A facile access to 2-deoxy-L-ribose

Article abstract of DOI:10.1016/S0957-4166(01)00386-X

The title compound was prepared in five steps starting from R-(+)-5-benzyloxymethyl-5H-furan-2-one 1 via syn-dihydroxylation of its double bond, regioselective tosylation of the 2-OH group in the thus obtained diol 2 followed by selective deoxygenation of that position.

Full text of DOI:10.1016/S0957-4166(01)00386-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2143–2145
A facile access to 2-deoxy- -ribose
L
Fabio Fazio and Manfred P. Schneider*
FB 9-Bergische Universita¨t-GH-Wuppertal, D-42097 Wuppertal, Germany
Received 16 July 2001; accepted 31 August 2001
Abstract—The title compound was prepared in five steps starting from R-(+)-5-benzyloxymethyl-5H-furan-2-one 1 via syn-dihy-
droxylation of its double bond, regioselective tosylation of the 2-OH group in the thus obtained diol 2 followed by selective
deoxygenation of that position. © 2001 Elsevier Science Ltd. All rights reserved.
furan-2-one 1, which in turn was obtained (a) in six steps
1. Introduction
from L
-ascorbic acid5,6 or (b) in three steps from (R)-ben-
zyl glycidol.7 The key step was the diastereoselective
introduction of a ‘masked% hydroxyl group (PhMe2Si-)
using Fleming chemistry,8 followed by conversion of the
resulting intermediate into 4 with retention of configura-
tion.
Selectively protected derivatives of
constitute central building blocks for
L
-configured riboses
-enantiomers of
L
natural and chemically modified nucleosides, several of
which are highly valuable anti-viral agents1 and are useful
in cancer2 and malaria3 therapy. Thus,
L
-thymidine (
-3-TC, ‘Lamivudine’), -5-fluoro-3%-
-2%,3%-dideoxy-cytidine ( -ddC),
-5-FddC) have shown
L-T),
L
-3%-thiacytidine (
L
L
Although this route leads to the title compound with high
enantiomeric excess, the method has a number of draw-
backs: the silyl reagent (PhMe2Si)2Cu(CN)Li2 has to be
prepared directly prior to use, it is also employed in a two-
fold excess and thus, the route is not very economical.
thiacytidine (
L
L
-FTC),
L
L
-5-fluoro-2%,3%-dideoxy-cytidine (
L
excellent antiviral activities with greatly reduced toxicities
in mammalian systems as compared to the correspond-
ing
applications and in contrast to the corresponding
oligodeoxynucleotides ( -DNA) such enantiomeric
D-nucleosides. As a great advantage for therapeutic
D
-
-
D
L
2. Results and discussion
DNA oligomers display considerably enhanced resistance
towards the action of nucleases.4
On this basis we explored the possibility of introducing
diastereoselectively two hydroxy groups at the double
bond of 1, followed by regioselective deoxygenation of
the 2-OH group (Scheme 1).
Recently we reported a novel synthesis of the title
compound5 starting from R-(+)-5-benzyloxymethyl-5H-
Scheme 1. Reagents and conditions: (a) KMnO4, dicyclohexano-18-crown-6, dichloromethane, −42°C, 2 h; (b) p-TsCl, Et3N,
dichloromethane, −20°C, 18 h; (c) aq. NH2NH2, Br2, THF, 0°C–rt, 30 min; (d) disiamylborane, THF, rt, 24 h; (e) HCOOH, Pd/C
10%, MeOH, rt, 1 h.
* Corresponding author. E-mail: schneid@uni-wuppertal.de
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00386-X

2144
F. Fazio, M. P. Schneider / Tetrahedron: Asymmetry 12 (2001) 2143–2145
Syn-dihydroxylation9 of 1 was carried out in dichloro-
methane at −42°C using KMnO4 as oxidant in the
presence of dicyclohexano-18-crown-6 as phase transfer
phases were dried over anhydrous Na2SO4 and the
solvent evaporated under reduced pressure. The crude
product was purified by column chromatography over
silica gel using as eluent AcOEt/n-hexane (2/1). The
diol 2 was obtained in 60% yield (291 mg) based on 1
and taking into account the recovered 1 (85 mg).
Recrystallization from AcOEt/n-hexane gave 2 in form
of white needles; mp 106–107°C; Rf: 0.25 AcOEt/n-hex-
catalyst.
(3S,4S,5S)-(−)-5-Benzyloxymethyl-3,4-dihy-
droxy-dihydro-furan-2-one 2 was obtained in 60% yield
as single diastereoisomer (13C NMR). Regioselective
protection10 of the 2-OH group in 2 was achieved
successfully by tosylation (p-TsCl, Et3N, CH2Cl2) lead-
ing to 3 in 82% yield. Deoxygenation of the tosylate
1
ane (2/1). [h]2D0=−23 (c 0.9, acetone). H NMR (ace-
11
function in 3 using an 80% aqueous solution of N2H4
tone-d6): l 7.36–7.23 (m, 5H, Ph), 4.62 (br, 2OH), 4.59
and Br2 in THF at 0°C afforded 4 in 75% yield. As
reported earlier, 4 can be converted into the title com-
pound by: (a) selective reduction of the carbonyl func-
tion using disiamylborane leading to 5 and (b) removal
of the benzyl protecting group (HCO2H, 10% Pd/C).5
(d, J=5.59 Hz, 1H, CO-CH
(t, J=3.05 Hz, 1H, BnOCH2-CH
1H, COCHOH-CH), 3.75 (dd, J=11.08 Hz, J=3.05
Hz, 1H, BnOCHa), 3.71 (dd, J=10.92 Hz, J=3.12 Hz,
1H, BnOCHb ꢀO),
). 13C NMR (acetone-d6): l 177.02 (C
139.57 (Car), 129.85 (Car), 129.14 (Car), 129.05 (Car),
84.99 (BnOCH2-CH), 74.65 (PhCH2), 71.64 (CO-CH),
70.93 (BnOCH2), 70.44 (COCHOH-CH). IR (KBr,
6
), 4.52 (s, 2H, PhCH2
6 ), 4.46
6
), 4.36 (d, J=5.59 Hz,
6
6
6
6
In comparison to the previously reported method for
the synthesis of the title compound we feel that the
above route has several advantages using: (a) simpler
procedures, (b) commercially available reagents and (c)
being faster. The only remaining drawback is the
requirement for one additional step and a lower overall
yield (18%) as compared to the silyl based procedure
(28%). This is, in our opinion, more than compensated
by the above rapid and facile procedure.
6
6
6
6
6
cm−1) 3474 (OH), 3298 (OH), 2923 (-CH2-asym), 2864
(-CH2-sym), 1756 (CꢀO). MS m/z 238 (M+), 107
(PhCH2O+), 91 (tropyllium ion). Anal. calcd for
C12H14O5: C, 60.50; H, 5.92. Found: C, 60.14; H,
5.45%.
3.3. (3S,4S,5S)-(+)-5-Benzyloxymethyl-4-hydroxy-3-(4-
methylbenzenesulfonate)-dihydro-furan-2-one 3
3. Experimental
3.1. General
To a solution of 2 (280 mg, 1.17 mmol) in dry
dichloromethane (10 mL) was added Et3N (248 ml, 1.76
mmol, 1.5 equiv.) at 0°C followed by the addition of
solid p-TsCl (224 mg, 1.17 mmol, 1 equiv.). The mix-
ture was allowed to stand in a freezer at −20°C for 18
Reagents were obtained from commercial suppliers and
used without further purification. Dichloromethane was
dried over P2O5. Merck silica gel 60 (70–230 mesh) was
used for column chromatography. TLC analyses were
run on SiO2 60F254 (Merck), detection with UV and
Vaniline/H2SO4 reagent. 1H and 13C NMR spectra were
measured at 400 MHz (Bruker). Chemical shifts are
reported relative to CDCl3 at 7.27 ppm. IR spectra
were measured with a Perkin–Elmer Infrared Spec-
trophotometer 1420; optical rotations with a Perkin–
Elmer 241 (thermostated at +20°C, chloroform
stabilized with 1% ethanol). Mass spectra were mea-
sured with a Variant MAT 311 A (EI, 70 eV). Elemen-
tal analyses were carried out with an Elementar Vario
EL. Melting points are uncorrected.
h
without stirring and then diluted with
dichloromethane (10 mL). The organic layer was
washed with 1N aqueous HCl, brine and then dried
over anhydrous Na2SO4. The crude product was
purified by column chromatography on silica gel using
as eluent AcOEt/n-hexane (1/1) and 3 was isolated as a
pale yellow oil (363 mg, 82%). Rf: 0.38 AcOEt/n-hexane
1
(1/1). [h]2D0=+37 (c 1.0, CHCl3). H NMR (CDCl3): l
7.80 (d, J=8.14 Hz, 2H, CH
7H, 1Ph+CH3CHCCH), 5.34 (d, J=5.09 Hz, 1H,
COCH), 4.62 (d, J=5.09 Hz, 1H, COCHOTsCH), 4.59
(m, BnOCH2CH), 4.53 (d, J=11.69 Hz, 1H, PhCHa),
4.48 (d, J=11.69 Hz, 1H, PhCHb), 3.73 (t, J=2.03 Hz,
2H, BnOCH2), 2.56 (br, 1OH), 2.45 (s, 3H, CH3Ph).
13C NMR (CDCl3): l 169.27 (C
ꢀO), 145.88 (Car),
6 CCH6 SO3), 7.40–7.22 (m,
6
6
6
6
6
6
6
6
6
6
3.2. (3S,4S,5S)-(−)-5-Benzyloxymethyl-3,4-dihydroxy-
dihydro-furan-2-one 2
136.79 (Car), 131.56 (Car), 130.01 (Car), 128.62 (Car),
128.28 (Car), 127.97 (Car), 127.70 (Car), 83.61
(BnOCH2C
(COCHOTsC
6
H), 74.30 (COC
6
H), 73.85 (PhC
6
H2), 70.15
6 H3Ph). IR
To a vigorously stirred solution of 1 (500 mg, 2.45
mmol) and dicyclohexano-18-crown-6 (91.2 mg, 0.24
mmol, 0.1 equiv.) in dry dichloromethane (15 mL,
under argon, at −42°C (CH3CN/CO2 bath) was added
KMnO4 (465 mg, 2.94 mmol, 1.2 equiv.) in several
portions over 30 min. The mixture was stirred for 2 h at
−42°C and then transferred into a separatory funnel.
Solid Na2SO3 (2 g) was added followed by the dropwise
addition of 1 M aqueous H2SO4 under shaking until
complete decolorization was observed. The mixture was
filtered by suction in order to remove any remaining
solids and the aqueous phase was extracted with
dichloromethane (2×20 mL). The collected organic
6
H), 68.86 (BnOC
6
H2), 21.70 (C
(film, cm−1) 3508 (OH), 2924 (-CH2-asym), 2870 (-CH2-
sym), 1797 (CꢀO), 1370 (-SO3-). MS m/z 392 (M+), 237
(M+−CH3PhSO.2), 220 (C12H12O+4), 155 (CH3PhSO+2),
107 (PhCH2O+), 91 (tropyllium ion). Anal. calcd for
C19H20O7S: C, 58.15; H, 5.14; S, 8.17. Found: C, 58.01;
H, 5.07; S, 8.05%.
3.4. (4R,5S)-(−)-5-Benzyloxymethyl-4-hydroxy-dihydro-
furan-2-one 4
To a stirred solution of 3 (300 mg, 0.79 mmol) in THF
(5 mL) at 0°C, hydrazine (80% aq. solution, 370 ml, 3.96

F. Fazio, M. P. Schneider / Tetrahedron: Asymmetry 12 (2001) 2143–2145
2145
mmol, 5 equiv.) was added and the mixture stirred for
30 min at rt. The mixture was cooled to 0°C and Br2
(304 ml, 5.92 mmol, 7.5 equiv.) was added dropwise
until no more N2 evolution was observed. The organic
solvent was removed under vacuum and the remaining
aqueous solution diluted with water (10 mL). The pH
was adjusted to $7 and the aqueous phase was
extracted with dichloromethane (3×10 mL). Chromato-
graphic purification on silica gel using as eluent n-hex-
ane/AcOEt (1/1) yielded 4 as an oil (132 mg, 75%), Rf:
0.26 hexane/AcOEt (1/1). [h]2D0=−5 (c 1.4, CHCl3). All
spectroscopic data were consistent to those reported
earlier (see Ref. 5).
1995, 123, 249; (b) Danis, M.; Gentilini, M. Rev. Prat.
1998, 48, 254.
4. (a) Anderson, D. J.; Reisher, R. J.; Taylor, A. J.; Wechter,
W. J. Nucleosides Nucleotides 1984, 3, 499; (b) Fujimori,
S.; Shudo, K.; Hashimoto, Y. J. Am. Chem. Soc. 1990, 112,
7436; (c) Morvan, F.; Genu, C.; Rayner, B.; Gosselin, G.;
Imbach, J. L. Biochem. Biophys. Res. Commun. 1990, 172,
537.
5. (a) Fazio, F.; Schneider, M. P. Tetrahedron: Asymmetry
2000, 11, 1869; (b) Fazio, F.; Schneider, M.P. German
patent application DE 100 275.6.
6. (a) Hubschwerlen, C. Synthesis 1986, 962; (b) Ha¨fele, B.;
Ja¨ger, V. Liebigs Ann. Chem. 1987, 85.
7. Fazio, F.; Maliakal, D.; Schneider, M. P. Heterocycles
2001, 55, 1323.
References
8. (a) Fleming, I.; Reddy, N. L.; Takaky, K.; Ware, A. C. J.
Chem. Soc., Chem. Commun. 1987, 1472; (b) Crump, R. A.
N. C.; Fleming, I.; Urch, C. J. J. Chem. Soc., Perkin Trans.
1 1994, 701; (c) Fleming, I.; Newton, T. W. J. Chem. Soc.,
Perkin Trans. 1 1984, 1805; (d) Fleming, I.; Newton, T. W.;
Roessier, F. J. Chem. Soc., Perkin Trans. 1 1981, 2527; (e)
Fleming, I.; Parker, D. C.; Plaut, H. E.; Sanderson, P. E.
J. J. Chem. Soc., Perkin Trans. 1 1995, 317.
1. (a) Okabe, M.; Sun, R. C.; Tam, S. Y. K.; Todaro, L. J.;
Coffen, D. L. J. Org. Chem. 1988, 53, 4780; (b) Balzarini,
J.; Naesens, L.; De Clercq, E. Curr. Opin. Microbiol. 1998,
1, 535; (c) Lin, T. S.; Luo, M. Z.; Liu, M. C.; Pai, B.;
Dutschman, G. E.; Cheng, Y. C. J. Med. Chem. 1994, 37,
798; (d) Hoong, L. K.; Strange, L. E.; Liotta, D. C.;
Koszalka, G. W.; Burns, C. L.; Schinazi, R. F. J. Org.
Chem. 1992, 57, 5563.
9. Mukaiyama, T.; Tabusa, F.; Suzuki, K. Chem. Lett. 1983,
173.
2. (a) Casillas, T.; Delicado, E. G.; Carmona, F. G.; Portugal,
M. T. M. Biochemistry 1993, 32, 14203; (b) Verri, A.;
Montecucco, A.; Gosselin, G.; Boudou, V.; Imbach, J. L.;
Spadari, S.; Focher, F. Biochem. J. 1999, 337, 585; (c)
Grove, K. L.; Cheng, Y. C. Cancer Res. 1996, 56, 4187.
3. (a) Upston, J. M.; Gero, A. M. Biochim. Biophys. Acta
10. (a) Reed, A. D.; Hegedus, L. S. J. Org. Chem. 1995, 60,
3787; (b) Lundt, I.; Madsen, R. Synthesis 1992, 1129.
11. (a) Paulsen, H.; Stoye, D. Chem. Ber. 1966, 99, 908; (b)
Dax, K.; Rauter, A. P.; Steutz, A. E.; Weidmann, H.
Liebigs Ann. Chem. 1981, 10, 1768; (c) Malle, B. M.; Lundt,
I.; Furneaux, R. H. J. Carbohydr. Chem. 2000, 19, 573.