture of hexane/EtOAc (3:2) as eluent to
afford 66 mg (95% yield) of pure compound 37 as a white solid: Rf
0.30 (hexane/EtOAc, 1:9); m.p. 154–156 °C. UV (methanol): λmax
=
[6] N. Gathergood, K. R. Knudsen, K. A. Jorgensen, J. Org.
Chem. 2001, 66, 1014–1017.
266 nm. 1H NMR (500.13 MHz, CDCl3): δ = 9.05 (s, 1 H, NH),
7.14 (d, J = 8.1 Hz, 1 H, 6-H), 5.74 (dd, J = 8.0, 1.5 Hz, 1 H, 5-
H), 5.13 (d, J = 7.3 Hz, 1 H, 2Ј-H), 3.60 (t, J = 3.4 Hz, 1 H, 5Ј-
H), 3.29 (d, J = 4.1 Hz, 1 H, 1Ј-H), 2.37 (ddt, J = 14.4, 9.3, 7.7 Hz,
1 H, 4Јb-H), 2.26 (m, 2 H, 3Јb-H, 4Јa-H), 1.72 (m, 1 H, 3Јa-H) ppm.
13C NMR (125.77 MHz, CDCl3): δ = 162.9 (C-4), 150.6 (C-2),
141.1 (C-6), 102.7 (C-5), 59.6 (C-2Ј), 42.0 (C-5Ј), 41.5 (C-1Ј), 28.7
(C-4Ј), 27.2 (C-3Ј) ppm. MS: m/z (%) = 210 (43) [M]+, 177 (22),
134 (27), 113 (58), 99 (100). C9H10N2O2S: C 51.41, H 4.79, N 13.32,
S 15.25; found C 51.25, H 4.83, N 13.17, S 15.16.
[7] J. Gagneron, G. Gosselin, C. Mathé, J. Org. Chem. 2005, 70,
6891–6897.
[8] M. C. Bonache, C. Chamorro, A. Cordeiro, M. J. Camarasa,
M. L. Jimeno, A. San Félix, J. Org. Chem. 2004, 69, 8758–8766.
[9] Z.-G. Gao, L. S. Jeong, H. R. Moon, H. O. Kim, W. J. Choi,
D. H. Shin, E. Elhalem, M. J. Comin, N. Melman, L. Mame-
dova, A. S. Gross, J. B. Rodriguez, K. A. Jacobson, Biochem.
Pharmacol. 2004, 67, 893–901.
[10] A. Renard, J. Lhomme, M. Kotera, J. Org. Chem. 2002, 67,
1302–1307.
[11] K. Singha, B. Achari, S. B. Mandal, Arkivoc 2005, 75–86.
[12] K. Singha, A. Roy, P. K. Dutta, S. Tripathi, S. Sahabuddin, B.
Achari, S. B. Mandal, J. Org. Chem. 2004, 69, 6507–6510.
[13] M. J. Comin, J. B. Rodriguez, P. Russ, V. E. Marquez, Tetrahe-
dron 2003, 59, 295–301.
[14] M. J. Comin, C. A. Pujol, E. B. Damonte, J. B. Rodriguez, Nu-
cleosides Nucleotides 1999, 18, 2219–2231.
[15] M. J. Comin, J. B. Rodriguez, Tetrahedron 2000, 56, 4639–4649.
[16] M. J. Comin, S. C. Pellegrinet, J. B. Rodriguez, Arkivoc 2005,
205–213.
( )-4-Amino-1-[(1RS,2SR,5SR)-6-thiabicyclo[3.1.0]hex-2-yl]pyr-
imidin-2(1H)-one (38): Triethylamine (296 µL, 3.88 mmol) was
added to a stirred mixture of 1,2,4-triazole (155 mg, 2.25 mmol),
phosphorus oxychloride (44 µL, 0.867 mmol) and anhydrous aceto-
nitrile (2.0 mL) under argon. Compound 37 (52 mg, 0.45 mmol)
dissolved in acetonitrile (1.0 mL) was added to this mixture, and
the reaction mixture was stirred at room temperature for 36 h. An
additional amount of triethylamine (204 µL, 1.47 mmol) and water
(54 µL, 3.0 mmol) was added and the mixture was stirred for
10 min more before removing the solvent. The residue was parti-
tioned between dichloromethane (50 mL) and an aqueous saturated
solution of sodium hydrogencarbonate (50 mL) and the organic
layer was separated. The aqueous layer was extracted further with
dichloromethane (2×50 mL) and the combined organic extract was
dried (MgSO4) and the solvent evaporated. The residue was dis-
solved in dioxane (10 mL) and stirred with ammonium hydroxide
(d = 0.9, 1.0 mL) at room temperature overnight. The solvent was
evaporated and the product was purified by column chromatog-
raphy (silica gel) eluting with EtOAc/methanol (19:1) to afford
21 mg (43% yield) of pure 38 as a white solid: Rf 0.25 (EtOAc/
[17] L. Goodman, R. R. Baker, J. Am. Chem. Soc. 1959, 81, 4924–
4926.
[18] E. E. van Tamelen, J. Am. Chem. Soc. 1951, 73, 3444–3448.
[19] C. C. J. Culvenor, W. Davies, K. H. Pausacker, J. Chem. Soc.
1946, 1050.
[20] U. Zoller, F.-P. Chen, J. Org. Chem. 2000, 65, 8083–8085.
[21] N. Iranpoor, F. Kazemi, Synthesis 1996, 821–822.
[22] N. Iranpoor, F. Kazemi, Tetrahedron 1997, 53, 11377–11382.
[23] W. Adam, R. M. Bargon, Chem. Rev. 2004, 104, 251–261.
[24] E. Vedejs, G. A. Krafft, Tetrahedron 1982, 38, 2857–2881.
[25] R. J. Young, S. Shaw-Ponter, J. B. Thomson, J. A. Miller, J. G.
Cumming, A. W. Pugh, P. Rider, Bioorg. Med. Chem. Lett.
1995, 5, 2599–2604.
methanol, 4:1); m.p. 162 °C (decomp.). UV (methanol): λmax
=
[26] T. H. Chan, J. R. Finkenbine, J. Am. Chem. Soc. 1972, 94,
277 nm. 1H NMR (500.13 MHz, [D6]DMSO): δ = 7.45 (d, J =
7.5 Hz, 1 H, 6-H), 7.06 (br. s, 2 H, NH2), 5.69 (d, J = 7.3 Hz, 1 H,
5-H), 4.98 (d, J = 7.1 Hz, 1 H, 2Ј-H), 3.67 (t, J = 3.6 Hz, 1 H, 5Ј-
H), 3.38 (d, J = 4.1 Hz, 1 H, 1Ј-H), 2.29 (m, 1 H, 4Јb-H), 2.06 (m,
2 H, 3Јb-H, 4Јa-H), 1.59 (m, 1 H, 3Јa-H) ppm. 13C NMR
(125.77 MHz, CDCl3): δ = 165.5 (C-4), 155.5 (C-2), 142.8 (C-6),
93.8 (C-5), 58.9 (C-2Ј), 43.4 (C-5Ј), 43.1 (C-1Ј), 28.2 (C-4Ј), 26.6
(C-3Ј) ppm. MS: m/z (%) = 209 (14) [M]+, 176 (43), 112 (71), 99
(27), 97 (25), 44 (100).
2880–2882.
[27] J. S. Yadav, B. V. S. Reddy, C. Srinivas Reddy, K. Rajasekhar,
J. Org. Chem. 2003, 68, 2525–2527.
[28] J. S. Yadav, B. V. S. Reddy, G. Baishya, Synlett 2003, 396–398.
[29] W. Adam, R. M. Bargon, W. A. Schenk, J. Am. Chem. Soc.
2003, 125, 3871–3876.
[30] F. G. Calvo-Flores, P. García-Mendoza, F. Hernández-Mateo,
J. Isac-García, F. Santoyo-González, J. Org. Chem. 1997, 62,
3944–3961.
[31] F. Capozzi, G. Capozzi, S. Menichetti, Tetrahedron Lett. 1988,
29, 4177–4180.
Supporting Information (see also the footnote on the first page of
this article): Copies of the 1H and 13C NMR spectra for representa-
tive compounds described in this work and copies of the elemental
analyses for the title compounds.
[32] Z.-X. Yu, Y.-D. Wu, J. Org. Chem. 2003, 68, 6049–6052.
[33] G. Capozzi, S. Menichetti, S. Neri, A. Skowronska, Synlett
1994, 267–268.
[34] J. C. Hinshaw, Tetrahedron Lett. 1972, 13, 3567–3569.
Eur. J. Org. Chem. 2006, 4473–4482
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4481

E. Elhalem, M. J. Comin, J. B. Rodriguez
FULL PAPER
[35] J. A. Franz, W. J. Shaw, C. N. Lamb, T. Autrey, D. S. Kolwaite, [45] O. Mitsunobu, Synthesis 1981, 1–28.
D. M. Camaioni, M. S. Alnajjar, J. Org. Chem. 2004, 69, 1020– [46] T. F. Jenny, N. Previsani, S. A. Brenner, Tetrahedron Lett. 1991,
1027.
32, 7029–7032.
[36] D. R. Hogg, N. C. Dann, Int. J. Sulfur Chem. A 1971, 1, 117–
[47] T. F. Jenny, J. Horlacher, N. Previsani, S. Brenner, Helv. Chim.
Acta 1992, 75, 1944–1954.
120.
[37] R. Csuk, L. Eversmann, Tetrahedron 1998, 54, 6445–6456.
[38] M. Botta, V. Summa, R. Saladino, R. Nicoletti, Synth. Com-
mun. 1991, 21, 2181–2187.
[48] K. J. Divakar, C. B. Reese, J. Chem. Soc., Perkin Trans. 1 1982,
1171–1176.
[49] Antiviral activity was evaluated by two methods: reduction of
virus plaque formation for HSV-1 and HSV-2, and inhibition
of the cytopathic effect (CPE) for HCMV. In the plaque re-
duction assay, Vero cell monolayers grown in 24 well plates
were infected with about 50 PFU (plaque forming units) of
virus per well in the absence or presence of various concentra-
tions of the compounds. After adsorption for 1 h, residual in-
oculum was replaced by MEM containing 0.7% methylcellu-
lose and the corresponding dose of compound. Plaques were
counted after 2 d of incubation at 37 °C. The antiviral activity
was calculated as the percentage reduction of virus plaque for-
mation in treated cultures with respect to untreated control cul-
tures. The values obtained represent the mean of two indepen-
dent experiments with duplicate determinations for each con-
centration. Acyclovir was used as a positive control with an
ID50 of 0.16 µ. The anti-HCMV activity was determined by a
cytopathic effect reduction assay. Briefly, PH monolayers were
infected in quadruplicate with HCMV at a multiplicity of infec-
tion of 0.1 in the absence or presence of various concentrations
of the compounds. Cell controls were included in each experi-
ment. After 7 d of incubation at 37 °C, the cytopathic effect
was examined under an inverted microscope.
[39] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, V. G. Zakrzewski, J. A. Mont-
gomery Jr, R. E. Stratmann, J. C. Burant, S. Dapprich, J. M.
Millam, A. D. Daniels, K. N. Kudin, M. C. Strain, O. Farkas,
J. Tomasi, V. Barone, M. Cossi, R. Cammi, B. Mennucci, C.
Pomelli, C. Adamo, S. Clifford, J. Ochterski, G. A. Petersson,
P. Y. Ayala, Q. Cui, K. Morokuma, D. K. Malick, A. D. Rab-
uck, K. Raghavachari, J. B. Foresman, J. Cioslowski, J. V. Or-
tiz, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komar-
omi, R. Gomperts, R. L. Martin, D. J. Fox, T. Keith, M. A.
Al-Laham, C. Y. Peng, A. Nanayakkara, C. Gonzalez, M.
Challacombe, P. M. W. Gill, B. Johnson, W. Chen, M. W.
Wong, J. L. Andres, C. Gonzalez, M. Head-Gordon, E. S. Re-
plogle, J. A. Pople, Gaussian 98, Revision A.7, Gaussian, Inc.,
Pittsburgh PA, 1998.
[40] H. B. Henbest, R. A. L. Wilson, J. Chem. Soc. 1957, 1958–
1965.
[41] J. B. Rodriguez, V. E. Marquez, M. C. Nicklaus, J. J. Barchi Jr,
Tetrahedron Lett. 1993, 34, 6233–6236.
[42] J. B. Rodriguez, V. E. Marquez, M. C. Nicklaus, H. Mitsuya,
J. J. Barchi Jr, J. Med. Chem. 1994, 37, 3389–3399.
[43] K.-H. Altmann, R. Kesselring, E. Francotte, G. Rihs, Tetrahe-
dron Lett. 1994, 35, 2331–2334.
Received: June 6, 2006
Published Online: August 7, 2006
[44] K.-H. Altmann, R. Imwinkelried, R. Kesselring, G. Rihs, Tet-
rahedron Lett. 1994, 35, 7265–7268.
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