Synthesis of 3′-deoxy-3′-C-methyl-β-d-ribonucleoside analogs

Article abstract of DOI:10.1016/j.tet.2007.08.092

3′-Deoxy-3′-C-methyl-β-d-ribonucleoside analogs bearing the five canonical bases of nucleic acids have been synthesized. All these derivatives were prepared by glycosylation of the corresponding heterocyclic bases with a suitable peracylated 3-C-methyl su

Full text of DOI:10.1016/j.tet.2007.08.092

Tetrahedron 63 (2007) 11260–11266
Synthesis of 30-deoxy-30-C-methyl-b-D-ribonucleoside analogs
Sarah Couturier,a Mohamed Aljarah,a Gilles Gosselin,b
a,
ꢀa
ꢀ
Christophe Mathe and Christian Perigaud
*
a
´
´
Institut des Biomolecules Max Mousseron (IBMM), UMR 5247 CNRS-UM 1-UM 2, Universite Montpellier 2,
´
Case Courrier 1705, Place E. Bataillon, 34095 Montpellier Cedex 05, France
b
´
Laboratoires Idenix Sarl, Cap Gamma, 1682 rue de la Valsieꢁre, 34819 Montpellier Cedex 04, France
Received 13 July 2007; revised 28 August 2007; accepted 29 August 2007
Available online 1 September 2007
Abstract—30-Deoxy-30-C-methyl-b-D-ribonucleoside analogs bearing the five canonical bases of nucleic acids have been synthesized. All
these derivatives were prepared by glycosylation of the corresponding heterocyclic bases with a suitable peracylated 3-C-methyl sugar
precursor. The synthesis of the 3-C-methyl sugar precursor is described following a new stereoselective synthetic pathway.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
30-C-methyl nucleosides.3 Except the adenine nucleoside
derivative, which has been succinctly described,4,5 all the
target compounds are hitherto unknown. This fact prompted
us to elaborate a synthetic route to reach such kind of com-
pounds. Basically, nucleoside analogs can be obtained
through the reaction of persylilated heterocyclic bases with
a peracylated sugar precursor, in the presence of a Lewis
Nucleoside analogs constitute an important class of thera-
peutic agents in the treatment of cancers and viral infec-
tions.1 The mode of action of these derivatives is based
upon their intracellular conversion to their phosphorylated
forms (nucleotides), which can interact with different cellu-
lar or viral enzymatic systems involved in the nucleic acids
biosynthesis. During the last decades, an intensive research
was dedicated to the discovery of more effective, selective,
and non-toxic new nucleoside derivatives.2 These efforts
have concerned the chemical modifications of the base
and/or the sugar moiety of natural nucleosides. In the latter,
the main modifications involved changes in the sugar moiety
like, inversion of hydroxyl group configurations, their
elimination leading to dideoxy-or dideoxy-didehydro-
nucleosides, their substitution/functionalization by various
synthetic groups, or cleavage of the sugar ring leading to
acyclic nucleosides. Modifications of the sugar moiety of
nucleosides may lead to significant changes in the spectrum
of their biological activity and degree of selective toxicity, as
well as in their physico-chemical properties. In the course of
our ongoing research on the synthesis and biological evalu-
ation of modified sugar nucleoside analogs, we became in-
terested in a stereoselective strategy for the preparation of
30-deoxy-30-C-methyl-b-D-ribonucleoside analogs (Fig. 1).
Surprisingly, although a tremendous work has been done
in the synthesis of new series of nucleoside analogs, few
work has been reported regarding the synthesis of 30deoxy-
€
acid as a catalyst, according to the Vorbruggen’s procedure.
Under these conditions, the neighboring group participation
of the 2-C-acyloxygroup controls the stereochemistry of
the reaction leading exclusively to the formation of the b-
nucleoside (trans rule).6 Consequently, we embarked on the
synthesis of an appropriate sugar precursor, namely, 1,2-di-
O-acetyl-5-O-benzoyl-3-deoxy-3-C-methyl-D-ribofuranose 1
(Fig. 1).
Herein, according to the literature data, we report on the dif-
ferent attempts for the preparation of this precursor and we
describe here a new stereoselective synthetic pathway. Addi-
tionally, the synthesis of the corresponding 30-deoxy-
30-C-methyl-b-D-ribonucleoside analogs bearing the five
canonical bases of nucleic acids is also reported.
B
BzO
HO
O
O
OAc
CH3
OAc
CH3
OH
1
Uracil-1-yl
Thymin-1-yl
B = Cytosin-1-yl
Adenin-9-yl
Guanin-9-yl
* Corresponding author. Tel.: +33 (0) 467143855; fax: +33 (0) 467042029;
e-mail: perigaud@univ-montp2.fr
Figure 1. 30-Deoxy-30-C-methyl-b-D-ribonucleoside analogs.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.08.092

S. Couturier et al. / Tetrahedron 63 (2007) 11260–11266
11261
2. Results and discussion
were the addition of an organomagnesium reagent, followed
by a radical deoxygenation of the resulting tertiary alcohol.
Thus, addition of methyl magnesium bromide in dry Et2O at
ꢁ20 ꢀC to compound 3 (Scheme 2) gave stereoselectively10
the 3-C-methyl sugar 7. In contrast to the deoxygenation of
alcohols using Barton–McCombie type methodology,11 the
use of methyl oxalyl esters provide good alternative for re-
moval of hindered secondary or tertiary alcohols.12 Thus,
treatment of 7 with methyl oxalyl chloride in anhydrous di-
chloromethane gave the corresponding ester derivative,
which was subsequently deoxygenated with tris(trimethyl-
silyl)silane hydride in the presence of AIBN to afford a mix-
ture of compounds 5 and 6 with a ratio 2:98 (as determined
by chiral HPLC, data not shown) in favor of 6. From the
diastereoisomeric mixture, we were able to separate by crys-
tallization from petroleum ether pure compound 6.
Our first synthesis (Scheme 1) was centered on the catalytic
hydrogenation of the olefin intermediate 4. Such a reduction
was described to be stereospecific leading only to the desired
modified sugar with a-stereochemistry of the methyl
group.5,7 This result appeared to be consistent with previous
observations of the approach of reducing agents to the b-face
of furanosyl carbohydrates, with erythro or ribo configura-
tions, bearing a 1,2-O-isopropylidene group in the a-stereo-
chemistry.8 The olefin should be readily available from the
xylofuranoside 2 through an usual sequence involving the
oxidation of unprotected secondary alcohol, followed by
a Wittig reaction. Starting from D-xylose, precursor 2 was
obtained in 70% overall yield according to a procedure
involving the initial formation of the bis-isopropylidene
derivative, selective deprotection of the six-membered iso-
propylidene ring, and selective benzoylation of the primary
5-hydroxyl group.9 The preparation of the osidic precursor
required introduction of a methyl group on position 3 of
the sugar moiety. In our first synthetic pathway, this intro-
duction involved reduction of an exocyclic methylene group
previously obtained by a Wittig reaction on the keto sugar 3
(Scheme 1). Hydrogenation of the resulting exocyclic dou-
ble bond in the presence of Pd/C 5% was not as stereoselec-
tive as previously reported and lead to the formation of two
diastereoisomers 5 and 6 with a ratio 20:80 (as determined
by 1H NMR) in favor of the desired isomer 6.
CH3
O
BzO
BzO
a
O
O
O
O
O
O
HO
3
7
b
R1
BzO
BzO
c
O
O
OAc
O
O
CH3
OAc
R2
1
5 R1 = CH3, R2 = H
6 R1 = H, R2 = CH3
OH
O
BzO
BzO
a
b
O
D-xylose
O
O
O
O
Scheme 2. Reagents and conditions: (a) CH3MgBr, Et2O, ꢁ20 ꢀC, 80%; (b)
(i) MeCO2COCl, DMAP, CH2Cl2, 0 ꢀC to rt, (ii) (Me3Si)3SiH, AIBN, tolu-
ene, reflux, 80% overall yield, ratio 5/6: 2:98; (c) (i) TFA 80%, rt, (ii) Ac2O,
DMAP, pyridine, rt, 85% overall yield.
O
2
3
c
R1
R2
The stereoselectivity observed in this reaction, compared to
the one obtained during the hydrogenation step can be justi-
fied on the basis of steric and stereoelectronic effects.13 In-
deed, after formation of the 3-C-methyl tertiary radical,
the chirality of such a radical as well as its pyramidal shape14
induce the preferential addition of the hydride on the less
hindered sugar b-face.
BzO
BzO
d
O
O
O
O
O
O
4
5 R1 = CH3, R2 = H
6 R1 = H, R2 = CH3
Scheme 1. Reagents and conditions: (a) Ref. 9; (b) Dess–Martin periodi-
nane, CH2Cl2, 0 ꢀC to rt, 95%; (c) Ph3PCH3Br, sodium tert-pentylate,
THF, ꢁ78 ꢀC then 5–6 ꢀC, 87%; (d) H2, Pd/C 5%, MeOH, rt, 98%, ratio
5/6: 20:80.
Finally, compound 6 was converted in a two-step procedure
into 1,2-di-O-acetyl-5-O-benzoyl-3-deoxy-3-C-methyl-D-
ribofuranose 1, which was obtained in 85% after silica gel
column chromatography.
The influence of pressure, temperature, nature of the solvent,
and the catalyst on the stereoselectivity of the hydrogenation
reaction has been investigated (data not shown). Whatever
the conditions used, the two diastereoisomers have been ob-
tained with a diastereoisomeric excess in favor of the desired
compound 6 up to 60%. Furthermore, many attempts to sep-
arate the mixture of the two diastereoisomers have been per-
formed including crystallization, chromatography on silica
gel, and reverse phase, however, without any success. There-
fore, at this stage of the synthesis, the compound 4 seemed
not to be the ideal candidate for the preparation of an osidic
precursor having a methyl group in position 3 with a R con-
figuration. Thus, the synthesis of such a precursor was recon-
sidered from compound 3. The modifications envisioned
The syntheses of the 30-deoxy-30-C-methyl-b-D-ribonucleo-
side pyrimidine and purine derivatives are depicted in
Schemes 3 and 4. Glycosylation reactions with uracil, thy-
mine, and sugar 1, under Vorbr€uggen conditions using
(trimethylsilyl) trifluoromethane sulfonate (TMSOTf) as
a catalyst in anhydrous acetonitrile, afforded compounds 8
and 9. The target nucleosides 10 and 11 were obtained
from 8 and 9 by following treatment with methanolic am-
monia and purification on silica gel column chromato-
graphy. Subsequently, protected derivative
8
was
converted into the corresponding cytosine derivative 12
via the formation of a thioamide intermediate followed by
aminolysis.

11262
S. Couturier et al. / Tetrahedron 63 (2007) 11260–11266
X
their effects on the replication of HIV and several RNA
viruses in cell culture experiments. However, none of these
compounds did not show any significant antiviral activity
nor cytoxicity at the highest concentration tested (usually
100 mM).
Y
N
N
O
BzO
R1O
a
O
O
OAc
CH3
CH3
OR2
OAc
1
3. Experimental
3.1. General
8 (X = OH, Y = H, R1 = Bz, R2 = Ac)
9 (X = OH, Y = CH3, R1 = Bz, R2 = Ac)
10 (X = OH, Y = H, R1 = R2 = H)
11 (X = OH, Y = CH3, R1 = R2 = H)
12 (X = NH2, Y = H, R1 = R2 = H)
b
c
b
Evaporation of solvents was carried out on a rotary evapora-
tor under reduced pressure. Melting points were determined
Scheme 3. Reagents and conditions: (a) silylated uracil or thymine,
TMSOTf, CH3CN, 0 ꢀC to rt, 82% for 8, 64% for 9; (b) MeOH/NH3, rt,
92% for 10, 83% for 11; (c) (i) Lawesson’s reagent, (CH2Cl)2, reflux, (ii)
MeOH/NH3, 100 ꢀC, 92% overall yield.
€
in open capillary tubes on a Buchi-545 and are uncorrected.
UV spectra were recorded on an Uvikon 931 (Kontron). 1H
NMR and 13C NMR spectra were recorded at ambient tem-
perature on a Bruker 300 Avance and DRX 400. Chemical
shifts (d) are quoted in parts per million (ppm) referenced
to the residual solvent peak (CHCl3 fixed at 7.26 and
77 ppm, DMSO-d5 fixed at 2.49 and 39.5 ppm) relative to
tetramethylsilane (TMS). Deuterium exchange and COSY
experiments were performed in order to confirm proton as-
signments. Coupling constants, J, are reported in hertz. 2D
1H–13C heteronuclear COSY were recorded for the attribu-
tion of 13C signals. FAB mass spectra were recorded in the
positive-ion or negative-ion mode on a JEOL JMS DX
300. The matrix was a mixture (50:50, v/v) of glycerol and
thioglycerol (G/T). Specific rotations were measured on
a Perkin–Elmer Model 341 spectropolarimeter (path length
1 cm), and are given in units of 10ꢁ1 cmꢁ2 gꢁ1. Elemental
analyses were carried out by the Service de Microanalyses
du CNRS, Division de Vernaison (France). Thin layer chro-
matography was performed on precoated aluminum sheets
of Silica 60 F254 (Merck, Art. 5554), visualization of prod-
ucts being accomplished by UV absorbency followed by
charring with 5% ethanolic sulfuric acid and heating. All
moisture-sensitive reactions were carried out under rigorous
anhydrous conditions and under an argon atmosphere using
over-dried glassware. Solvents were dried and distilled prior
to use and solids were dried over P2O5 under reduced
pressure.
NHR1
N
N
N
N
BzO
R1O
O
a
c
O
OAc
CH3
OAc
CH3
OR2
1
13 (R1 = Bz, R2 = Ac)
14 (R1 = R2 = H)
b
OR3
ODPC
N
N
N
N
N
N
Ac
N
NH
R2
N
N
R1O
BzO
O
O
+
O
OAc
CH3
CH3
CH3
OAc
OR2
BzO
15 (R1 = Bz, R2 = Ac)
17 (R1 = R2 = R3 = H)
16
b
Scheme 4. Reagents and conditions: (a) silylated N6-benzoyl adenine,
TMSOTf, CH3CN, 0 ꢀC to rt, 62%; (b) MeOH/NH3, rt, 79% for 14, 70%
for 17; (c) silylated N2-acetyl-O6-(DPC)guanine, TMSOTf, toluene, reflux,
55% for 15, 14% for 16.
3.1.1. 5-O-Benzoyl-1,2-O-isopropylidene-a-D-xylofura-
nose (2). Compound 2 was prepared from commercially
available D-xylose following a protocol established in the lit-
erature.9 1H NMR (CDCl3) d 1.25 (3H, s, C(CH3)2), 1.43
(3H, s, C(CH3)2), 3.15 (1H, sl, OH-3), 4.11 (1H, d, H-3,
J3–4¼2.2), 4.32 (2H, m, H-4, H-5), 4.52 (1H, d, H-2,
J2–1¼3.6), 4.73 (1H, m, H-50), 5.89 (1H, d, H-1, J1–2¼3.6),
7.37–7.98 (5H, m, C6H5CO). Anal. Calcd for C15H18O6:
C, 61.22; H, 6.16. Found: C, 61.30, H 5.87.
A glycosylation reaction with N6-benzoyl adenine and 1
provided compound 13, which upon deprotection and puri-
fication gave the desired nucleoside 14. In order to prepare
the guanosine analog (17), a condensation reaction of N2-
acetyl-O6-(diphenylcarbamoyl)guanine with 1 following
Robins’ procedure15 was achieved to give the N9-isomer
15 with 55% yield. No N7-isomer was detected (1H NMR)
in the purified product as well as in the crude coupling
mixture. However, compound 16, a byproduct resulting
from an attachment of a second sugar residue at N2, was
isolated with 14% yield. Such a kind of bis(sugar) byproduct
has been previously reported.15
3.1.2. 5-O-Benzoyl-3-deoxy-1,2-O-isopropylidene-a-D-
erythro-3-pentulofuranose (3). Dess–Martin periodinane
(60 g, 0.14 mol) was added to a solution of compound 2
(20.8 g, 0.07 mol) in anhydrous dichloromethane (400 mL)
at 0 ꢀC. The mixture was stirred for 4 h at room temperature,
then concentrated, and diluted with diethyl ether (400 mL).
The resulting precipitate was filtered. The clear filtrate was
concentrated to dryness and coevaporated with anhydrous
toluene to afford compound 3 as a white solid (19 g, 95%),
which was crystallized from diethyl ether. Mp 93–95 ꢀC
(lit.9 97–98.5 ꢀC); 1H NMR (CDCl3) d 1.36 (3H, s,
In summary, the syntheses of 30-deoxy-30-C-methyl-b-D-
ribonucleoside analogs bearing the five naturally occurring
nucleic acid bases were undertaken with the hope of discov-
ering new nucleoside analogs endowed with potential bio-
logical properties. The target nucleosides were tested for

S. Couturier et al. / Tetrahedron 63 (2007) 11260–11266
11263
C(CH3)2), 1.44 (3H, s, C(CH3)2), 4.39 (2H, m, H-2, H-5),
4.63 (2H, m, H-4, H-50), 6.07 (1H, d, H-1, J1–2¼4.4),
7.37–7.88 (5H, m, C6H5CO). Anal. Calcd for
C15H16O6$1H2O: C, 58.06; H, 5.85. Found: C, 57.99; H,
5.89.
heated under reflux for 3 h. After cooling to room tempera-
ture, the solvent was removed under reduced pressure. Chro-
matography of the residue on a silica gel column using
a stepwise gradient of ethyl acetate (0–8%) in petroleum
ether afforded a mixture of compounds 5 and 6 (4.6 g,
80%) in 2:98 ratio. Crystallization from petroleum ether
provided pure compound 6. Mp 52–53 ꢀC (lit.17 49 ꢀC);
m/z (FAB>0) 293 (M+H)+; m/z (FAB<0) 291 (MꢁH)ꢁ;
3.1.3. 5-O-Benzoyl-3-deoxy-1,2-O-isopropylidene-3-C-
methylidene-a-D-pentofuranose (4). To a suspension of
methyl magnesium bromide (8.51 g, 23.8 mmol) in anhy-
drous THF (260 mL) was added sodium tert-pentylate
(2.31 g, 21.0 mmol). The reaction mixture was stirred over-
night at room temperature. The resulting orange solution
was cooled down at ꢁ78 ꢀC and a solution of compound 3
(3.46 g, 11.9 mmol) in anhydrous THF (52 mL) was added.
The reaction mixture was stirred at 5–6 ꢀC for 4 h, then di-
luted with ethyl acetate (200 mL), and successively washed
with brine (100 mL), saturated NaHCO3 solution (100 mL),
and water (100 mL). The organic phase was dried over so-
dium sulfate and evaporated to dryness. Chromatography
of the residue on a silica gel column using a stepwise gradi-
ent of ethyl acetate (0–20%) in cyclohexane afforded com-
1H NMR (CDCl3) d 1.08 (3H, d, CH3-3, JCH ꢁ3¼6.9), 1.27
3
(3H, s, C(CH3)2), 1.47 (3H, s, C(CH3)2), 1.94 (1H, m,
H-3), 4.02 (1H, m, H-4), 4.29 (1H, dd, H-5, J5–4¼5.3,
0
0
0
0
J5–5 ¼12.4), 4.50 (1H, dd, H-5 , J5 –4¼2.7, J5 –5¼12.4),
4.51 (1H, m, H-2), 5.78 (1H, d, H-1, J1–2¼3.7), 7.35–7.99
(5H, m, C6H5CO); 13C NMR (CDCl3) d 9.7 (CH3-3), 26.7
(C(CH3)2), 27.1 (C(CH3)2), 40.5 (C-3), 64.7 (C-5), 80.9
(C-4), 82.9 (C-2), 105.4 (C-1), 112.0 (C(CH3)2), 128.7–
133.5 (Car), 166.8 (CO). Anal. Calcd for C16H20O5: C,
65.74; H, 6.90. Found: C, 65.40; H, 7.16.
3.1.5. 5-O-Benzoyl-1,2-O-isopropylidene-3-C-methyl-
a-D-ribofuranose (7). To a suspension of compound 3
(14.4 g, 49.4 mmol) in dry diethyl ether (250 mL) was added
over 1 h a methyl magnesium bromide (3 M) solution in
Et2O (29.6 mL). The reaction mixture was stirred for 1 h
at room temperature then 1 N NH4Cl solution (50 mL) was
added. The two layers were separated and the organic phase
was washed with brine (100 mL) and water (100 mL), dried
over sodium sulfate, and evaporated under reduced pressure.
The residue was purified on silica gel column chromato-
graphy using a stepwise gradient of ethyl acetate (0–10%)
in dichloromethane to afford compound 7 as a white solid
(12.1 g, 80%), which was crystallized from diethyl ether/
petroleum ether (1:1, v/v). Mp 110–111 ꢀC; m/z (FAB>0)
pound
4 (3 g, 87%), which was crystallized from
petroleum ether. Mp 62–64 ꢀC (lit.16 60–61.5 ꢀC); 1H
NMR (CDCl3) d 1.32 (3H, s, C(CH3)2), 1.46 (3H, s,
0
C(CH3)2), 4.33 (1H, dd, H-5, J5–2¼3.3, J5–5 ¼11.8), 4.47
(1H, dd, H-50, J5 –2¼5.5, J5 –5¼11.8), 4.88 (1H, m, H-2),
5.00 (1H, m, H-4), 5.23 (1H, m, ]CH2), 5.44 (1H, m,
]CH2), 5.85 (1H, d, H-1, J1–2¼4.0), 7.35–7.97 (5H, m,
C6H5CO). Anal. Calcd for C16H18O5: C, 66.20; H, 6.25.
Found: C, 66.12; H, 6.24.
0
0
3.1.4. 5-O-Benzoyl-3-deoxy-1,2-O-isopropylidene-3-C-
methyl-a-D-threo-pentofuranose (5) and 5-O-benzoyl-3-
deoxy-1,2-O-isopropylidene-3-C-methyl-a-D-erythro-
pentofuranose (6).
1
309 (M+H)+; H NMR (CDCl3) d 1.19 (3H, s, CH3-3),
1.30 (3H, s, C(CH3)2), 1.53 (3H, s, C(CH3)2), 2.67 (1H, s,
0
3.1.4.1. Hydrogenation. A solution of compound 4
(7.45 g, 25.7 mmol) in methanol (300 mL) was hydroge-
nated in the presence of Pd/C 5% (1 g) at room temperature
and atmospheric pressure. After 15 h of stirring, the suspen-
sion was filtered through a sintered funnel covered with Cel-
ite and the filtrate was evaporated under reduced pressure to
give an inseparable mixture of compounds 5 and 6 (7.35 g,
98%) in a ratio 20:80, as determined by 1H NMR, re-
OH), 4.04 (1H, dd, H-4, J4–5¼3.2, J4–5 ¼8.0), 4.09 (1H, d,
H-2, J2–1¼3.8), 4.31 (1H, dd, H-50, J5 –4¼8.0, J5 –5¼11.9),
0
0
0
4.50 (1H, dd, H-5, J5–4¼3.2, J5–5 ¼11.9), 5.76 (1H, d, H-1,
J1–2¼3.8), 7.34–8.00 (5H, m, C5H6CO); 13C NMR
(CDCl3) d 18.3 (CH3-3), 26.5 (C(CH3)2), 26.6 (C(CH3)2,
63.0 (C-5), 79.6 (C-4), 84.0 (C-2), 103.7 (C-1), 112.7
(C(CH3)2), 128.3–133.0 (Car), 166.4 (CO). Anal. Calcd for
C16H20O6: C, 62.33; H, 6.54. Found: C, 62.22; H, 6.52.
1
spectively. H NMR (CDCl3) d 0.97 (3H, d, CH3-3 threo,
JCH ꢁ3¼7.5), 1.18 (3H, d, CH3-3 erythro, JCH ꢁ3¼6.9),
3.1.6. 1,2-Di-O-acetyl-5-O-benzoyl-3-deoxy-3-C-methyl-
a,b-D-ribofuranose (1). A solution of compound 6 (1 g,
3.42 mmol) in aqueous 80% trifluoroacetic acid (8.9 mL)
was stirred at room temperature for 1 h and 30 min, and
then trifluoroacetic acid was neutralized with addition of
aqueous sodium hydrogen carbonate solution. After extrac-
tions with ethyl acetate, the organic phases were combined,
dried over sodium sulfate, filtered, and evaporated under
reduced pressure. The crude material was then dissolved in
anhydrous pyridine (23.3 mL), and catalytic amount of
DMAP and acetic anhydride (4.2 mL, 47.9 mmol) was
added. The mixture was stirred for 30 min at room tempera-
ture, and then neutralized by aqueous sodium hydrogen
carbonate solution. After extractions with diethyl ether, the
organic phases were combined, dried over sodium sulfate,
filtered, and evaporated to dryness. The residue was sub-
jected to silica gel column chromatography, with a stepwise
gradient of ethyl acetate (0–15%) in petroleum ether to
afford compound 1 as a white solid (970 mg, 85%) and as
3
3
1.34 (3H, s, C(CH3)2 threo), 1.37 (3H, s, C(CH3)2 erythro),
1.56 (6H, s, C(CH3)2), 2.03 (1H, m, H-3 erythro), 2.45 (1H,
m, H-3 threo), 4.11 (2H, m, H-4), 4.35–4.63 (6H, m, H-2,
H-5, H-50), 5.87 (1H, d, H-1 erythro, J1–2¼3.7), 5.91 (1H,
d, H-1 threo, J1–2¼3.6), 7.40–8.05 (10H, m, C6H5CO).
3.1.4.2. Radical deoxygenation. To a solution of com-
pound 7 (6 g, 19.5 mmol) and DMAP (7.2 g, 58.4 mmol) in
anhydrous dichloromethane (64 mL) was added methyl
oxalyl chloride (3.6 mL, 39 mmol) at 0 ꢀC. The reaction
mixture was stirred for 30 min at room temperature, and
then washed with saturated NaHCO3 solution (100 mL)
and water (100 mL). The organic layer was dried over
sodium sulfate, evaporated to dryness, and coevaporated
with anhydrous toluene. The crude material was then dis-
solved in anhydrous toluene (175 mL), and AIBN (2.26 g,
13.6 mmol) and tris(trimethylsilyl)silane hydride (12 mL,
39 mmol) were added to it. The resulting solution was

11264
S. Couturier et al. / Tetrahedron 63 (2007) 11260–11266
an anomeric a,b mixture (ratio a/b: 14:86, determined by 1H
NMR). An analytical sample of 1 was obtained after crystal-
lization from petroleum ether providing the b anomer. Mp
89 ꢀC; m/z (FAB>0) 337 (M+H)+; 1H NMR (CDCl3)
(DMSO-d6) d 10.0 (CH3-30), 35.7 (C-30), 60.5 (C-50), 77.9
(C-20), 86.8 (C-40), 91.9 (C-10), 101.3 (C-5), 141.3 (C-6),
151.3 (C-2), 164.2 (C-4). Anal. Calcd for C10H14N2O5: C,
49.58; H, 5.83; N, 11.56. Found: C, 49.43; H, 5.67; N, 11.48.
d 1.04 (3H, d, CH3-3, JCH ꢁ3¼6.9), 1.89 (3H, s, CH3CO),
3
2.06 (3H, s, CH3CO), 2.50 (1H, m, H-3), 4.14 (1H, m, H-
0
3.1.9. 1-(2-O-Acetyl-5-O-benzoyl-3-deoxy-3-C-methyl-b-
D-ribofuranosyl)thymine (10). A mixture of thymine
(712.5 mg, 5.66 mmol), hexamethyldisilazane (56.6 mL),
and a catalytic amount of ammonium sulfate was refluxed
for 12 h. The resultant clear solution was concentrated to
dryness under reduced pressure. TMSOTf (1.14 mL,
5.66 mmol) was added slowly at 0 ꢀC to a solution of sugar
1 (951 mg, 2.83 mmol) and silylated base in dry acetonitrile
(26.5 mL). The reaction mixture was stirred for 30 min at
room temperature, poured into saturated sodium hydrogen
carbonate solution, and extracted with dichloromethane.
The organic phase was dried over sodium sulfate, filtered,
and evaporated to dryness. Chromatography of the residue
on a silica gel column using as eluent a stepwise gradient
of methanol (0–1%) in dichloromethane afforded compound
10 (726 mg, 64%) as a white foam. Mp 85 ꢀC; [a]D20 ꢁ7.1 (c
0.98, Me2SO); UV lmax (EtOH)/nm 265 (3 10,000); m/z
(FAB>0) 403 (M+H)+, 277 (S)+, 127 (BH2)+, 105
(C6H5CO)+; m/z (FAB<0) 401 (MꢁH)ꢁ, 125 (B)ꢁ, 121
4), 4.29 (1H, dd, H-50, J5 –4¼4.8, J5 –5¼12.1), 4.52 (1H,
0
0
dd, H-5, J5–4¼3.2, J5–5 ¼12.1), 5.14 (1H, d, H-2, J2–3
¼
4.7), 6.05 (1H, s, H-1), 7.36–8.00 (5H, m, C6H5CO); 13C
NMR (CDCl3) d 10.0 (CH3-3), 21.1 (CH3CO), 21.4
(CH3CO), 36.4 (C-3), 64.9 (C-5), 79.0 (C-2), 84.5 (C-4),
99.5 (C-1), 128.8–133.6 (Car), 166.7 (CO), 169.7 (CO),
170.4 (CO). Anal. Calcd for C17H20O7: C, 60.71; H, 5.99.
Found: C, 60.56; H, 6.21.
3.1.7. 1-(2-O-Acetyl-5-O-benzoyl-3-deoxy-3-C-methyl-b-
D-ribofuranosyl)uracil (8). A mixture of uracil (394 mg,
3.52 mmol), hexamethyldisilazane (35 mL), and a catalytic
amount of ammonium sulfate was refluxed for 12 h. The
resultant clear solution was concentrated to dryness under
reduced pressure. TMSOTf (712 mL, 3.52 mmol) was added
slowly at 0 ꢀC to a solution of sugar 1 (592 mg, 1.76 mmol)
and silylated base in dry acetonitrile (17 mL). The reaction
mixture was stirred for 30 min at room temperature, poured
into saturated sodium hydrogen carbonate solution, and ex-
tracted with dichloromethane. The organic phase was dried
over sodium sulfate, filtered, and evaporated to dryness.
Chromatography of the residue on a silica gel column using
as eluent a stepwise gradient of methanol (0–1%) in di-
chloromethane afforded compound 8 (557 mg, 82%) as a
white foam. Mp 79 ꢀC; [a]D20 +15.0 (c 1.07, Me2SO); UV
lmax (EtOH)/nm 259 (3 10,700); m/z (FAB>0) 389
(M+H)+, 277 (S)+, 113 (BH2)+, 105 (C6H5CO)+; m/z
1
(C6H5CO2)ꢁ; H NMR (CDCl3) d 1.02 (3H, d, CH3-30,
0
JCH ꢁ3 ¼6.9), 1.60 (3H, d, CH3-5, JCH ꢁ6¼1.2), 2.09 (3H,
3
3
s, CH3CO), 2.47 (1H, m, H-30), 4.09 (1H, m, H-40), 4.45
(1H, dd, H-500, J5 –4 ¼4.2, J5 –5 ¼12.6), 4.66 (1H, dd, H-5 ,
0
00
0
00
0
0
0
0
0
00
0
0
J5 –4 ¼2.3, J5 –5 ¼12.6), 5.37 0 (1H, dd, H-2 , J2 –1 ¼1.8,
0
0
0
0
J2 –3 ¼6.4), 5.74 (1H, d, H-1 , J1 –2 ¼1.8), 7.13 (1H, d,
H-6, J6ꢁCH ¼1.2), 7.34–7.98 (5H, m, C6H5CO), 8.63 (1H,
3
13
s, NH); C NMR (CDCl3) d 9.6 (CH3-30), 12.3 (CH3-5),
20.6 (CH3CO), 36.6 (C-30), 63.2 (C-50), 78.5 (C-20), 83.4
(C-40), 90.4 (C-10), 111.0 (C-5), 128.4–133.6 (Car), 135.3
(C-6), 149.9 (C-2), 163.4 (C-4), 166.2 (CO), 169.8 (CO).
1
(FAB<0) 387 (MꢁH)ꢁ, 121 (C6H5CO2)ꢁ, 111 (B)ꢁ; H
NMR (CDCl3) d 1.04 (3H, d, CH3-30, JCH ꢁ3 ¼6.8), 2.13
0
3
(3H, s, CH3CO), 2.40 (1H, m, H-30), 4.15 (1H, m, H-40),
4.55 (1H, dd, H-500, J5 –4 ¼3.8, J5 –5 ¼12.7), 4.67 (1H, dd,
3.1.10. 1-(3-Deoxy-3-C-methyl-b-D-ribofuranosyl)thy-
mine (11). A solution of 10 (582 mg, 1.45 mmol) in metha-
nolic ammonia (previously saturated at ꢁ10 ꢀC and tightly
stoppered) (50 mL) was stirred for 12 h at room temperature,
and then evaporated to dryness. The residue was subjected to
silica gel column chromatography with a stepwise gradient
of methanol (0–5%) in dichloromethane to afford the com-
pound 11 as a white solid (308 mg, 83%), which was lyoph-
ilized. Mp 202 ꢀC; [a]D20 +7.5 (c 1.06, Me2SO); UV lmax
(EtOH)/nm 267 (3 8400); m/z (FAB>0) 257 (M+H)+, 131
00
0
00
0
H-50, J5 –4 ¼2.4, J5 –5 ¼12.7), 5.41 (1H, dd, H-20,
0
0
0
00
0
0
0
0
J2 –1 ¼0.9, J2 –3 ¼5.9), 5.47 (1H, dd, H-5, J5-NH¼2.0,
J5–6¼8.2), 5.77 (1H, d, H-10, J1 –2 ¼0.9), 7.42–8.00 (6H,
m, C6H5CO, H-6), 8.94 (1H, s, NH); 13C NMR (CDCl3)
d 8.2 (CH3-30), 19.6 (CH3CO), 35.3 (C-30), 61.7 (C-50),
77.7 (C-20), 82.8 (C-40), 89.6 (C-10), 101.2 (C-5), 127.6–
132.6 (Car), 138.4 (C-6), 148.8 (C-2), 161.9 (C-4), 165.1
(CO), 168.5 (CO).
0
0
3.1.8. 1-(3-Deoxy-3-C-methyl-b-D-ribofuranosyl)-uracil
(9). A solution of 8 (162 mg, 0.42 mmol) in methanolic
ammonia (previously saturated at ꢁ10 ꢀC and tightly stop-
pered) (15 mL) was stirred for 12 h at room temperature,
and then evaporated to dryness. The residue was subjected
to silica gel column chromatography, with a stepwise gradi-
ent of methanol (0–4%) in dichloromethane to afford
compound 9 as a white solid (93 mg, 92%), which was
crystallized from acetonitrile. Mp 208 ꢀC; [a]D20 +21.3 (c
1.08, Me2SO); UV lmax (EtOH)/nm 262 (3 10,200); m/z
(FAB>0) 243 (M+H)+, 131 (S)+, 113 (BH2)+; m/z
(S)+, 127 (BH2)+; m/z (FAB<0) 255 (MꢁH)ꢁ, 125 (B)ꢁ;
1
H NMR (DMSO-d6) d 0.92 (3H, d, CH3-30, JCH ꢁ3 ¼6.8),
0
3
1.74 (3H, d, CH3-5, JCH ꢁ6¼1.01), 2.12 (1H, m, H-30),
3
3.55 (1H, m, H-500), 3.77 (2H, m, H-40, H-50), 3.99 (1H, pt,
H-20), 5.16 (1H, pt, OH-50), 5.53 (1H, d, OH-20, JOH-2 ¼5.0),
0
5.62 (1H, d, H-10, J1 –2 ¼0.8), 8.01 (1H, d, H-6, J6ꢁCH ¼1.0),
0
0
3
13
11.21 (1H, s, NH); C NMR (DMSO-d6) d 9.2 (CH3-30),
12.2 (CH3-5), 34.8 (C-30), 59.7 (C-50), 76.9 (C-20), 85.8
(C-40), 90.6 (C-10), 108.0 (C-5), 136.3 (C-6), 150.3 (C-2),
163.9 (C-4).
1
(FAB<0) 241 (MꢁH)ꢁ, 111 (B)ꢁ; H NMR (DMSO-d6)
3.1.11. 1-(3-Deoxy-3-C-methyl-b-D-ribofuranosyl)cyto-
sine (12). Lawesson’s reagent (75 mg, 0.19 mmol) was
added to a solution of 8 (103 mg, 0.27 mmol) in anhydrous
1,2-dichloroethane (8.5 mL) and the reaction mixture was
refluxed for 1 h. The solvent was then evaporated under
reduced pressure and the residue was purified using silica
0
d 0.91 (3H, d, CH3-30, JCH ꢁ3 ¼6.7), 2.07 (1H, m, H-3 ),
0
3
3.54 (1H, m, H-500), 3.78 (2H, m, H-40, H-50), 4.00 (1H, pt,
H-20), 5.14 (1H, pt, OH-50), 5.54 (1H, d, H-5, J5–6¼8.1),
5.58 (1H, d, OH-20, JOH-2 ¼5.2), 5.60 (1H, s, H-1 ), 8.13
0
0
(1H, d, H-6, J6–5¼8.1), 11.28 (1H, s, NH); 13C NMR

S. Couturier et al. / Tetrahedron 63 (2007) 11260–11266
11265
gel column chromatography with a stepwise gradient of
methanol (0–1%) in dichloromethane to give the corre-
sponding 4-thio intermediate as a yellow foam. A solution
of the 4-thio intermediate in methanolic ammonia (3 mL)
(saturated beforehand at ꢁ10 ꢀC and stoppered tightly)
was heated at 100 ꢀC in a stainless-steel bomb for 12 h,
and then cooled to room temperature. The solution was evap-
orated to dryness under reduced pressure and the residue was
subjected to a silica gel column chromatography using
a stepwise gradient of methanol (0–20%) in dichlorome-
thane to afford the compound 12 as a white solid (59 mg,
92%), which was lyophilized. Mp 162 ꢀC; [a]D20 +38.8 (c
1.03, Me2SO); UV lmax (EtOH)/nm 272 (3 8000); m/z
(FAB>0) 242 (M+H)+, 112 (BH2)+; m/z (FAB<0) 240
Me2SO); UV lmax (EtOH)/nm 260 (3 14,500); m/z
(FAB>0) 266 (M+H)+, 136 (BH2)+; m/z (FAB<0) 264
1
(MꢁH)ꢁ; H NMR (DMSO-d6) d 0.99 (3H, d, CH3-30,
0
00
0
JCH ꢁ3 ¼6.8), 2.41 (1H, m, H-3 ), 3.55 (1H, m, H-5 ), 3.76
3
(1H, m, H-50), 3.85 (1H, m, H-40), 4.32 (1H, pt, H-20,
0
0
0
0
0
00
J2 -OH¼4.7, J2 –3 ¼4.5), 5.14 (1H, t, OH-5 , JOH-5 ¼JOH-5
¼
5.4), 5.70 (1H, d, OH-20, JOH-2 ¼4.9), 5.91 (1H, s, H-1 ), 7.28
(2H, s, NH2), 8.15 (1H, s, H-2), 8.42 (1H, s, H-8); 13C NMR
(DMSO-d6) d 9.7 (CH3-30), 35.6 (C-30), 60.7 (C-50), 76.8 (C-
20), 86.1 (C-40), 90.2 (C-10), 119.0 (C-5), 138.8 (C-8), 148.7
(C-4), 152.4 (C-2), 156.0 (C-6). Anal. Calcd for
C11H15N5O3: C, 49.81; H, 5.70; N, 26.40; O, 18.09. Found:
C, 49.82; H, 5.71; N, 26.26.
0
0
1
(MꢁH)ꢁ; H NMR (DMSO-d6) d 0.90 (3H, d, CH3-30,
3.1.14. 2-N-Acetyl-9-(2-O-acetyl-5-O-benzoyl-3-deoxy-3-
C-methyl-b-D-ribofuranosyl)-6-O-diphenylcarbamoyl-
guanine (15) and 2-N-acetyl-9-N2-(2-O-acetyl-5-O-benzo-
yl-3-deoxy-3-C-methyl-b-D-ribofuranosyl)-6-O-diphe-
nylcarbamoylguanine (16). BSA (1.7 mL, 7.12 mmol) was
added to a suspension of 2-N-acetyl-6-O-diphenylcarb-
amoylguanine (1.38 g, 3.56 mmol) in anhydrous dichloro-
ethane (25 mL), and stirring was continued at 80 ꢀC for
1 h. The clear solution was evaporated and the residue was
dissolved in toluene (25 mL). Then a solution of 1 (1 g,
2.97 mmol) in toluene (25 mL) was added followed by
TMSOTf (918 mL, 4.75 mmol) at 0 ꢀC. The solution was
stirred at 80 ꢀC for 1 h and 30 min, cooled down, and ethyl
acetate was added. The organic phase was washed with sat-
urated sodium hydrogen carbonate solution and water, dried
over sodium sulfate, filtered, and evaporated. The residue
was purified by silica gel column chromatography using
a stepwise gradient of methanol (0–2%) in dichloromethane
to give in order of elution compound 16 (396 mg, 14%) and
compound 15 (1.08 g, 55%) as a white foam, which was re-
crystallized from acetonitrile. Compound 16: mp 101 ꢀC;
[a]2D0 ꢁ17.3 (c 0.98, Me2SO); UV lmax (EtOH)/nm 270 (3
25,400); m/z (FAB>0) 941 (M+H)+, 389 (BH2)+, 277 (S)+,
105 (C6H5CO)+, 43 (CH3CO)+; m/z (FAB<0) 939
0
00
0
JCH ꢁ3 ¼6.7), 1.99 (1H, m, H-3 ), 3.55 (1H, m, H-5 ), 3.77
3
(2H, m, H-40, H-50), 3.88 (1H, pt, H-20), 5.09 (1H, pt, OH-
50), 5.51 (1H, d, OH-20, JOH-2 ¼4.9), 5.60 (1H, s, H-1 ),
0
0
5.65 (1H, d, H-5, J5–6¼7.4), 7.10 (2H, 2ꢂsl, NH2), 8.09
(1H, d, H-6, J6–5¼7.4); 13C NMR (DMSO-d6) d 8.6 (CH3-
30), 34.1 (C-30), 59.3 (C-50), 77.0 (C-20), 85.4 (C-40), 91.2
(C-10), 92.3 (C-5), 140.7 (C-6), 154.6 (C-2), 165.1 (C-4).
3.1.12. N6-Benzoyl-9-(2-O-acetyl-5-O-benzoyl-3-deoxy-
3-C-methyl-b-D-ribofuranosyl)adenine (13). A mixture
of N6-benzoyl adenine (3.55 g, 14.9 mmol), N,O-bis-
trimethylsilylacetamide (7.3 mL, 29.8 mmol), and dry
acetonitrile (104 mL) was refluxed under anhydrous condi-
tions for 1 h. A solution of 1 (1 g, 2.97 mmol) in dry aceto-
nitrile (27 mL) followed by TMSOTf (2.3 mL, 11.9 mmol)
was added. The reaction mixture was refluxed for 6 h, and
then partitioned between aqueous saturated sodium hydro-
gen carbonate solution and dichloromethane (100 mL).
The organic layer was washed with water, dried over sodium
sulfate, filtered, and concentrated in vacuo to give the crude
product. Purification by silica gel column chromatography
with a stepwise gradient of methanol (0–1.5%) in dichloro-
methane afforded the compound 13 (947 mg, 62%) as
a white foam. Mp 93 ꢀC; [a]D20 ꢁ3.9 (c 1.03, Me2SO); UV
lmax (EtOH)/nm 278 (3 20,100); m/z (FAB>0) 516
(M+H)+, 277 (S)+, 240 (BH2)+, 105 (C6H5CO)+; m/z
1
(MꢁH)ꢁ, 387 (B)ꢁ; H NMR (DMSO-d6) d 0.90 (3H, d,
0
CH3-30, JCH ꢁ3 ¼6.8), 1.08 (3H, d, CH3-3 , JCH ꢁ3 ¼6.8),
0
0
3
3
1.99 (3H, s, CH3CO), 2.09 (3H, s, CH3CO), 2.14 (3H, s,
CH3CO), 2.33 (1H, m, H-30), 2.94 (1H, m, H-30), 3.89
(1H, m, H-40), 3.99 (1H, m, H-500), 4.22 (1H, m, H-40),
4.31 (1H, m, H-50), 4.47 (1H, m, H-500), 4.56 (1H, m,
1
(FAB<0) 514 (MꢁH)ꢁ, 238 (B)ꢁ, 121 (C6H5CO2)ꢁ; H
NMR (DMSO-d6) d 1.13 (3H, d, CH3-30, JCH ꢁ3 ¼6.8),
0
3
2.18 (3H, s, CH3CO), 3.21 (1H, m, H-30), 4.23 (1H, m,
H-40), 4.51 (1H, dd, H-500, J5 –4 ¼4.8, J5 –5 ¼12.8), 4.63
H-50), 5.76 (1H, dd, H-20, J2 –1 ¼1.6, J2 –3 ¼6.4), 5.84 (1H,
00
0
00
0
0
0
0
0
(1H, dd, H-50, J5 –4 ¼2.4, J5 –5 ¼12.4), 5.84 (1H, dd, H-2 ,
dd, H-20, J2 –1 ¼0.8, J2 –3 ¼5.7), 6.04 (1H, d, H-1 ,
0
0
0
0
0
00
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
J2 –1 ¼0.8, J2 –3 ¼6.0), 6.25 (1H, d, H-1 , J1 –2 ¼1.2), 7.49–
8.04 (10H, m, 2ꢂC6H5CO), 8.62 (1H, s, H-2), 8.69 (1H, s,
H-8), 11.2 (1H, s, NH); 13C NMR (DMSO-d6) d 9.7
(CH3-30), 21.1 (CH3CO), 36.8 (C-30), 64.1 (C-50), 78.8
(C-20), 83.5 (C-40), 88.9 (C-10), 126.2 (C-5), 129.0–133.9
(Car), 143.9 (C-8), 151.0 (C-4), 152.0 (C-6), 152.3 (C-2),
166.0 (CO), 166.1 (CO), 170.5 (CO). Anal. Calcd for
C27H25N5O6: C, 62.91; H, 4.89; N, 13.59; O, 18.62. Found:
C, 62.47; H, 5.10; N, 13.18.
J1 –2 ¼1.7), 6.18 (1H, d, H-1 , J1 –2 ¼0.8), 7.31–7.76 (20H,
m, 4ꢂC6H5CO), 8.76 (1H, s, H-8); 13C NMR (DMSO-d6)
d 9.5 (CH3-30), 9.9 (CH3-30), 20.6 (CH3CO), 20.8
(CH3CO), 37.0 (C-30), 37.4 (C-30), 63.7 (C-50), 65.1 (C-50),
78.5 (C-20), 79.0 (C-20), 82.1 (C-40), 84.1 (C-40), 89.3
(C-10), 92.7 (C-10), 123.1 (C-5), 126.5–133.4 (Car), 143.5
(C-8), 150.1 (C-4), 153.8 (C-2), 156.0 (C-6), 166.3–171.4
(6ꢂCO). Anal. Calcd for C50H48N6O3: C, 63.82; H, 5.14;
N, 8.93; O, 22.10. Found: C, 63.73; H, 5.32; N, 8.56. Com-
pound 15: mp 211 ꢀC; [a]D20 +25.0 (c 1.01, Me2SO); UV lmax
(EtOH)/nm 273 (3 20,200); m/z (FAB>0) 665 (M+H)+, 470
(Mꢁ(C6H5)2NCO+H)+, 389 (BH2)+, 277 (S)+, 196
((C6H5)2NCO)+, 105 (C6H5CO)+, 43 (CH3CO)+; m/z
(FAB<0) 663 (MꢁH)ꢁ, 468 (Mꢁ(C6H5)2NCOꢁH)ꢁ, 387
3.1.13. 9-(3-Deoxy-3-C-methyl-b-D-ribofuranosyl)-ade-
nine (14). A solution of 13 (931 mg, 1.81 mmol) in metha-
nolic ammonia (previously saturated at ꢁ10 ꢀC and tightly
stoppered) (36 mL) was stirred for 24 h at room temperature,
and then evaporated to dryness. The residue was crystallized
from methanol and water (8:2, v/v) to afford the compound
14 (377 mg, 79%). Mp 243 ꢀC; [a]D20 ꢁ41.6 (c 0.99,
(B)ꢁ; H NMR (DMSO-d6) d 1.10 (3H, d, CH3-30,
1
0
JCH ꢁ3 ¼6.8), 2.13 (3H, s, CH3CO), 2.14 (3H, s, CH3CO),
3
3.66 (1H, m, H-30), 4.18 (1H, m, H-40), 4.48 (1H,

11266
S. Couturier et al. / Tetrahedron 63 (2007) 11260–11266
0
dd, H-500, J5 –4 ¼5.1, J5 –5 ¼12.5), 4.58 (1H, dd, H-5 ,
00
0
00
0
Eldrup, A. B.; Guinosso, C. J.; Prhavc, M.; Praksh, T. P. PCT
WO2002057425, 2002; Chem. Abstr. 2002, 137, 125359; (b)
Gaudriault, G.; Kilinc, A.; Bousquet, O.; Goupil-Lamy, A.;
Itzik, H. PCT WO 2004037159, 2004; Chem. Abstr. 2004,
140, 386000; (c) Hardee, G.; Dellamary, L. PCT
WO2005020885, 2005; Chem. Abstr. 2005, 142, 291323; (d)
Cappellacci, L.; Franchetti, P.; Petrelli, R.; Riccioni, S.; Vita,
P.; Jayaram, H. N.; Grifantini, M. Collect. Czech. Chem.
Commun. 2006, 71, 1088–1098; (e) Eldrup, A. B.; Allerson,
C. R.; Bennett, C. F.; Bera, S.; Bhat, B.; Bhat, N.;
Bosserman, M. R.; Brooks, J.; Burlein, C.; Carroll, S. S.;
Cook, P. D.; Getty, K. L.; MacCoss, M.; McMasters, D. R.;
Olsen, D. B.; Prakash, T. P.; Prhavc, M.; Song, Q. L.;
Tomassini, J. E.; Xia, J. J. Med. Chem. 2004, 47, 2283–2295;
(f) Franchetti, P.; Cappellacci, L.; Pasqualini, M.; Petrelli, R.;
Vita, P.; Jayaram, H. N.; Horvath, Z.; Szekeres, T.; Grifantini,
M. J. Med. Chem. 2005, 48, 4983–4989.
0
0
0
0
00
0
0
J5 –4 ¼2.6, J5 –5 ¼12.5), 5.79 (1H, d, H-2 , J2 –3 ¼6.2),
6.13 (1H, d, H-10, J1 –2 ¼0.8), 7.31–7.53 (15H, m,
3ꢂC6H5CO), 8.52 (1H, s, H-8), 10.78 (1H, s, NH); 13C
NMR (DMSO-d6) d 9.7 (CH3-30), 21.0 (CH3CO), 25.0
(CH3CO), 36.4 (C-30), 64.2 (C-50), 79.1 (C-20), 83.9 (C-40),
89.7 (C-10), 120.9 (C-5), 127.4–133.8 (Car), 142.0 (C-8),
150.5 (C-4), 154.1 (C-2), 155.7 (C-6), 165.9–170.5
(4ꢂCO). Anal. Calcd for C35H32N6O8: C, 63.25; H, 4.85;
N, 12.64; O, 19.26. Found: C, 63.13; H, 4.90; N, 12.59.
0
0
3.1.15. 9-(3-Deoxy-3-C-methyl-b-D-ribofuranosyl)gua-
nine (17). A solution of 15 (450 mg, 0.68 mmol) in metha-
nolic ammonia (30 mL, saturated at ꢁ10 ꢀC) in a sealed
flask was stirred at ambient temperature for 24 h. Volatiles
were evaporated and the residue was crystallized from water
to give compound 17 (133.4 mg, 70%). Mp 265 ꢀC; [a]D20
ꢁ15.2 (c 1.02, Me2SO); UV lmax (EtOH)/nm 255 (3
11,700); m/z (FAB>0) 282 (M+H)+, 152 (BH2)+; m/z
4. (a) Rosenthal, A.; Sprinzl, M. Can. J. Chem. 1969, 47, 3941–
3946; (b) Cass, C. E.; Paterson, R. P. Biochim. Biophys. Acta
1973, 291, 734–746; (c) Bruns, R. F. Can. J. Physiol.
Pharmacol. 1980, 58, 673–691.
5. Rosowsky, A.; Lazarus, H.; Yamashita, A. J. Med. Chem. 1976,
19, 1265–1270.
6. Baker, B. R. The Ciba Fondation Symposium on the Chemistry
and Biology of the Purines; Wolstenholme, G. E. W.,
O’Connor, C. M., Eds.; Churchill: London, 1957; pp 120–133.
7. Nair, V.; Mickle, T.; Bera, S. Nucleosides, Nucleotides Nucleic
Acids 2003, 22, 239–247.
8. (a) Nair, V.; Emmanuel, D. J. J. Am. Chem. Soc. 1977,
99, 1571–1576; (b) Robins, M. J.; Doboszewski, B.;
Timoshchuk, V. A.; Peterson, M. A. J. Org. Chem. 2000, 65,
2939–2945.
(FAB<0) 280 (MꢁH)ꢁ; H NMR (DMSO-d6) d 0.97 (3H,
1
d, CH3-30, JCH ꢁ3 ¼6.7), 2.35 (1H, m, H-3 ), 3.53 (1H, m,
0
0
3
H-500), 3.74 (2H, m, H-40, H-50), 4.19 (1H, t, H-20,
J2 –3 ¼J2 -OH¼5.0), 5.01 (1H, t, OH-50, JOH-5 ¼JOH-5
¼
0
0
0
0
000
5.1), 5.56 (1H, d, OH-20, JOH-2 ¼5.1), 5.71 (1H, s, H-1 ),
6.47 (2H, s, NH2), 7.99 (1H, s, H-8), 10.62 (1H, s, NH);
13C NMR (DMSO-d6) d 9.7 (CH3-30), 35.9 (C-30), 60.8
(C-50), 77.0 (C-20), 85.8 (C-40), 89.3 (C-10), 116.6 (C-5),
135.1 (C-8), 150.5 (C-4), 153.5 (C-2), 156.7 (C-6). Anal.
Calcd for C11H15N5O4$0.5H2O: C, 45.51; H, 5.56; N,
24.13; O, 24.80. Found: C, 45.45; H, 5.74; N, 23.26.
0
9. Tong, G. L.; Lee, W. W.; Goodman, L. J.Org. Chem. 1967, 32,
1984–1986.
Acknowledgements
10. (a) Walton, E.; Jenkis, S.; Nutt, R. F.; Zimmerman, M.; Holly,
F. W. J. Am. Chem. Soc. 1966, 88, 4524–4525; (b) Nutt, R. F.;
Dickinson, M. J.; Holly, F. W.; Walton, E. J. Org. Chem. 1968,
33, 1789–1795.
ꢁ
S.C. and M.A. are particularly grateful to the Ministere de
l’Education Nationale, de la Recherche et de la Technologie,
France, for a doctoral fellowship. We gratefully acknowl-
edge Professor P. La Colla (Universita degli Studi di
ꢁ
11. Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin
Trans. 1 1975, 1574–1585.
12. Dollan, S. C.; McMillan, J. J. Chem. Soc., Chem. Commun.
1985, 1588–1589.
Cagliari, Italy) for the biological results. This work was
supported by Grants from the European Economic Commu-
nity program ‘Flavitherapeutics’ (QLK3-CT-2001-00506).
13. Baumberger, F.; Vasella, A. Helv. Chim. Acta 1983, 66, 2210–
2222.
References and notes
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