A facile synthesis of 1-(5'-O-acetyl-3'-O-benzyl-β-D-xylofuranosyl)thymidine: A potentially viable intermediate for the preparation of the anti-AIDS drugs, AZT and D4T

Article abstract of DOI:10.1016/S0008-6215(00)00048-3

The title compound has been synthesized by smooth condensation of 1,2-anhydro-5-O-acetyl-3-O-benzyl-α-D-xylofuranose, obtained from D-xylose through a series of mild and effective reactions, with activated thymine in the absence of catalyst. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0008-6215(00)00048-3

www.elsevier.nl/locate/carres
Carbohydrate Research 326 (2000) 235–239
Note
A facile synthesis of
1-(5%-O-acetyl-3%-O-benzyl-b-
D
-xylofuranosyl)thymidine: a
potentially viable intermediate for the preparation of the
anti-AIDS drugs, AZT and D4T
Jun Ning, Fanzuo Kong *
Research Center for Eco-En6ironmental Sciences, Academia Sinica, PO Box 2871, Beijing 100085, PR China
Received 28 October 1999; accepted 13 January 2000
Abstract
The title compound has been synthesized by smooth condensation of 1,2-anhydro-5-O-acetyl-3-O-benzyl-a-
D-xylo-
furanose, obtained from -xylose through a series of mild and effective reactions, with activated thymine in the
D
absence of catalyst. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: Nucleoside; 1,2-Anhydro sugar; Xylose
D4T using
D
-xylose [5] or
D-glucofuranose [6]
1. Introduction
as the starting material by taking advantage of
the 2%,a-hydroxy group (in the carboxylic ester
form) to direct the required b-coupling. This
method seems most hopeful because of the use
of inexpensive and readily available materials
and the highly anomeric selectivity in the
thymine-base coupling, but the lengthy selec-
tive 5-protection and 2-deprotection of the
sugar moieties and tedious separation and
purification of the regioisomers and the gly-
cose-base coupling product remain problems.
Here we would like to report a facile proce-
dure for preparation of 1-(5%-O-acetyl-3%-
3%-Azido-3%-deoxythymidine (AZT) and
2%,3%-didehydro-3%-deoxythymidine (D4T) are
known to be useful for the treatment of viral
infections, most notably for the treatment of
AIDS [1]. AZT and D4T are prepared from
the 2%-deoxyribonucleoside, thymidine [2,3].
Recently effective syntheses of AZT and D4T
with the ribonucleoside, 5-methyluridine, as
the starting material, have been reported [4].
However, thymidine and 5-methyluridine are
relatively expensive materials, and their com-
mercial availability is relatively limited. Thus,
extensive research has been focused on devel-
oping more efficient procedures for AZT and
O-benzyl-b- -xylofuranosyl)thymidine: a po-
D
tentially viable intermediate for the synthesis
of anti-AIDS drugs, AZT and D4T.
Intermediate 4 was prepared in four steps in
* Corresponding author. Tel.: +86-10-62936613; fax: +
86-10-62923563.
75% overall yield starting from
D-xylose [7,8].
E-mail address: fzkong@mail.rcees.ac.cn (F. Kong)
Treatment of 4 in methanol containing NaOH
0008-6215/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S 0 0 0 8 - 6 2 1 5 ( 0 0 ) 0 0 0 4 8 - 3

236
J. Ning, F. Kong / Carbohydrate Research 326 (2000) 235–239
the synthesis of anti-AIDS drugs, AZT and
D4T.
smoothly gave methyl 3,5-di-O-benzyl-a- -
D
lyxofuranoside (5) in nearly quantitative yield.
This is a highly effective two-step, one-pot
reaction via an intermediate of 1,2-anhydro-
2. Experimental
3,5-di-O-benzyl-b- -lyxofuranose. Tosylation
D
of 5 quantitatively afforded the corresponding
xylofuranoside 2-sulfonate 6. Selective acetol-
ysis of 6 using AcOH–Ac2O–H2SO4 gave the
corresponding 1,5-diacetate 7. It was found
that selective removal of the 1-O-acetyl group
of 7 by known methods such as using SnCl4
[9] or N2H4·AcOH [10] suffered from low
yields and tedious separation. However the
1-O-acetyl group was very successfully re-
moved under the conditions designated for
selective removal of the 2-O-trichloroacetyl
General methods.—Optical rotations were
determined at 25 °C with a Perkin–Elmer
model 241-Mc automatic polarimeter. Melting
points were determined with a ‘Mel-Temp’
1
apparatus. H NMR spectra were recorded
with Bruker ARX 400 spectrometers for solu-
tions in CDCl3. Chemical shifts are given in
parts per million (ppm) downfield from inter-
nal SiMe4. Mass spectra were recorded with a
JMS-D300S mass spectrometer using a direct
sample introduction technique. Thin-layer
chromatography (TLC) was performed on Sil-
ica Gel HF254 with detection by charring with
30% (v/v) H2SO4 in MeOH or in some cases
by UV detection. Column chromatography
was conducted by elution of a column (16×
240, 18×300, 35×400 mm) of silica gel
(100–200 mesh) with EtOAc–petroleum ether
(60–90 °C) as the eluent. Solutions were con-
centrated at B60 °C under diminished
pressure.
group
trichloroacetyl-b-
[11]
of
3,4,6-tri-O-acetyl-2-O-
D-glucopyranosyl chloride.
Thus the key intermediate 8 was quantita-
tively obtained from treatment of 7 in anhy-
drous ether saturated with dry ammonia.
Since most of the above-applied reactions
gave very high yields, the intermediates 2, 3, 5,
6, and 7 involved in the procedure could be
subjected directly to the next reaction without
chromatographic separation. We were also
gratified to note that ring closure of 8 with
KOtBu in THF gave the 5-O-acetyl-1,2-anhy-
Methyl 3,5-di-O-benzyl-h-
D
-lyxofuranoside
-xylofura-
(5).—3,5-Di-O-benzyl-2-O-tosyl-
D
nose (4) [8] (3.5 g, 7.23 mmol) was dissolved in
anhyd MeOH (50 mL) containing NaOH
(0.35 g, 8.75 mmol), and the mixture was
stirred at room temperature (rt) for 30 min.
TLC (2:1 petroleum ether–EtOAc) indicated
that the reaction was complete. The solution
was concentrated to dryness, the residue was
repeatedly extracted with 3:1 petroleum
ether–EtOAc, and the combined extracts were
concentrated to afford 5 quantitatively as a
syrup. The 1H NMR data of compound 5 thus
obtained were identical to those of the same
compound prepared from methanolysis of 1,2-
dro-3-O-benzyl-a- -xylofuranose (9) in al-
D
most quantitative yield. The anhydro sugar 9
1
was identified from its H NMR spectrum
showing upfield peaks from H-2 at 3.50 ppm,
a salient feature of the epoxide ring. Reaction
of 9 with trimethylsilylated thymine in the
absence of Lewis acid provided a mixture of
10 (60%) and 11 (26%) in a total yield of 86%.
Compound 10 is unstable and easily converted
to 11 under weakly acidic conditions.
In summary, we have successfully developed
facile procedure for preparation of
a
1-(5%-O-acetyl-3%-O-benzyl-b- -xylofuranosyl)-
D
anhydro-3,5-di-O-benzyl-b-
D
-lyxofuranose [8].
-lyxo-
thymidine. Most of the reactions involved in
the procedure were carried out readily in high
yields under mild conditions (see Scheme 1),
and coupling of the base with the xylofura-
nosyl donor was neat, giving the target nu-
cleoside in high yield. Compound 11, as well
as its precursors such as 9, may be useful for
other applications in organic synthesis, e.g., it
may be a potentially viable intermediate for
Methyl 3,5-di-O-benzyl-2-O-tosyl-h-
D
furanoside (6).—To a soln of 5 (5.2 g, 15.1
mmol) in pyridine (50 mL) was added TsCl
(4.3 g, 22.8 mmol). The mixture was stirred at
50 °C for about 24 h. Then the reaction mix-
ture was poured into ice-cold water and ex-
tracted with CH2Cl2 (3×25 mL). The organic
layer was washed with 1 N HCl (3×50 mL)
dried over Na2SO4, concentrated to a syrup,

J. Ning, F. Kong / Carbohydrate Research 326 (2000) 235–239
237
which was subjected to column chromatogra-
1,5-Di-O-acetyl-3-O-benzyl-2-O-tosyl-h- -
D
phy with 3:1 petroleum ether–EtOAc as the
lyxofuranose (7).—A soln of compound 6 (3.4
g, 6.83 mmol) in AcOH (34 mL) and Ac2O (5
mL) was cooled to 10 °C in an ice bath, and
H2SO4 (3 mL) was added dropwise over 20
min. After the addition was complete, the
ice-bath was removed, and the reaction was
continued for 16 h at ambient temperature.
The reaction soln was poured into a soln of
ice-water (120 mL). Stirring was continued for
an additional 30 min, and the aq soln was
extracted with CHCl3 (3×25 mL). The com-
eluent. Compound 6 was obtained as a syrup
1
(7.2 g, 96%,); [h]D +46° (c 5.5, CHCl3); H
NMR: l 7.79 (d, 2 H, Ph-H of Ts), 7.39–7.19
(m, 12 H, 2 Ph-H), 4.90 (d, 1 H, J1,2 3.0 Hz,
H-1), 4.78 (dd, 1 H, J1,2 3.0, J2,3 6.3 Hz, H-2),
4.58, 4.46 (2 d, 2 H, J 11.8 Hz, PhCH2), 4.51,
4.34 (2 d, 2 H, J 12.1 Hz, PhCH2), 4.37–4.26
(m, 2 H, H-3, 4), 3.74–3.58 (m, 2 H, H-5, 5%),
3.23 (s, 3 H, OCH3), 2.40 (s, 3 H, PhCH3).
Anal. Calcd for C27H30O7S: C, 65.04; H, 6.07.
Found: C, 65.14; H, 6.05.
Scheme 1. Reagents and reaction conditions: (a) BnBr (2.2 equivalents)/THF/NaH (3.3 equivalents), reflux, 4 h, 94%. (b) 30%
AcOH, reflux, 3 h, 95%. (c) TsCl (1.5 equivalents)/K2CO3 (1.5 equivalents)/pyridine, rt, 75%. (d) CH3OH/NaOH (1.2 equivalents),
rt, 1 h, 98%. (e) TsCl (1.5 equivalents), pyridine, 50 °C, 10 h, 96%. (f) 7:1:0.6 (v/v) AcOH–Ac2O–H2SO4, rt, 24 h, 97%. (g)
anhydrous ether saturated with dry ammonia, rt, 24 h, 96%. (h) potassium tert-butoxide (1.1 equivalents), THF, rt, 20 min, 97%.
(i) silylated thymine (1.3 equivalents), CH2Cl2, rt, 12 h, 86%. (j) CH3CN containing 4% HCOOH, rt, 15 min, 100%.

238
J. Ning, F. Kong / Carbohydrate Research 326 (2000) 235–239
ether–EtOAc. Concentration of the combined
bined CHCl3 extracts were carefully washed
with 10% aq NaHCO3 (3×70 mL), and the
solvent was removed in vacuo to a constant
weight affording 3.17 g (97%) of compound 7
extracts yielded 9 as a syrup (314 mg, 96%);
1
[h]D −20.3° (c 2.9, CHCl3); H NMR: l
7.44–7.24 (m, 5 H, Ph-H), 5.28 (d, 1 H, J1,2
1.4 Hz, H-1), 4.63, 4.58 (2 d, 2 H, J 11.8 Hz,
PhCH2), 4.39–4.10 (m, 4 H, H-3,4,5a,5b), 3.60
(t, 1 H, J1,2 =J2,3=1.4 Hz, H-2), 2.02 (s, 3 H,
COCH3); m/z: [M]+ 264, [M−Bn]+ 173.
1
as a syrup; [h]D +18° (c 6.3, CHCl3); H
NMR: (Mainly a anomer), l 7.80 (d, 2 H,
Ph-H of Ts), 7.41–7.22 (m, 7 H, Ph-H), 6.15
(d, 1 H, J1,2 3.4 Hz, H-1), 5.0 (dd, 1 H, J1,2 3.4,
J2,3 8.8 Hz, H-2), 4.68, 4.47 (2 d, 2 H, J 12.1
Hz, PhCH2), 4.50–4.30 (m, 2 H, H-3, 4),
4.18–4.04 (m, 2 H, H-5, 5%), 2.41 (s, 3 H,
PhCH3), 2.02, 1.98 (2 s, 6 H, 2 COCH3). Anal.
Calcd for C23H26O9S: C, 57.73; H, 5.48.
Found: C, 57.83; H, 5.48.
1-(5%-O-Acetyl-3%-O-benzyl-i- -xylofuran-
D
osyl)thymidine (11).—To a stirred soln of
O,O-bis-(trimethylsilyl)thymidine (235 mg,
0.87 mmol) in dry CH2Cl2 (4 mL) with molec-
,
ular sieves (4 A, 0.5 g) was added compound
9 (204.8 mg, 0.80 mmol) in dry CH2Cl2 (4
mL). The mixture was stirred for 10 h at rt, at
the end of which time TLC (1:1 petroleum
ether–EtOAc) indicated that the starting ma-
terial 9 had disappeared. The mixture was
diluted with CH2Cl2 (30 mL) and filtered, and
the filtrate was concentrated to a syrup, which
was subjected to column chromatography
with 1:2 petroleum ether–EtOAc as the elu-
ent. Compound 10 (225.4 mg, 61%) and 11 (78
5-O-Acetyl-3-O-benzyl-2-O-tosyl- -lyxo-
D
furanose (8).—A soln of compound 7 (3.5 g,
7.32 mmol) in anhyd ether (100 mL) satd with
dry NH3 was stirred for 24 h, at the end of
which time TLC (2:1 petroleum ether–EtOAc)
indicated that the reaction was complete. The
soln was concentrated to afford 3.06 g (96%)
of compound 8 as an approx equal mixture of
a and b anomers. An analytical sample was
obtained as an anomeric mixture by column
chromatographic purification using 3:1
petroleum ether–EtOAc as the eluent; [h]D
1
mg, 25%) were obtained. H NMR For 10: l
9.16 (s, 1 H, N-H), 7.61 (s, 1 H, H-6), 7.41–
7.20 (m, 5 H, PhH), 5.74 (s, 1 H, H-1%),
4.71–4.05 (7 H, H-2%,3%,4%,5%a,5%b, PhCH2),
2.03 (s, 3 H, COCH3), 1.53 (s, 3 H, CH3), 0.09
(s, 9 H, Si(CH3)3). Compound 10 was quanti-
tatively converted to 11 in a solution of
CH3CN (10 mL) containing HCOOH (0.4
mL) within 5 min. Compound 11 crystallized
from its dilute soln of 1:2 petroleum ether–
EtOAc; mp 81–83 °C; [h]D −33.1° (c 2.9,
1
+19° (c 4.3, CHCl3); H NMR: l 7.85 (d,
2×0.5 H, PhH of Ts of b anomer), 7.80 (d,
2×0.5 H, Ph-H of Ts of a anomer), 7.41–
7.18 (m, 7 H, PhH), 5.45 (d, 0.5 H, J1,2 3.0 Hz,
H-1 of a anomer), 4.98 (d, 0.5 H, J1,2 6.8 Hz,
H-1 of b anomer), 4.84 (dd, 0.5 H, H-2 of a
anomer), 4.71 (t, J1,2 =J2,3=6.8 Hz, H-2 of b
anomer), 4.66–4.24 (m, 4 H, PhCH2, H-3, 4),
4.19–4.04 (m, 2 H, H-5, 5%), 2.44 (s, 3×0.5 H,
PhCH3 of a anomer), 2.41 (s, 3×0.5 H,
PhCH3 of b anomer), 2.02 (s, 3×0.5 H,
COCH3 of a anomer), 2.00 (s, 3×0.5 H,
COCH3 of b anomer). Anal. Calcd for
C21H24O8S: C, 57.78; H, 5.54. Found: C,
57.88; H, 5.46.
1
CHCl3);. H NMR: l 9.44 (s, 1 H, N-H), 7.54
(s, 1 H, H-6), 7.40–7.21 (m, 5 H, PhH), 5.82
(s,
1
H, H-1%), 4.70–4.00 (7 H, H-
2%,3%,4%,5%a,5%b, PhCH2), 3.10 (bs, 1 H, OH),
2.04 (s, 3 H, COCH3), 1.52 (s, 3 H, CH3).
Anal. Calcd for C19H22N2O7: C, 58.45; H,
5.68. Found: C, 58.38; H, 5.71.
1,2-Anhydro-5-O-acetyl-3-O-benzyl-h- -
D
xylofuranose (9).—To a soln of 8 (560 mg,
1.28 mmol) in dry oxolane (6 mL) was added
potassium tert-butoxide (158 mg, 1.41 mmol),
and the mixture was stirred at rt for 10 min, at
the end of which time TLC (2:1 petroleum
ether–EtOAc) indicated that the starting ma-
terial had disappeared. The mixture was con-
centrated to dryness, and the residue was
repeatedly extracted with 3:1 petroleum
Acknowledgements
This work was supported by the Chinese
Academy of Sciences (KJ952J1510 and KIP-
RCEES9904) and the National Natural Sci-
ence Foundation of China (59973026 and
39970864).

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