A short and novel synthesis of carbocyclic nucleosides and 4′-epi-carbocyclic nucleosides from 2-cyclopenten-1-ones

Article abstract of DOI:10.1016/j.tet.2005.10.037

Carbocyclic nucleoside analogues remain interesting target molecules having the potential to combine biological activity with greater metabolic stability than their sugar counterparts. This paper describes a rapid and versatile synthetic approach to such

Full text of DOI:10.1016/j.tet.2005.10.037

Tetrahedron 62 (2006) 906–914
A short and novel synthesis of carbocyclic nucleosides and
0
*
4
-epi-carbocyclic nucleosides from 2-cyclopenten-1-ones
a
Gilles Gosselin, Ludovic Griffe, Jean-Christophe Meillon
a
a,
b
*
and Richard Storer
a
Laboratoire Coop e´ ratif Idenix-CNRS-UM II, Universit e´ Montpellier II, place Eug e` ne-Bataillon, case courrier 008,
F-34095 Montpellier Cedex 5, France
b
Laboratoire de Chimie M e´ dicinale Idenix, Cap Gamma, 1682 rue de la Valsi e` re, BP 50001, F-34184 Montpellier Cedex 4, France
Received 22 September 2005; revised 13 October 2005; accepted 13 October 2005
Available online 8 November 2005
Abstract—Carbocyclic nucleoside analogues remain interesting target molecules having the potential to combine biological activity with
greater metabolic stability than their sugar counterparts. This paper describes a rapid and versatile synthetic approach to such compounds
0
based on commercial cyclopentenones (e.g., 1) that has been developed in our laboratory. Carbocyclic nucleosides like 2 -methyl-
aristeromycin 6 were synthesized in racemic form in 5 steps via key intermediate 4. The procedure was also adapted to the preparation of
0
4 -epi-carbocyclic nucleosides using epoxide 17 instead of 4 and employing the same methodology.
q 2005 Elsevier Ltd. All rights reserved.
1
. Introduction
the adaptation of a known procedure to the synthesis of our
molecules seemed to be problematic and would have led to
synthetic routes of more than 15 steps. It was therefore
decided to try and find a novel approach allowing a rapid
and efficient access to 2 -branched carbocycles. This
research resulted in the shortest synthesis of racemic
carbocycles reported so far and is disclosed herein.
Modified nucleosides are presently the object of intense
research activity in medicinal chemistry due to their
potential as antiviral agents. As part of our on-going
antiviral program, we have found that 2 -methyl-branched
nucleosides showed particularly promising potential.
Most notably to date, a prodrug of 2 -methyl-cytidine is
currently in Phase II clinical trials as an anti-hepatitis C
drug. It was therefore relevant to consider the preparation
0
0
1
–3
0
4
2. Results and discussion
2.1. General strategy
0
of carbocyclic analogues of our lead compounds. Since 2 -
branched carbocycles had not been reported when this
5
work was initiated, it was necessary to design a synthetic
route giving rapid access to this class of molecules. Many
enantioselective syntheses of carbocycles have been
0
In every approach we considered, introduction of the 2 -
branching seemed to be the weak link of the synthesis and it
was therefore decided to opt for a starting compound
already bearing it. The retrosynthetic analysis for purine
derivatives is shown in Figure 1. Epoxide ring opening was
6
–9
reported starting with D- or L-ribose
L-ribonolactone.
and D- or
All of them are non-trivial or lengthy
1
0–13
and, appeared difficult to adapt to the preparation of
branched carbocycles. Furthermore, the powerful antiviral
1
4–16
activity of some L-nucleosides like Telbivudine
Lamivudine
or
prompted us to opt for a synthesis of our
X
1
7,18
N
N
targets as racemic mixtures in the first instance. Most
synthetic procedures for racemic preparation of carbocycles
N
R
HO
N
Y
R O
1
1
9–22
23,24
use either Vince lactam
or cyclopentadiene.
Again,
R
O
OH OH
OR
2
*
A part of this work was presented at the XVI International Roundtable on
Nucleosides, Nucleotides and Nucleic Acids; Minneapolis, MN, USA;
September 12–16, 2004.
R O
1
Keywords: Nucleoside analogues; Carbocycles; Aristeromycin; Hepatitis
C; Antivirals.
R O
O
R
2
R
*
Corresponding author. Tel.: C33 4 67637324; fax: C33 4 67637326;
e-mail: meillon.jean-christophe@idenix.com
Figure 1. Retrosynthetic analysis.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.10.037

G. Gosselin et al. / Tetrahedron 62 (2006) 906–914
5–27
907
2
chosen as the means of introduction of the base
taking
The ratio remained similar at K30 and 0 8C with the
concomitant formation of side products. To our delight,
alcohols 3a/3b were very easily separated on silica gel
chromatography. The two last nucleoside stereogenic
carbons were introduced in one step during the peroxy
acid-promoted epoxidation of 3a. The allylic alcohol
allowed perfect control on the stereochemistry of the
reaction and epoxide 4 was obtained as the sole product in
excellent yield.
0
advantage of the presence of the 2 -branching to control the
regioselectivity of the reaction. The core of carbocyclic
pseudo-nucleosides being a cyclopentane, we were naturally
led to cyclopentenones, appropriately substituted in position
2, as our starting point. This class of molecules present
0
several key advantages (a) bearing the targeted 2 -branching,
which can be changed by switching to another ketone,
0
(
b) having the 3 -oxygen of the future carbocycle, (c) having
a double bond ready for epoxidation, (d) having a keto group
making possible an a-alkylation for introduction of the
0
2
.3. Synthesis of carbocyclic nucleosides
5 -carbon, (e) being achiral and (f) being commercially
available at a reasonable price.
Having everything in place for the introduction of the base,
4
was treated with the sodium salt of adenine in DMF at
00 8C. The 2 -methyl induced a perfect regio- and
0
stereoselectivity, the attack occurring from the b-face on
the 1 -carbon exclusively. Due to its poor solubility,
1
2
.2. Preparation of key epoxide 4
0
purification of nucleoside 5 from the excess of adenine
was not satisfactory but could be made much easier when
0
Introduction of the nucleoside 4 -hydroxymethyl group on
ketone 1 (Scheme 1) was not a trivial task: 2-cyclopenten-1-
ones are notoriously troublesome substrates for a-alkylation
0
0
2
8,29
crude 5 was directly protected as its 2 ,3 -isopropylidene
derivative 7. Target compound 6 was obtained by either
palladium-catalyzed hydrogenolysis of the benzyl protect-
ing group of 5 or double deprotection of 7. This synthesis
resulted in the efficient first synthesis of (C/K)-2 -methyl-
aristeromycin 6 in 5–7 steps and 23% overall yield.
reactions.
For instance, attempts to react gaseous
formaldehyde on the enolate of 1 failed. The successful
method came from the use of benzyloxymethyl (BOM)
halides as the alkylating agent, which would potentially help
0
0
introduce an already protected 4 -hydroxymethyl group.
Whilst this reaction failed when attempted with BOM
chloride at K50 8C and the formation of a complex mixture
of products was observed at higher temperatures, freshly
A confirmation of the structure of this series of molecules
was given by X-ray analysis performed on a single-crystal
of 7 grown in DCM/acetone (Fig. 2).
3
0
prepared BOM bromide gave acceptable yields when it
was reacted with the lithium enolate of 1 at K78 8C. When
ketone 2 was treated with LiAlH at K78 8C, alcohols 3
4
were obtained in 84% yield as a 2:1 mixture of
diastereoisomers favoring the desired trans.
This synthetic method is applicable to other purines,
sometimes with minor changes. For instance, guanine
reacted very poorly with 4 (ca. 6% yield) but after protection
BnO
BnO
BnO
a
b
+
trans/cis 2:1
O
65%
O
84%
HO
(+/-) 3b
HO
(+/-) 3a
1
(+/-) 2
NH2
N
N
N
N
HO
OH OH
+/-) 6
NH2
N
e
(
N
BnO
3
9%
c
d
N
(2 steps)
BnO
N
g, e
83% (2 steps)
NH
O
HO
9
2%
f
2
OH OH
N
N
(
+/-) 4
(+/-) 5
8
1%
(
2 steps)
N
BnO
N
O
O
(
+/-) 7
Scheme 1. Reagents and conditions: (a) LDA, BOM bromide, THF, K78 to K50 8C; (b) LiAlH
adenine, DMF, 100 8C; (e) palladium hydroxide on charcoal, cyclohexene, MeOH, reflux; (f) p-toluenesulfonic acid, 2,2-dimethoxypropane, acetone, RT;
g) trifluoroacetic acid 90%, 0 8C.
4
, ether, K78 to K60 8C; (c) m-CPBA, DCM, 0 8C; (d) NaH,
(

908
G. Gosselin et al. / Tetrahedron 62 (2006) 906–914
get acceptable yields. Even though uracil salts were shown
3
2
to react slowly with epoxides, it was found more
advantageous to build the pyrimidine ring by elaboration
of the amine group of 10 (Scheme 3). Key epoxide 4 was
opened with ammonia with perfect regio- and stereoselec-
tive control. Cyclopentylamine 10 was used without
purification in a uracil ring-construction process. In order
3
3–35
to do that, we adapted previously described procedures:
ethylvinyl ether 11 was reacted with chlorocarbonyl
isocyanate then treated with triethylamine to give iso-
cyanate 12. The latter compound was directly condensed
with 10 in situ. Without prior purification, 13 was cyclized
under acidic conditions to afford carbocycle 14. This 3-step-
1-pot synthesis gave access to two pyrimidine derivatives.
First, removal of the benzyl-protecting group of 14 afforded
uridine analogue 15 in 27% yield from 4.
Figure 2. Single-crystal structure of fully protected carbocycle 7
0 0 0 0
1 S,2 R,3 S,4 S enantiomer).
(
3
1,32
of the base with a methoxyethoxy group,
proceeded smoothly and 8 was obtained in reasonable yield
the reaction
(Scheme 2). Carbocycle 8 was then deprotected to afford
0
racemic 2 -methyl-guanosine analogue 9.
On the other hand, a simple adaptation of the method of
3
6
We then turned our attention to the preparation of
carbocyclic nucleosides having a pyrimidine base. A slight
modification to the general synthesis proved necessary to
Miah et al. provided the cytidine analogue. After
protection with an isopropylidene, 14 was activated with
p-nitrophenol and treated with ammonia. The product was
MeO
O
O
N
N
N
NH
BnO
N
a
N
b, c
78% (2 steps)
N
NH2
HO
N
BnO
NH
2
O
HO
60%
OH OH
OH OH
(+/-) 4
(+/-) 8
(+/-) 9
Scheme 2. Reagents and conditions: (a) NaH, 2-amino-6-(methoxyethoxy)-purine, DMF, 125 8C; (b) 3 N HCl, dioxane, 80 8C; (c) palladium hydroxide on
charcoal, cyclohexene, MeOH, reflux.
BnO
NH2
BnO
a
O
HO
(
OH OH
(+/-) 10
O
+/-) 4
O
N
EtO
BnO
NH
NH
O
1
0
c
b
HN
O
O
NCO
BnO
O
O
30% (3 steps)
OH OH
OH OH
1
1
12
(+/-) 13
(+/-) 14
O
N
NH2
N
NH
d
e-h, d
O
N
O
HO
HO
(+/-) 14
(+/-) 14
9
1%
54% (5 steps)
OH OH
+/-) 15
OH OH
(
(+/-) 16
Scheme 3. Reagents and conditions: (a) NH
dioxane, 100 8C; (d) palladium hydroxide on charcoal, cyclohexene, MeOH, reflux; (e) p-toluenesulfonic acid, 2,2-dimethoxypropane, acetone, RT;
f) trifluoroacetic anhydride, N-methylpyrrolidine then p-nitrophenol, MeCN, 0 8C; (g) NH , MeOH, 60 8C; (h) trifluoroacetic acid 90%, 0 8C.
3 3 2 4
, MeOH, 130 8C; (b) N-(chlorocarbonyl)-isocyanate, THF, 0 8C then Et N, 0 8C then 10, K40 8C; (c) 1 N H SO ,
(
3

G. Gosselin et al. / Tetrahedron 62 (2006) 906–914
BnO
BnO
909
BnO
BnO
a
b
+
cis/trans 3:1
O
9
3%
91%
O
HO
(+/-) 3b
HO
+/-) 3a
HO
(+/-) 17
(
(
+/-) 2
NH2
N
NH2
N
N
N
N
N
N
N
c, d
e, f
(
+/-) 17
BnO
HO
7
6%
O
O
85%
OH OH
(
2 steps)
(2 steps)
(
+/-) 18
(+/-) 19
O
NH
NH2
h, i, f
g
N
O
(+/-) 17
BnO
2
7%
OH OH
+/-) 20
(
4 steps)
HO
OH OH
(
(+/-) 21
3 2 4
Scheme 4. Reagents and conditions: (a) CeCl $7H O, NaBH , MeOH, 0 8C; (b) m-CPBA, DCM, 0 8C; (c) NaH, adenine, DMF, 100 8C; (d) p-toluenesulfonic
acid, 2,2-dimethoxypropane, acetone, RT; (e) trifluoroacetic acid 90%, 0 8C; (f) palladium hydroxide on charcoal, cyclohexene, MeOH, reflux; (g) NH
3
,
3 2 4
MeOH, 130 8C; (h) N-(chlorocarbonyl)-isocyanate, THF, 0 8C then Et N, 0 8C then 20, K40 8C; (i) 1 N H SO , dioxane, 100 8C.
0
directly deprotected to give (C/K)-2 -methyl-carbodine 16
in 5 steps and 54% yield from 14.
potential antiviral interest through key intermediates 4 and
17. Furthermore, the introduction of any 2 -branching-group
0
can be achieved by using the appropriate ketone as a starting
material. This versatile approach gives the shortest access to
racemic carbocylic nucleosides reported so far.
0
2
.4. Synthesis of 4 -epi-carbocyclic nucleosides
An interesting feature of our carbocycle synthesis is the
possibility of using the minor product of the reduction step
of ketone 2 (Scheme 1), cis-alcohol 3b, for the straight-
Compounds 6, 9, 15, 16, 19 and 21 were evaluated for
antiviral activity in cell culture experiments toward the
following viruses: Bovine Viral Diarrhea, Hepatitis B,
Human Immunodeficiency, Dengue and West Nile. No
activity was found for any of these molecules, nor was there
any cytotoxicity to the host cells.
0
forward preparation of seldom reported 4 -epi-carbo-
3
7
cycles. Moreover, after reinvestigation of the reduction
of 2, it proved possible to change dramatically the
stereochemical outcome of the reaction. When 2 was
subjected to Luche’s reduction conditions (NaBH in
4
3
presence of Ce ),
C 38,39
3b was obtained as the major
product of a 3:1 mixture in excellent yield (Scheme 4). Diol
4
. Experimental
3
1
b was epoxidized with m-chloroperoxybenzoic acid to give
7 as the sole product of the reaction. Then, the chemistry
4
.1. General
previously described for 4 was applied to 17. Reaction with
adenine sodium salt followed by protection led to
carbocycle 18. In a similar fashion to 7, the structure of
this compound was confirmed by X-ray diffraction of a
single crystal grown in DCM/acetone. After two depro-
1
All H chemical shifts are reported in d relative to CHCl (d
3
13
.26) or DMSO (d 2.55). All C chemical shifts are
7
reported in d relative to CDCl (centre of triplet, d 77.2) or
3
0
0
DMSO-d
are indicated by the symbols s (singlet), d (doublet), t
triplet), m (multiplet) and, br (broad). Reactions were
6
(centre of septet, d 39.5). The spin multiplicities
tections, racemic 2 -methyl-4 -epi-aristeromycin 19 was
obtained in good yield. On the other hand, when submitted
to epoxide-opening conditions with ammonia, 17 led to
cyclopentylamine 20. The latter was used in the uracil-ring
construction process described for 10 to afford uridine
derivative 21 in moderate yield.
(
monitored by thin-layer chromatography (TLC) using
Merck silica gel 60-F254 precoated plates with visualization
by irradiation with a UV lamp or by charring after
immersion in a solution of (NH ) SO and H SO in
4
2
4
2
4
aqueous EtOH or by charring after immersion in a 5%
solution of ninhydrin in EtOH. TLC plates were developed
with solvent systems (A) EtOAc/hexanes 1:1, (B) DCM/
MeOH 9:1 or (C) DCM/MeOH 8:2. Column chromato-
graphies were performed on either silica gel 60 (normal
phase) or C -branched silica gel 40–63 mm (reverse phase)
3
. Conclusion
We have developed a new route for the synthesis of
carbocyclic nucleosides. This method was also used for the
1
8
0
give rapid access to a large number of compounds of
preparation of 4 -epi-carbocycles. 2-Cyclopenten-1-ones
and eluted with the indicated solvent system. Yields refer
to chromatographically and spectroscopically (NMR)

910
G. Gosselin et al. / Tetrahedron 62 (2006) 906–914
homogeneous materials. The reactions were generally
carried out in an argon atmosphere using Fluka dry solvents.
BOM bromide was synthesized according to Ref. 30 using
either paraformaldehyde or trioxane indifferently. 2-Amino-
Then, NaBH4 (0.7 g, 18.4 mmol) was carefully added
portionwise. The milky suspension was allowed to warm
up to room temperature and stirred for 3 h. The reaction was
quenched by addition of acetic acid (3 mL) and MeOH
was evaporated. The remaining solid was taken up in
6
-(methoxyethoxy)-purine was synthesized according to
Ref. 31. All other chemicals were purchased from Sigma-
Aldrich or Acros.
EtOAc (100 mL) and extracted with sat. NH Cl solution
4
(2!100 mL), sat. NaHCO solution (100 mL) and brine
3
(100 mL). The organic phase was dried over Na SO and
2 4
4
.1.1. (C/K)-2-Methyl-5-(benzyloxymethyl)-2-cyclopen-
the solvent was evaporated. The residue was purified by
column chromatography (hexanes/EtOAc 9:1) to afford
3b (1.4 g, 70%) and 3a (0.5 g, 23%) as colorless oils.
ten-1-one (2). To a solution of 2-methyl-2-cyclopenten-1-
one 1 (15.0 g, 156 mmol) in THF (600 mL) was added
dropwise a 1.8 M solution of LDA in hexanes (87 mL,
1
57 mmol) at K78 8C over 10 min. The solution was stirred
for 1 h at K78 8C. Then, freshly prepared BOM bromide
purity ca. 70% by NMR) (48.0 g, 167 mmol) was added
4.1.3. (C/K)-(1a,2b,3a,5a)-1-Methyl-2-hydroxy-3-
(benzyloxymethyl)-6-oxabicyclo[3.1.0]hexane (4). To a
solution of 3a (2.0 g, 9.2 mmol) in DCM (45 mL) was added
m-chloroperoxybenzoic acid 77% (2.8 g, 12.0 mmol) at
0 8C. The solution was stirred at 0 8C for 1 h and then
allowed to warm-up to room temperature over 2 h. To the
(
dropwise over 10 min. The solution was stirred for 3 h at
K78 8C then allowed to warm up to K50 8C over 1.5 h. The
reaction was quenched with sat. NaHCO solution (300 mL)
3
and THF was evaporated. The residue was taken up in
EtOAc (400 mL) and the solution was extracted with sat.
NaHCO solution (2!400 mL) and brine (400 mL). The
white suspension was added sat. NaHCO solution (50 mL).
3
The mixture was extracted with EtOAc/sat. NaHCO3
solution (100 mL each). The organic phase was washed
with H O (2!100 mL), dried over Na SO and evaporated
3
organic phase was dried over Na SO and the solvent was
2
4
2
2
4
evaporated. The residue was purified by column chromato-
graphy (hexanes/EtOAc 9:1) to afford 2 (22.0 g, 65%) as a
to dryness. The residue was purified by column chromato-
graphy (hexanes/EtOAc 8:2) to afford 4 (2.0 g, 92%) as a
1
pale yellow oil: TLC R Z0.47 (A); H NMR (300 MHz,
colorless oil, which solidified in the fridge: TLC R Z0.25
f
f
1
(A); H NMR (300 MHz, CDCl ) d 1.51 (s, 3H), 1.56 (m,
CDCl ) d 1.81 (m, 3H), 2.55–2.80 (m, 3H), 3.64 (dd, 1H,
JZ6.4, 9.2 Hz), 3.77 (dd, 1H, JZ3.8, 9.2 Hz), 4.52 (s, 2H),
3
3
1H), 1.89 (m, 1H), 2.12 (m, 1H), 2.29 (br, 1H), 3.31 (s, 1H),
3.49 (dd, 1H, JZ6.3, 9.1 Hz), 3.62 (dd, 1H, JZ5.1, 9.1 Hz),
1
.36 (m, 6H); C NMR (75.5 MHz, CDCl ) d 9.6, 30.6,
3
7
3
1
3
45.1, 69.2, 72.4, 126.9, 127.6, 137.5, 140.7, 157.2, 208.7;
HRMS(FAB) Calcd [MCH] (C H O ): 217.1229,
found: 217.1216.
3.90 (d, 1H, JZ7.4 Hz), 4.54 (s, 2H), 7.36 (m, 5H);
C
NMR (75.5 MHz, CDCl ) d 14.1, 27.9, 40.9, 60.7, 64.6,
C
1
4
17
2
3
69.9, 72.4, 76.6, 126.9, 127.7; 137.7; HRMS(FAB) Calcd
[
C
MCH] (C H O ): 235.1334, found: 235.1348.
14 19 3
4
.1.2. (C/K)-2-Methyl-5-(benzyloxymethyl)-2-cyclo-
penten-1-ol (3). Method A. To a suspension of LiAlH4
2.2 g, 57.1 mmol) in ether (175 mL) at K78 8C was added
dropwise a solution of 2 (12.3 g, 57.0 mmol) in ether
75 mL) over 10 min. The slurry was stirred and slowly
0
0
4.1.4. (C/K)-2 -C-Methyl-5 -O-benzyl-aristeromycin
(5). Method A. To a suspension of adenine (1.75 g,
12.9 mmol) in DMF (30 mL) was added NaH (60% oil
dispersion) (0.43 g, 10.8 mmol) at room temperature. After
the evolution of hydrogen had ceased, the creamy
suspension was stirred at 80 8C for 20 min. Epoxide 4
(1.04 g, 4.3 mmol) dissolved in DMF (20 mL) was added
via a syringe. The resulting suspension was stirred at 100 8C
for 18 h then cooled down to room temperature. The solid
was filtered over celite and rinsed with DCM. The filtrate
was evaporated. The brown residue was purified by column
chromatography (DCM/MeOH 94:6) to afford 5 (0.65 g,
(
(
warmed up to K60 8C over 2 h. Then, the reaction was
quenched with successive careful additions of EtOAc
(30 mL), MeOH (30 mL) and H O (200 mL). The milky
2
aqueous phase was washed with ether (2!100 mL). The
organic phases were pooled and washed with H O (2!
2
3
evaporated. The residue was purified by column chromato-
graphy (hexanes/EtOAc 9:1). The first eluted product was
00 mL), dried over Na SO and the solvents were
2 4
3
b (3.5 g, 28%), which was obtained as a colorless oil: TLC
41%) as a beige powder: TLC R Z0.20 (B); mp 180.4–
f
1
1
181.5 8C; H NMR (200 MHz, DMSO) d 0.68 (s, 3H), 2.09–
R Z0.47 (A); H NMR (200 MHz, CDCl ) d 1.81 (m, 3H),
f
3
2
.26 (m, 2H), 2.59 (m, 2H), 3.69 (m, 2H), 4.57 (s, 2H), 4.61
br, 1H), 5.52 (m, 1H), 7.36 (m, 5H); C NMR (75.5 MHz,
2.46 (m, 3H), 3.65–3.74 (m, 3H), 4.56 (s, 2H), 4.65 (s, 1H),
4.73 (m, 1H), 4.90 (d, 1H, JZ6.3 Hz), 7.23 (br, 2H), 7.32
1
3
(
CDCl ) d 13.4, 33.0, 40.8, 69.8, 72.6, 79.1, 126.5, 127.1,
1
3
(m, 5H), 8.12 (s, 1H), 8.16 (s, 1H); C NMR (75.5 MHz,
DMSO) d 20.6, 28.9, 42.0, 60.8, 70.7, 72.0, 76.2, 78.4,
118.5, 127.2, 127.3, 128.1, 138.4, 139.8, 149.7, 152.0,
3
C
1
(
27.8; 137.6, 141.3; HRMS(FAB) Calcd [MCH]
C H O ): 219.1385, found: 219.1403. This product was
1
4 19 2
C
followed by 3a (7.0 g, 56%) as a colorless oil: TLC R Z
155.8; HRMS(FAB) Calcd [MCH] (C H N O ):
19 24
f
5
3
1
.42 (A); H NMR (200 MHz, CDCl ) d 1.78 (m, 3H), 1.96
m, 1H), 2.12 (br, 1H), 2.37–2.59 (m, 2H), 3.56 (m, 2H),
0
(
370.1879, found: 370.1861.
3
1
3
4
.46 (br, 1H), 4.58 (s, 2H), 5.45 (m, 1H), 7.35 (m, 5H);
NMR (75.5 MHz, CDCl ) d 13.0, 32.6, 47.6, 72.3, 72.4,
C
Method B. A solution of 7 (500 mg, 1.22 mmol) in TFA
90% (8 mL) was stirred for 1 h at 0 8C. Then, the solution
was basified by the addition of ammonia-saturated methanol
and the solvents were evaporated. The residue was taken up
3
81.7, 125.5, 127.0, 127.1, 127.7, 137.8, 140.5; HRMS(FAB)
Calcd [MCH] (C H O ): 219.1385, found: 219.1404.
C
1
4 19 2
in cold H O (ca. 10 mL) and filtered. The solid was washed
2
Method B. To a solution of 2 (2.0 g, 9.2 mmol) in MeOH
55 mL) was added CeCl $7H O (3.4 g, 14.0 mmol) at 0 8C.
The solution was stirred for 30 min at this temperature.
with cold H O and dried in the oven at 60 8C under vacuum.
2
Carbocyclic nucleoside 5 was obtained (400 mg, 90%) as a
white solid.
(
3
2

G. Gosselin et al. / Tetrahedron 62 (2006) 906–914
911
0
of 5 (330 mg, 0.89 mmol) in MeOH (30 mL) was treated
C
4
.1.5. (C/K)-2 -C-Methyl-aristeromycin (6). A solution
138.4, 154.5, 159.3, 160.0; HRMS(FAB) Calcd [MCH]
(C H N O ): 444.2247, found: 444.2254.
2
2 30 5 5
with palladium hydroxide (20% on charcoal) (200 mg) at
0
0
8C. Cyclohexene (10 mL) was added and the mixture was
4.1.8. (C/K)-2 -C-Methyl-carbocyclic guanosine (9). A
solution of 8 (400 mg, 0.90 mmol) in 3 N HCl (70 mL) was
stirred for 3 h at 80 8C. Then, the solution was cooled down,
evaporated and the residue was basified with ammonia-
saturated MeOH. The solvent was evaporated and the
residue was rapidly purified by column chromatography
refluxed for 15 h. The suspension was cooled down to room
temperature, filtered over celite and the solvents were
evaporated. The residue was crystallized from H O to afford
2
6
(228 mg, 92%) as a white powder: TLC R Z0.21 (C); mp
f
1
209.1–210.2 8C; UV (H O) l Z259 nm (3Z13,100); H
NMR (300 MHz, DMSO) d 0.68 (s, 3H), 1.95–2.22 (m, 2H),
2
max
0
0
(DCM/MeOH 88:12) to afford 2 -C-methyl-5 -O-benzyl-
2
.38 (m, 1H), 3.58–3.77 (m, 3H), 4.62 (m, 1H), 4.68–4.89
m, 3H), 7.23 (br, 2H), 8.14 (s, 1H), 8.26 (s, 1H); C NMR
carbocyclic guanosine as a beige solid: TLC R Z0.30 (C);
H NMR (200 MHz, DMSO) d 0.71 (s, 3H), 1.88 (m, 1H),
f
1
3
1
(
(
7
75.5 MHz, DMSO) d 20.6, 28.4, 44.0, 60.6, 61.1, 75.7,
8.7, 118.4, 139.8, 149.8, 152.0, 155.8; HRMS(FAB) Calcd
2.23 (m, 1H), 2.40 (m, 1H), 3.59–3.66 (m, 3H), 4.49–4.55
(m, 4H), 4.93 (d, 1H, JZ6.2 Hz), 6.52 (br, 2H), 7.34 (m,
5H), 7.75 (s, 1H), 10.64 (br, 1H). A solution of the above
C
[
MCH] (C H N O ): 280.1410, found: 280.1402.
12 18 5 3
0
0
2
-C-methyl-5 -O-benzyl-carbocyclic guanosine (295 mg,
.77 mmol) in MeOH (20 mL) was treated with palladium
0
hydroxide (20% on charcoal) (150 mg) at 0 8C. Cyclo-
0
0
0
0
4
.1.6. (C/K)-2 -C-Methyl-2 ,3 -O-isopropylidene-5 -O-
benzyl-aristeromycin (7). This synthesis began like the
preparation of 5 using 500 mg (2.13 mmol) of epoxide 4.
After evaporation of DMF, the brown residue was
suspended in acetone (32 mL) and 2,2-dimethoxypropane
hexene (5 mL) was added and the mixture was refluxed for
15 h. The suspension was cooled down to room temperature,
filtered over celite and the solvents were evaporated. The
residue was purified by reverse phase column chromato-
graphy (H O/MeOH 95:5) to afford 9 (205 mg, 78% from 8)
(
8 mL). The suspension was acidified with p-toluene-
2
sulfonic acid (300 mg, 1.75 mmol) and stirred for 2 h at
room temperature. The mixture was filtered, the solid was
washed with acetone and the filtrate was neutralized with
pyridine (300 mL). The solvents were evaporated. The
residue was taken up in DCM (100 mL) and extracted
as a white solid: TLC R Z0.10 (C); mp O230 8C (dec); UV
f
1
(
H O) lmaxZ252 nm (3Z11,200); H NMR (300 MHz,
2
DMSO) d 0.73 (s, 3H), 1.88 (m, 1H), 2.06 (m, 1H), 2.36 (m,
1
4
H), 3.60–3.66 (m, 3H), 4.42 (s, 1H), 4.52 (m, 1H), 4.73–
.79 (m, 2H), 6.42 (br, 2H), 7.82 (s, 1H), 10.56 (br, 1H);
13
C
successively with H O (100 mL), 1 N HCl (100 mL), sat.
2
NMR (75.5 MHz, DMSO) d 15.7, 20.6, 43.9, 59.5, 60.7,
5.6, 78.8, 116.1, 135.8, 151.5, 153.3, 157.1; HRMS(FAB)
NaHCO3 solution (100 mL) and brine (100 mL). The
organic phase was dried over Na SO and the solvent was
evaporated. The remaining solid was purified by column
7
2
4
C
Calcd [MCH]
96.1339.
(C H N O ): 296.1359, found:
12 18 5 4
2
chromatography (DCM/MeOH 96:4) to afford 7 (695 mg,
8
1%) as a beige powder: TLC R Z0.38 (B); mp 200.4–
f
1
01.3 8C; H NMR (300 MHz, CDCl ) d 1.19 (s, 3H), 1.39
s, 3H), 1.68 (s, 3H), 2.46 (m, 1H), 2.57 (m, 1H), 2.85 (m,
4.1.9. (C/K)-(1b,2b,3a,5a)-1,2-Dihydroxy-1-methyl-3-
benzyloxymethyl)-5-amino-cyclopentane (10). A solu-
tion of 4 (900 mg, 3.84 mmol) in ammonia-saturated MeOH
20 mL) was heated at 130 8C under pressure for 3 h. The
2
(
3
(
1
5
7
1
1
1
4
H), 3.65 (m, 2H), 4.27 (d, 1H, JZ2.7 Hz), 4.63 (s, 2H),
(
.05 (dd, 1H, JZ6.7, 13.5 Hz), 5.97 (br, 2H), 7.35 (m, 5H),
1
.87 (s, 1H), 8.36 (s, 1H); C NMR (75.5 MHz, CDCl ) d
3
solution was cooled down, degassed and evaporated to
dryness to get 960 mg of 10 as an oily brown residue, which
was found homogeneous by TLC and used in the next step
3
8.7, 25.9, 27.8, 30.3, 40.2, 63.9, 70.1, 72.6, 86.3, 88.3,
12.4, 119.2, 127.0, 127.1, 127.8, 137.4, 139.8, 150.3,
51.5, 154.4; HRMS(FAB) Calcd [MCH] (C H N O ):
C
without purification: TLC R
f
Z0.14 (C).
2
2 28 5 3
10.2192, found: 410.2203.
0
0
4
.1.10. (C/K)-2 -C-Methyl-5 -O-benzyl-carbocyclic
uridine (14). To a solution of N-(chlorocarbonyl) iso-
cyanate (894 mg, 8.51 mmol) in THF (9 mL) was slowly
added a solution of ethylvinyl ether (804 mg, 11.15 mmol)
in THF (6 mL) at 0 8C. The resulting solution was stirred for
20 min at 0 8C. Then, triethylamine (852 mg, 8.42 mmol) in
THF (9 mL) was slowly added. The resulting suspension
was stirred for 5 min at 0 8C and then, cooled down to
K40 8C. A solution of amine 10 (1.920 g, 7.64 mmol) in
THF (9 mL) was rapidly added to the mixture and the
suspension was allowed to slowly warm up to room
temperature. Then, THF was evaporated and the residue
was dissolved in dioxane (6 mL). To this solution was added
1 N H SO (9 mL) and the mixture was heated at 100 8C for
4
2
.1.7. (C/K)-2-Amino-6-deamino-6-(methoxyethoxy)-
-C-methyl-5 -O-benzyl-aristeromycin (8). A suspension
0
0
of 2-amino-6-(methoxyethoxy)-purine (950 mg, 4.54 mmol)
in DMF (8 mL) was treated with NaH (60% oil dispersion)
(
160 mg, 4.00 mmol) at room temperature. After the
evolution of hydrogen had ceased, the suspension was
stirred at 80 8C for 20 min. Epoxide 4 (375 mg, 1.60 mmol)
dissolved in DMF (8 mL) was added via a syringe. The
resulting brown solution was stirred at 125 8C for 48 h then
cooled down to room temperature. The DMF was
evaporated. The brown residue was purified by column
chromatography (DCM/MeOH 96:4) to afford 8 (425 mg,
2
4
6
1
0%) as a beige powder: TLC R Z0.45 (B); mp 175.7–
2 h. Then, the solution was cooled down to room
temperature and basified with 3 N ammonia (7 mL). The
ammonium salts were precipitated with MeOH and the
suspension was filtered. The filtrate was evaporated to
dryness and the crude material was purified by column
chromatography (DCM/MeOH 96:4) to afford 14 (798 mg,
f
1
76.6 8C; H NMR (200 MHz, DMSO) d 0.70 (s, 3H), 1.94
(
3
m, 1H), 2.23 (m, 1H), 2.44 (m, 1H), 3.32 (s, 3H), 3.62–
.72 (m, 5H), 4.49–4.66 (s, 6H), 4.91 (d, 1H, JZ6.4 Hz),
13
.41 (br, 2H), 7.33 (m, 5H), 7.92 (s, 1H); C NMR
6
(
6
75.5 MHz, DMSO) d 20.6, 29.2, 41.9, 57.9, 59.8, 64.4,
9.9, 70.8, 72.0, 76.2, 78.5, 113.3, 127.2, 128.1, 138.3,
30%) as a white solid: TLC R Z0.32 (B); mp
f

912
G. Gosselin et al. / Tetrahedron 62 (2006) 906–914
1
83.1–184.2 8C; H NMR (300 MHz, DMSO) d 0.89
s, 3H), 1.61 (m, 1H), 2.16 (m, 1H), 2.29 (m, 1H), 3.48 (d,
0
0
0
0
1
(
above 2 -C-methyl-2 ,3 -O-isopropylidene-5 -O-benzyl-
carbodine (202 mg, 0.52 mmol) in TFA 90% (5 mL) was
stirred for 1 h at 0 8C. Then, the solution was basified by the
addition of ammonia-saturated methanol and the solvents
1
5
8
2
1
H, JZ9.5 Hz), 3.62 (m, 2H), 4.52 (s, 2H), 4.67 (m, 1H),
.25 (dd, 1H, JZ2.2, 8.1 Hz), 7.34 (m, 5H), 7.66 (d, 1H, JZ
.1 Hz), 11.26 (br, 1H); C NMR (75.5 MHz, DMSO) d
1
3
were evaporated. The residue was taken up in cold H O and
2
0.4, 27.5, 41.8, 61.2, 70.0, 72.2, 76.0, 78.6, 100.7, 127.3,
27.4, 128.1, 138.2, 142.9, 151.2, 162.7; HRMS(FAB)
filtered. The solid was washed with cold H O and dried in
2
0
carbodine was obtained as an off-white solid and used
0
the oven at 60 8C under vacuum. 2 -C-methyl-5 -O-benzyl-
C
Calcd [MCH]
3
(C H N O ): 347.1607, found:
5
1
8
23
2
47.1616.
directly in the next step: TLC R Z0.51 (C). A solution of
-C-methyl-5 -O-benzyl-carbodine (172 mg, 0.50 mmol)
f
0
0
2
0
4
.1.11. (C/K)-2 -C-Methyl-carbocyclic uridine (15). A
in MeOH (20 mL) was cooled down to 0 8C and treated
with palladium hydroxide (20% on charcoal) (120 mg).
Cyclohexene (7 mL) was added and the mixture was
refluxed for 15 h. The suspension was cooled down to
room temperature, filtered on celite and the solvents were
evaporated. The residue was crystallized from MeOH/i-
propyl ether to afford 16 (112 mg, 54% from 14) as a white
solution of 14 (250 mg, 0.72 mmol) in MeOH (20 mL) was
cooled down to 0 8C and treated with palladium hydroxide
(
20% on charcoal) (180 mg). Cyclohexene (7 mL) was
added and the mixture was refluxed for 15 h. The suspension
was cooled down to room temperature, filtered on celite and
the solvents were evaporated. The residue was crystallized
from MeOH/i-propyl ether to afford 15 (164 mg, 91%) as
powder: TLC R
l
Z0.20 (C); mp O200 8C (dec); UV (H O)
2
1
f
white crystals: TLC R Z0.27 (C); mp 181.6–182.5 8C; UV
maxZ274 nm (3Z7400); H NMR (200 MHz, DMSO) d
f
1
(
DMSO) d 0.92 (s, 3H), 1.61 (m, 1H), 2.00 (m, 1H), 2.17
H O) lmaxZ267 nm (3Z9900); H NMR (200 MHz,
0.85 (s, 3H), 1.60 (m, 1H), 1.92–2.19 (m, 2H), 3.49–3.63
(m, 3H), 4.54–4.79 (m, 4H), 5.73 (d, 1H, JZ7.4 Hz), 7.26
(br, 2H), 7.66 (d, 1H, JZ7.4 Hz); C NMR (75.5 MHz,
DMSO) d 20.9, 27.4, 44.0, 60.8, 62.3, 76.1, 78.5, 93.4,
143.8, 155.4; 164.0; HRMS(FAB) Calcd [MCH]
2
1
3
(
(
1
m, 1H), 3.44 (m, 1H), 3.56 (m, 2H), 4.39 (s, 1H), 4.67–4.76
m, 3H), 5.59 (d, 1H, JZ8.0 Hz), 7.72 (d, 1H, JZ8.0 Hz),
1
1.29 (br, 1H); C NMR (75.5 MHz, DMSO) d 20.6, 27.0,
3
C
4
3.6, 60.4, 61.1, 75.8, 78.6, 100.9, 142.9, 151.2, 162.8;
HRMS(FAB) Calcd [MCH] (C H N O ): 257.1137,
(C11H N O ): 256.1297, found: 256.1302.
18 3 4
C
1
1 17 2 5
found: 257.1139.
4.1.13. (C/K)-(1b,2b,3a,5b)-1-Methyl-2-hydroxy-3-
benzyloxymethyl)-6-oxabicyclo[3.1.0]hexane (17). The
preparation was carried out as described for 4, using 3b in
place of 3a. Epoxide 17 was obtained in 91% yield as a
(
0
4
.1.12. (C/K)-2 -C-Methyl-carbodine (16). A suspension
of 14 (300 mg, 0.87 mmol) in acetone (25 mL) and 2,2-
dimethoxypropane (8 mL) was treated with p-toluene-
sulfonic acid (50 mg, 0.3 mmol). After dissolution of the
materials, the solution was stirred for 1 h at room
temperature. Then, the mixture was neutralized with
pyridine (50 mL) and the solvents were evaporated. The
residue was rapidly purified by column chromatography
colorless oil, which solidified in the fridge: TLC R
Z0.25
) d 1.53 (s, 3H), 1.75 (dd,
3
f
1
(A); H NMR (200 MHz, CDCl
1H, JZ2.1, 14.9 Hz), 1.98 (dd, 1H, JZ9.5, 14.9 Hz), 2.51
(m, 1H), 3.29 (s, 1H), 3.38 (dd, 1H, JZ5.3, 9.0 Hz), 3.94
(dd, 1H, JZ9.0, 9.5 Hz), 4.29 (d, 1H, JZ8.2 Hz), 4.46 (d,
1H, JZ11.7 Hz), 4.58 (d, 1H, JZ11.7 Hz), 7.36 (m, 5H);
0
0
0
13
(DCM/MeOH 95:5) to afford 2 -C-methyl-2 ,3 -O-iso-
0
propylidene-5 -O-benzyl-carbocyclic uridine as a white
C NMR (75.5 MHz, CDCl ) d 14.3, 28.7, 37.0, 61.4, 66.8,
3
72.4, 72.5, 75.6, 127.1, 127.8; 137.1; HRMS(FAB) Calcd
1
C
solid: TLC R Z0.48 (B); H NMR (200 MHz, CDCl ) d
[MCH] (C14H O ): 235.1334, found: 235.1343.
19 3
f
3
1
2
4
7
.27 (s, 3H), 1.37 (s, 3H), 1.61 (s, 3H), 2.12–2.22 (m, 2H),
.47 (m, 1H), 3.51–3.67 (m, 2H), 4.17 (d, 1H, JZ2.9 Hz),
.58 (s, 2H), 5.13 (m, 1H), 5.67 (dd, 1H, JZ2.3, 8.1 Hz),
.22 (d, 1H, JZ8.1 Hz), 7.36 (m, 5H), 9.29 (br, 1H). To a
0
epi-5 -O-benzyl-aristeromycin (18). The preparation was
carried out as described for 7, using 17 in place of 4.
Carbocyclic nucleoside 18 was obtained in 76% yield (2
0
0
0
4.1.14. (C/K)-2 -C-Methyl-2 ,3 -O-isopropylidene-4 -
0
0
0
0
solution of the above 2 -C-methyl-2 ,3 -O-isopropylidene-
0
5
-O-benzyl-carbocyclic uridine (280 mg, 0.73 mmol) in
steps) as a beige powder: TLC R
105.7 8C; H NMR (200 MHz, CDCl ) d 1.01 (s, 3H), 1.40
f
Z0.37 (B); mp 104.8–
1
MeCN (8 mL) was added N-methylpyrrolidine (700 mL)
and trifluoroacetic anhydride (300 mL, 2.12 mmol) at 0 8C.
The mixture was stirred for 30 min then p-nitrophenol
3
(s, 3H), 1.56 (s, 3H), 2.34 (m, 1H), 2.48 (m, 1H), 3.11 (m,
1H), 3.74 (m, 2H), 4.44 (d, 1H, JZ4.0 Hz), 4.62 (m, 2H),
5.01 (dd, 1H, JZ2.2, 7.1 Hz), 6.38 (br, 2H), 7.35 (m, 5H),
(
300 mg, 2.16 mmol) was added. The yellow solution was
stirred for 3 h at 0 8C. The mixture was diluted with DCM
20 mL) and extracted with 1 N HCl (20 mL), sat. NaHCO3
1
3
7.88 (s, 1H), 8.40 (s, 1H); C NMR (75.5 MHz, CDCl ) d
20.0, 25.3, 26.9, 31.9, 42.3, 63.9, 68.9, 72.7, 85.9, 91.6,
110.5, 118.9, 127.0, 127.7, 137.6, 138.7, 149.9, 152.1,
3
(
solution (3!20 mL) and brine (20 mL). The organic phase
was dried over Na SO and the solvents were evaporated.
C
154.7; HRMS(FAB) Calcd [MCH] (C22H N O ):
28 5 3
2
4
The residue was taken up in ammonia-saturated MeOH
30 mL) and stirred at 60 8C for 15 h. The solvent was
evaporated and the residue was purified by column
410.2192, found: 410.2173.
(
0
0
4.1.15. (C/K)-2 -C-Methyl-4 -epi-aristeromycin (19).
The preparation was carried out as described for 6, using
18 in place of 7. Carbocyclic nucleoside 19 was obtained in
0
chromatography (DCM/MeOH 94:6) to afford 2 -C-
0
0
0
methyl-2 ,3 -O-isopropylidene-5 -O-benzyl-carbodine as a
1
yellowish solid: TLC R Z0.23 (B); H NMR (200 MHz,
85% yield (2 steps) as a white powder: TLC R Z0.23 (C);
f
f
CDCl ) d 1.23 (s, 3H), 1.36 (s, 3H), 1.60 (s, 3H), 2.09–2.22
(
mp 254.3–255.2 8C; UV (H O) lmaxZ260 nm (3Z13,600);
H NMR (200 MHz, DMSO) d 0.88 (s, 3H), 1.95 (m, 1H),
2.56 (m, 2H), 3.44 (m, 1H), 3.61 (m, 1H), 3.71 (m, 1H), 4.50
3
2
1
m, 2H), 2.44 (m, 1H), 3.51–3.64 (m, 2H), 4.15 (d, 1H, JZ
3
.5 Hz), 4.57 (s, 2H), 5.18 (m, 1H), 5.72 (d, 1H, JZ7.4 Hz),
.21 (d, 1H, JZ7.4 Hz), 7.35 (m, 5H). A solution of the
7
(t, 1H, JZ5.1 Hz), 4.80 (s, 1H), 4.87 (m, 1H), 4.90 (d, 1H,

G. Gosselin et al. / Tetrahedron 62 (2006) 906–914
913
1
3
JZ5.1 Hz), 7.21 (br, 2H), 8.12 (s, 1H), 8.17 (s, 1H);
NMR (75.5 MHz, DMSO) d 20.4, 27.5, 40.5, 60.9, 61.4,
6.5, 80.1, 118.7, 140.7, 150.0, 151.8, 155.8; HRMS(FAB)
C
3. Sommadossi, J.-P.; La Colla, P.; Standring, D. N.;
Bichko, V. V.; Qu, L. WO PCT Int. Appl. 2004058792, 2004.
4. Afdhal, N. H.; Rodriguez-Torres, M.; Lawitz, E. J.;
Godofsky, E. W.; Chao, G.; Fielman, B. A.; Knox, S.;
Brown, N. A. Enhanced Antiviral Efficacy for Valopicitabine
7
C
Calcd [MCH]
2
(C H N O ): 280.1410, found:
12 18 5 3
80.1417.
(
NM283) Plus PEG-Interferon in Hepatitic C Patients with
HCV Genotype-1 Infection: Results of a Phase IIa Multicenter
Trial; 39th Annual Meeting of the European Association for
the Study of the Liver; Paris, France; 13–17 April, 2005.
. In this paper, numbering of compounds is given by analogy
with the parent ribonucleosides.
4
(
.1.16. (C/K)-(1b,2b,3b,5a)-1,2-Dihydroxy-1-methyl-3-
benzyloxymethyl)-5-amino-cyclopentane (20). The pre-
paration was carried out as described for 10, using 17 in
place of 4. Cyclopentylamine 20 was obtained as a brown
oil and directly used in the next step without purification:
5
6
. Wang, P.; Gullen, B.; Newton, M. G.; Cheng, Y.-C.;
Schinazi, R. F.; Chu, C. K. J. Med. Chem. 1999, 42,
3390–3399.
TLC R Z0.13 (C).
f
0
21). The preparation was carried out as described for 15,
0
4
(
.1.17. (C/K)-2 -C-Methyl-4 -epi-carbocyclic uridine
7
8
. Wang, P.; Agrofoglio, L. A.; Newton, M. G.; Chu, C. K.
J. Org. Chem. 1999, 64, 4173–4178.
using 17 in place of 4. Carbocyclic nucleoside 21 was
obtained in 27% yield (4 steps from 17) as a white powder:
TLC R Z0.29 (C); mp 195.5–196.4 8C; UV (H O) lmaxZ
. Song, G. Y.; Paul, V.; Choo, H.; Morrey, J.; Sidwell, R. W.;
Schinazi, R. F.; Chu, C. K. J. Med. Chem. 2001, 44,
3985–3993.
f
2
1
267 nm (3Z10,400); H NMR (200 MHz, DMSO) d 1.00 (s,
3H), 1.87 (m, 2H), 2.31 (m, 1H), 3.40 (dd, 1H, JZ6.8,
10.5 Hz), 3.60 (m, 2H), 4.49 (m, 2H), 4.82 (d, 1H, JZ
4.2 Hz), 4.89 (m, 1H), 5.54 (d, 1H, JZ8.0 Hz), 7.67 (d, 1H,
9
. Jin, Y. H.; Liu, P.; Wang, J.; Baker, R.; Huggins, J.; Chu, C. K.
J. Org. Chem. 2003, 68, 9012–9018.
0. Borcherding, D. R.; Scholtz, S. A.; Borchardt, R. T. J. Org.
1
1
1
1
1
1
3
Chem. 1987, 52, 5457–5461.
1. Ali, S. M.; Ramesh, K.; Borchardt, R. T. Tetrahedron Lett.
1990, 31, 1509–1512.
JZ8.0 Hz), 11.23 (br, 1H); C NMR (75.5 MHz, DMSO) d
2
1
2
0.4, 27.1, 40.5, 60.7, 61.0, 76.5, 79.9, 100.3, 143.5, 151.4,
C
62.9; HRMS(FAB) Calcd [MCH] (C H N O ):
57.1137, found: 257.1140.
1
1
17
2
5
2. Wolfe, M. S.; Blake, L. A.; Borcherding, D. R.;
Borchardt, R. T. J. Org. Chem. 1990, 55, 4712–4717.
3. Song, G. Y.; Naguib, F. N. M.; El Kouni, M. H.; Chu, C. K.
Nucleosides Nucleotides Nucleic Acids 2001, 20, 1915–1925.
4. Bryant, M. L.; Bridges, E. G.; Placidi, L.; Faraj, A.; Loi, A.-G.;
Pierra, C.; Dukhan, D.; Gosselin, G.; Imbach, J.-L.;
Hernandez, B.; Juodawlkis, A.; Tennant, B.; Korba, B.;
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.2. X-ray crystallographic data
Crystallographic data for the structures in this paper have
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication numbers CCDC
2
84302 and 284303.
2
29–235.
1
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Acknowledgements
We wish to thank Dr. A. van der Lee and Dr. R. Astier of the
Universit e´ Montpellier II, Montpellier, France for single-
crystal structure determination. We also thank Dr. P. La
Colla of the Universita di Cagliari, Cagliari, Italy and Dr. V.
Bichko of Idenix Pharmaceuticals, Cambridge, MA, USA
for antiviral testing.
16. Hernandez-Santiago, B.; Placidi, L.; Cretton-Scott, E. M.;
Faraj, A.; Bridges, E. G.; Bryant, M. L.; Rodriguez-Santiago,
J.; Imbach, J.-L.; Gosselin, G.; Pierra, C.; Dukhan, D.;
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Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2005.10.
0
37
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