1,2-Di-O-acetyl-5-O-benzoyl-3-deoxy-L-erythro-pentofuranose, a convenient precursor for the stereospecific synthesis of nucleoside analogues with the unnatural β-L-configuration

Article abstract of DOI:10.1016/S0008-6215(99)00267-0

The title compound 1,2-di-O-acetyl-5-O-benzoyl-3-deoxy-L-erythro- pentofuranose (5), a useful precursor for the stereospecific synthesis of β- L-nucleoside analogues as potential antiviral agents, has been synthesised by a multi-step reaction sequence from L-xylose with a 38% overall yield. The preparation involved conversion of L-xylose to 1,2-O-isopropylidene-α-L- xylofuranose which, upon selective 5-O-benzoylation and subsequent radical deoxygenation, provided the protected 3-deoxy sugar derivative. Finally, cleavage of the acetonide group gave the resulting 5-O-benzoyl-3-deoxy-L- erythro-pentose which was acetylated to afford crystalline α,β-5. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0008-6215(99)00267-0

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Carbohydrate Research 323 (2000) 226–229
Note
1,2-Di-O-acetyl-5-O-benzoyl-3-deoxy- -erythro-pentofuran
L
ose, a convenient precursor for the stereospecific
synthesis of nucleoside analogues with the unnatural
b-L-configuration
Christophe Mathe´ *, Jean-Louis Imbach, Gilles Gosselin
Laboratoire de Chimie Organique Biomole´culaire de Synthe`se, UMR CNRS-UM II 5625, Uni6ersite´ Montpellier II,
Sciences et Techniques du Languedoc, Case courrier 008, Place Euge`ne Bataillon, F-34095 Montpellier, France
Received 4 July 1999; revised 16 September 1999; accepted 28 September 1999
Abstract
The title compound 1,2-di-O-acetyl-5-O-benzoyl-3-deoxy-
stereospecific synthesis of b- -nucleoside analogues as potential antiviral agents, has been synthesised by a multi-step
reaction sequence from -xylose with a 38% overall yield. The preparation involved conversion of -xylose to
1,2-O-isopropylidene-a- -xylofuranose which, upon selective 5-O-benzoylation and subsequent radical deoxygena-
tion, provided the protected 3-deoxy sugar derivative. Finally, cleavage of the acetonide group gave the resulting
L
-erythro-pentofuranose (5), a useful precursor for the
L
L
L
L
5-O-benzoyl-3-deoxy- -erythro-pentose which was acetylated to afford crystalline a,b-5. © 2000 Elsevier Science Ltd.
L
All rights reserved.
Keywords: L-Xylose; 1,2-Di-O-acetyl-5-O-benzoyl-3-deoxy-L-erythro-pentofuranose; L-Nucleosides; Antiviral agents
5-yl]cytosine (FTC) [3]. In connection with
these efforts, our research group and others
1. Introduction
have reported the synthesis of b- -2%,3%-
L
During recent years, there has been a grow-
ing interest in the synthesis and the biological
dideoxy-5-fluorocytidine, which showed po-
tent anti-HIV [4,5] and anti-HBV activity
[6,7]. In addition to these findings, we have
also described the synthesis and antiviral ac-
evaluation of -nucleoside analogues as poten-
L
tial antiviral drugs [1]. These investigations
have led to the discovery of potent and selec-
tive agents against human immunodeficiency
virus (HIV) and hepatitis B virus (HBV), such
as 1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathi-
olan-5-yl]cytosine (3TC) [2] and 5-fluoro-1-
[(2R,5S) - 2 - (hydroxymethyl) - 1,3 - oxathiolan-
tivity of various b-
didehydro-2%,3%-dideoxy purine nucleosides,
-2%,3%-didehydro-2%,3%-
L
-2%,3%-dideoxy and 2%,3%-
and among them, b-
L
dideoxyadenosine exhibited significant activity
against HIV and HBV in cell culture experi-
ments [8,9]. Various methodologies have been
used for the preparation of these b-
L
-pento-
* Corresponding author. Fax: +33-467-042-029.
E-mail address: cmathe@univ-montp2.fr (C. Mathe´)
furanonucleoside derivatives. For our part, we
0008-6215/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(99)00267-0

C. Mathe´ et al. / Carbohydrate Research 323 (2000) 226–229
227
Scheme 1. (a) Ref. [11]; (b) BzCl, pyridine, 0 °C; (c) TCDI, (CH2Cl)2, reflux; (d) (Me3Si)3SiH, AIBN, toluene, reflux; (e) (i) 85%
AcOH, H2SO4, 50 °C; (ii) Ac2O, pyridine, 50 °C.
chose a stereospecific synthesis by direct con-
densation of a suitably protected -sugar
then reacted with 1,1%-thiocarbonyldiimidazole
(TCDI) in anhydrous 1,2-dichloroethane to
give the corresponding 3-O-(imidazolylthio-
carbonyl) derivative 3, which was subse-
quently deoxygenated with tris(trimethylsilyl)-
silane [13] in refluxing anhydrous toluene in
the presence of a,a%-azobisisobutyronitrile
(AIBN) to afford the 5-O-benzoyl-3-deoxy-
L
derivative and the purine or pyrimidine bases,
followed by appropriate chemical modifica-
tions of the resulting nucleosides. As a starting
sugar, we selected 1,2-di-O-acetyl-5-O-ben-
zoyl - 3 - deoxy - - erythro - pentofuranose (5)
L
(Scheme 1). Although we have already cited
the use of 5 in the literature [4,8,10], its prepa-
ration has never been published. In this work,
we wish to report in detail the synthesis of this
useful synthetic precursor.
1,2-O-isopropylidene-a- -erythro-pentofura-
L
nose (4) in 92% yield after purification on
silica gel column. In our hands, the silicon
hydride [(CH3)3Si]3SiH] reagent proved to be
an attractive alternative to tributyltin hydride
for the radical deoxygenation of secondary
alcohol [14,15]. Finally, acid-catalysed cleav-
age of the remaining acetonide group in
aqueous 85% acetic acid with sulfuric acid
2. Results and discussion
In order to prepare the target 1,2-di-O-
gave 5-O-benzoyl-3-deoxy- -erythro-pentose,
L
acetyl-5-O-benzoyl-3-deoxy-
L
-erythro-pento-
-xylose
which was not isolated, but treated in situ
with acetic anhydride to afford 64% of crys-
talline a,b-5.
furanose (5), commercially available
L
was converted to 1,2-O-isopropylidene-a- -
L
xylofuranose (1), without purification of the
intermediates and following a synthetic path-
way previously reported by Gosselin et al. for
the corresponding compounds in the
D
series
3. Experimental
[11]. Selective protection of the primary 5-hy-
droxy group was achieved by treatment of 1
with benzoyl chloride in anhydrous pyridine
at 0 °C [12], resulting in 2 obtained as a
crystalline solid in 74% yield after silica gel
column chromatography. Compound 2 was
General methods.—Evaporation of solvents
was carried out on a rotary evaporator under
reduced pressure. Melting points were deter-
mined in open capillary tubes on a Gal-
lenkamp MFB-595-010 M apparatus and are

228
C. Mathe´ et al. / Carbohydrate Research 323 (2000) 226–229
1
1
[16]; H NMR (Me2SO-d6): l 8.0–7.5 (m, 5 H,
Ar), 5.87 (d, 1 H, J1,2 3.7 Hz, H-1), 5.49 (d, 1
H, J 3.5 Hz, D2O exchangeable, OH-3), 4.5–
4.3 (m, 4 H, H-2, H-4, H-5a,b), 4.11 (br s, 1
H, H-3), 1.38 and 1.23 (2 s, each 3 H, CMe2);
13C NMR (Me2SO-d6): l 166.5 (CO), 134.3,
130.3, 130.1, 129.6 (ArꢀC), 111.6 (CMe2),
105.4 (C-1), 85.8 (C-2), 79.0 (C-4), 74.6 (C-3),
64.0 (C-5), 27.5 (Me), 26.9, (Me). FAB-mass
spectrum (NBA): positive mode m/z 295
[M+H]+. Anal. Calcd for C15H18O6: C,
61.21; H, 6.16. Found: C, 60.86; H, 6.27.
5 -O-Benzoyl-3-O-(imidazolylthiocarbonyl)-
uncorrected. H NMR spectra were recorded
at 400 MHz and 13C NMR spectra at 100
MHz in Me2SO-d6 at ambient temperature
with a Bru¨ker DRX 400. Chemical shifts are
given in l values, Me2SO-d5 being set at lH
2.49 and lC 39.5 as a reference. Deuterium
exchange and COSY experiments were per-
formed in order to confirm proton assign-
ments. Coupling constants, J, are reported in
Hertz. 2D H–13C heteronuclear COSY were
1
recorded for the attribution of 13C signals.
FAB mass spectra were recorded in the posi-
tive-ion mode on a Jeol SX 102. The matrix
was 3-nitrobenzyl alcohol (NBA). Specific ro-
tations were measured on a Perkin–Elmer
model 241 spectropolarimeter (path length 1
1,2-O-isopropylidene-h- -xylofuranose (3).—
L
A soln of 2 (24.5 g, 83.5 mmol) and 1,1%-thio-
carbonyldiimidazole (19.3 g, 108 mmol) in
anhyd 1,2-dichloroethane (400 mL) was
stirred and refluxed for 2 h under argon. After
cooling to rt, the solvent was removed under
reduced pressure. The residue was chro-
matographed on a column of silica gel with a
stepwise gradient of EtOAc (0–14%) in
CH2Cl2 to give 3 (32 g, 95%), which was
crystallised from cyclohexane–EtOAc: mp
cm), and are given in units of 10−1 cm2 g−1
.
Elemental analyses were carried out by the
Service de Microanalyses du CNRS, Division
de Vernaison (France). Thin-layer chromatog-
raphy was performed on precoated aluminium
sheets of Silica Gel 60 F254 (E. Merck, Art.
5554), visualisation of products being accom-
plished by UV absorbance followed by char-
ring with 10% ethanolic H2SO4 and heating.
Column chromatography was carried out on
Silica Gel 60 (E. Merck, Art. 9385).
106–108 °C; [h]2D0+17.5° (c 1.2 Me2SO); H
1
NMR (CDCl3): l 8.3 (m, 1 H, imidazole),
8.0–7.4 (m, 6 H, Ar and imidazole), 7.0 (m, 1
H, imidazole), 6.05 (d, 1 H, J1,2 3.8 Hz, H-1),
6.00 (d, 1 H, J3.4 2.9 Hz, H-3), 4.8–4.7 (m, 2
H, H-2, H-4), 4.60 (d, 2 H, J5,4 6.1 Hz, H-
5a,b), 1.58 and 1.35 (s, 3 H, CMe2). FAB-
mass spectrum (NBA): positive mode m/z 405
[M+H]+. Anal. Calcd for C19H20N2O6S: C,
56.42; H, 4.98; N, 6.93; S, 7.93. Found: C,
56.48; H, 5.00; N, 6.89; S, 7.91.
1,2-O-Isopropylidene-h-
—Compound 1 was prepared from
L
-xylofuranose (1).
-xylose in
L
91% yield by the method reported in the liter-
ature [11].
5-O-Benzoyl-1,2-O-isopropylidene-h- -xylo-
L
furanose (2).—To a cooled (ice-bath) soln of 1
(57.5 g, 302 mmol) in anhyd pyridine (287
mL) was added benzoyl chloride (36.9 mL,
318 mmol) dropwise over a 30 min period
with stirring. The mixture was stirred for a
further 30 min at room temperature (rt) with
the exclusion of moisture. Water (2 mL) was
added and stirring was continued for 15 min.
The mixture was then concd to a low volume,
diluted with CH2Cl2 (400 mL), washed with
satd aq NaHCO3 (200 mL) and water (300
mL), dried (Na2SO4) and concd to dryness.
The resulting residue was chromatographed
on a column of silica gel with a stepwise
gradient of MeOH (0–8%) in CH2Cl2 to af-
ford 2, which was crystallised from hexane (66
g, 74%): mp 78–80 °C, lit. 82–83 °C [16];
[h]2D0+16° (c 1.0, Me2SO), [h]2D0 −10.8° (c
0.37, CHCl3), lit. −12.14° (c 0.37, CHCl3)
5-O-Benzoyl-3-deoxy-1,2-O-isopropylidene-
h- -erythro-pentofuranose (4).—To a soln of
L
3 (5.0 g, 12.4 mmol) in anhyd toluene were
added successively tris(trimethylsilyl)silane
(4.9 mL, 15.8 mmol) and a,a%-azobisisobuty-
ronitrile (0.65 g, 4.0 mmol). The resulting soln
was heated and stirred at 110 °C for 1 h under
argon. After cooling to rt, the solvent was
evaporated to dryness. Column chromatogra-
phy of the residue on silica gel with a stepwise
gradient of EtOAc (0–6%) in CH2Cl2 afforded
4 as an oil (3.17 g, 92%). Distillation under
diminished pressure gave analytically pure 4:
bp 128–130 °C (0.06 mmHg); [h]2D0+10° (c
1
1.2, Me2SO); H NMR (Me2SO-d6): l 8.0–7.5
(m, 5 H, Ar), 5.77 (d, 1 H, J1,2 3.7 Hz, H-1),

C. Mathe´ et al. / Carbohydrate Research 323 (2000) 226–229
229
4.76 (t, 1 H, J 4.2 Hz, H-2), 4.45 (dd, J5a,4 2.9,
References
J5a,5b 11.8 Hz, H-5a), 4.37 (m, 1 H, H-4), 4.25
(dd, 1 H, J5b,4 5.7 Hz, H-5b) 2.02 (dd, 1 H,
J3a,2 4.4, J3a,3b 13.3 Hz, H-3a), 1.7 (m, 1 H,
H-3b), 1.40 and 1.23 (2 s, each 3 H, CMe2);
13C NMR (Me2SO-d6): l 166.4 (CO), 134.3,
130.3, 130.1, 129.7 (ArꢀC), 111.2 (CMe2),
106.0 (C-1), 80.6 (C-2), 76.2 (C-4), 66.0 (C-5),
35.3 (C-3), 27.4 (Me), 26.9 (Me). Anal. Calcd
for C15H18O5: C, 64.73; H, 6.52. Found: C,
64.57; H, 6.62.
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1,2-Di-O-acetyl-5-O-benzoyl-3-deoxy- -
L
erythro-pentofuranose (5).—A stirred soln of 4
(1.0 g, 3.60 mmol) and H2SO4 (0.04 mL, 0.75
mmol) in aq 85% AcOH (3.7 mL) was heated
for 3 h at 50 °C. The mixture was concd under
diminished pressure to half vol, then diluted
with pyridine (3.7 mL). Acetic anhydride (4.6
mL, 48.7 mmol) was added dropwise with
stirring at 50 °C, and stirring was continued
for 30 min. After cooling to rt, the mixture
was concd under diminished pressure, diluted
with CH2Cl2 (100 mL), washed with aq 5%
NaHCO3 (2×50 mL), water (2×50 mL),
dried (Na2SO4) and concd to dryness. Toluene
was evaporated three times from the residue
followed by CHCl3 to give crude 5. Chro-
matography on a column of silica gel with a
stepwise gradient of EtOAc (0–6%) in CH2Cl2
gave pure 5 (0.75 g, 64%), which was crys-
tallised as an anomeric a,b mixture from
petroleum ether (boiling range 40–60 °C)
1
ꢀCH2Cl2: mp 54–56 °C; H NMR (Me2SO-
d6): l 8.0–7.5 (m, 10 H, Ar), 6.28 (d, 0.17 H,
J1,2 4.3 Hz, H-1a), 5.99 (s, 0.83 H, H-1b), 5.22
(m, 0.17 H, H-2a), 5.12 (m, 0.83 H, H-2b),
4.62 (m, 1 H, H-4), 4.5–4.2 (m, 2 H, H-5a,b),
2.3–2.1 (m, 2 H, H-3a,b), 2.05, 2.03, 2.02 (3s,
3 H, Ac), 1.84 (s, 3 H, Ac). FAB-mass spec-
trum (NBA): positive mode m/z 263 [M−
AcOH]+. Anal. Calcd for C16H18O7: C, 59.62;
H, 5.63. Found: C, 59.37; H, 5.74.
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Acknowledgements
The investigations were supported by
Grants from ANRS, ‘‘Agence Nationale de
Recherche sur le SIDA’’, France.
.