A practical synthesis of L-ribose

Article abstract of DOI:10.1248/cpb.50.866

L-Ribose was synthesized by a simple four-step method with overall yield of 76.3% from a protected L-arabinose derivative, which is a compatible intermediate for the synthesis of L-deoxyribose. The key step of this strategy is the Swern oxidation and subsequent stereoselective reduction accompanied by inversion of the 2-hydroxy group of protected L-arabinose.

Full text of DOI:10.1248/cpb.50.866

866
Notes
Chem. Pharm. Bull. 50(6) 866—868 (2002)
Vol. 50, No. 6
A Practical Synthesis of L-Ribose
Masao AKAGI,* Daichi OMAE, Yoshinori TAMURA, Tetsujiro UEDA, Tetsuya KUMASHIRO, and
Hidehito URATA
Osaka University of Pharmaceutical Sciences; 4–20–1 Nasahara, Takatsuki, Osaka 569–1094, Japan.
Received January 15, 2002; accepted February 13, 2002
L-Ribose was synthesized by a simple four-step method with overall yield of 76.3% from a protected L-arabi-
nose derivative, which is a compatible intermediate for the synthesis of L-deoxyribose. The key step of this strat-
egy is the Swern oxidation and subsequent stereoselective reduction accompanied by inversion of the 2-hydroxy
group of protected L-arabinose.
Key words mirror image; L-ribose; L-RNA; L-nucleoside
L-Nucleic acids are attractive molecules as diagnostic and Results and Discussion
therapeutic agents as well as probes for nucleic acid–ligand
Our synthetic strategy is summarized in Chart 1. We have
interactions,1,2) due to their unusual interaction with biomole- already reported that methyl 3,4-O-isopropylidene-b-L-arabi-
cules.3—11) For instance, several nucleoside derivatives com- noside (2) can be easily synthesized from L-arabinose in an
posed of L-sugars have been shown to have antiviral activity easy and highly efficient manner.7) The compound (2) was
superior to their D-enantiomers.12—14) In addition, ent-ap- subjected to Swern oxidation followed by reduction with
tamers are a potential candidate for therapeutic applications NaBH4 in EtOH at 0 °C. Although the product showed a sin-
with prolonged stability under physiological conditions.15—17) gle spot on TLC, the reduction was not highly stereoselective
L-Ribose is a key intermediate for the synthesis of L-ribonu- and gave the ribo derivative (4) and arabino derivative (2) in
1
cleosides and L-oligoribonucleotides, For this purpose, some a ratio of 4 : 1 as estimated by H-NMR spectra. Therefore,
methods for the conversion of L-arabinose,18—21) D-glucose,9) we tested some other reducing reagents to improve the stere-
L-xylose,18,22,23) D-galactose24) and D-ribose25) into the L-ri- oselectivety. The results are summarized in Table 1. The best
bose derivatives have been reported. Ikegami and coworkers results were obtained with LiAlH4 and LiAlH(OtBu)3, which
also reported an excellent method for the syntheses of L-sug- are even similar to those with the NaBH4 conditions. The
ars from D-sugar lactones.26) However, these methods have use of the bulky reagents L-Selectride, NaBH(OAc)3 and
some drawbacks such as low overall yields, the need for an NaBH(OCH3)3 significantly decreased the selectivity. The se-
expensive starting material, many reaction steps and diffi- lectivity thus may be controlled not sterically but electrostati-
culty for large-scale synthesis. Here, we report a simple, cally. The separation of the ribo derivative (4) from the ara-
short-step synthesis of L-ribose from L-arabinose. This strat- bino derivative (2) could not be achieved at this stage. How-
egy utilizes the key intermediate for the synthesis of L-de- ever, after deprotection of the isopropylidene group with
oxyribose7) as a starting material, and therefore is a compati- 80% AcOH, methyl b-L-ribopyranoside (5) and undesirable 1
ble method for the syntheses of both L-ribonucleosides and L- could be readily separated by silica gel column chromatogra-
deoxyribonucleosides.
phy to give pure 5 with 64.7% yield from 2. With recovered
Chart 1
To whom correspondence should be addressed. e-mail: akagi@gly.oups.ac.jp
© 2002 Pharmaceutical Society of Japan

June 2002
867
Table 1. Stereoselectivities for the Reduction of 3a)
Run
Reducing agent
Solvent
Temp. (°C)
Time (h)
Yield (%)a)
1 : 5b)
1
2
3
4
5
6
7
8
9
NaBH4
NaBH4
EtOH
EtOH
THF
THF
Et2O
EtOH
EtOH
EtOH
THF
0→r.t.c)
Ϫ20
Ϫ78
r.t.
r.t.
r.t.
Ϫ20
r.t.
0
0.5
1
1
1
2
0.5
0.5
1.5
0.5
92.6
93.6
96.3
79.2
73.4
98.5
88.6
Quant.
82.6
1 : 4.0
1 : 3.3
1 : 0.8
1 : 0.8
1 : 4.0
1 : 1.8
1 : 2.0
1 : 0.8
1 : 4.0
L-Selectride
L-Selectride
LiAlH4
NaBH(OMe)3
NaBH(OMe)3
NaBH(OAc )3
LiAl[O-tert-Bu)3]3H
a) Isolated yields of a mixture of 1 and 5. b) Ratios of 1 and 5 were estimated by 1H-NMR spectra. c) r.t., room temperature.
tracted several times, and the organic layers were combined, dried with
Na2SO4 and evaporated to give a pale brown crystalline solid of 3 (33.76 g,
quant.). An analytical sample was recrystallized from chloroform–n-hexane
to afford colorless crystals of 3, mp 102—103 °C. 1H-NMR (CDCl3) d: 1.39,
1.46 (3H each, 2s), 3.49 (3H, s), 4.08 (1H, ddd, Jϭ13.5, 0.9, 0.7 Hz), 4.23
1, the reactions were conducted again to give an additional
11.6% of 5 and the overall yield of 5 from 2 was 76.3%. De-
protection of the anomeric position of 5 was conducted first
by treatment with 0.8 M HCl. Neutralization of the reaction
mixture with an anion exchange resin (OHϪ form) gave L-ri- (1H, ddd, Jϭ13.5, 2.0, 0.5 Hz), 4.54 (1H, m), 4.68 (1H, d, Jϭ5.7 Hz), 4.70
(1H, s). MS (electron impact (EI)) m/z: 203 (Mϩϩ1). HR-MS m/z: 203.0917
(Calcd for C9H15O5: 203.0919).
Methyl b-L-Ribopyranoside (5) To a stirred solution of the above
residue of 3 (137 mmol) in EtOH (800 ml), NaBH4 (4.42 g, 117 mmol) was
bose with relatively lower yields and reproducibility. There-
fore, we conducted the reaction using the Dowex 50w cation
exchange resin (Hϩ form) as an acid catalyst. After filtration
of the resin, L-ribose was obtained quantitatively without any
laborious purification steps.
added portionwise at 0 °C. After stirring at room temperature for 30 min, the
solvent was evaporated. The residue was extracted with chloroform and
washed with distilled water. The organic layer was dried with Na2SO4 and
concentrated to give yellowish syrup of a mixture of 4 and 2. This mixture
was then treated with 80% AcOH (400 ml) and stirred overnight. The sol-
vent was evaporated, and the residue was coevaporated with toluene three
times. The residue was purified with silica gel column chromatography to
give a colorless crystalline solid of 5 (14.55 g, 64.7%). Recovered 1 was
subjected to the same reactions to give another crop of 5 (2.61 g, 11.6%).
1H-NMR (D2O) d: 3.46 (3H, s), 3.60 (1H, dd, Jϭ5.3, 3.2 Hz), 3.69 (1H, dd,
Jϭ11.8, 6.9 Hz), 3.82 (1H, dd, Jϭ11.8, 3.4 Hz), 3.87 (1H, m), 4.00 (1H, dd,
Jϭ3.2, 3.2 Hz), 4.66 (1H, d, Jϭ5.3 Hz). MS (SI-MS) m/z: 165 (Mϩϩ1). HR-
MS m/z: 165.0770 (Calcd for C6H13O5: 165.0762); Anal. Calcd for C6H12O5:
C, 43.90; H, 7.37. Found: C, 43.76; H, 7.33.
In conclusion, we synthesized L-ribose from compound (2)
in four steps with 76.3% overall yield. This synthetic strategy
requires only four reaction steps and only one silica gel chro-
matographic purification step with moderate overall yield.
Compound 2 is a common key intermediate for the syntheses
of both L-ribose and L-deoxyribose,7) since we have already
reported the synthesis of L-deoxynucleosides via this com-
pound. This method would be a useful and practical synthetic
approach to mirror image nucleic acids.
Experimental
L-Ribose (6) To a stirred solution of 5 (2.51 g, 15.3 mmol) in distilled
water (110 ml) was added 15 ml of Dowex 50w X4 resin (Hϩ form) and
heated at 90 °C for 17 h. After cooling, the resin was removed by filtration
and the solution was concentrated. The residue was coevaporated with EtOH
several times to give colorless syrup of 6 (2.59 g, quant.). An analytical sam-
ple was recrystallized from EtOH to afford colorless crystals of 6, mp 86 °C.
[a]D25ϭϩ20.0° (cϭ2.0, H2O); the corresponding D-isomer, [a]D25ϭϪ19.7°
(cϭ2.0, H2O). The 1H-NMR spectrum and SI-MS of 6 completely coincided
with those of the corresponding D-isomer. Anal. Calcd for C5H10O5: C,
40.00; H, 6.71. Found: C, 39.93; H, 6.72.
Melting points were measured on a Yanagimoto apparatus and are uncor-
1
rected. H-NMR spectra were obtained by a Varian gemini-200 or a Varian
XL-300 spectrometer. Chemical shifts were measured relative to internal
tetramethylsilane for CDCl3 or internal tert-butyl alcohol, 1.23 ppm from
sodium 2,2-dimethyl-2-silapentane-5-sulfonate (DSS) for D2O. Specific ro-
tations were measured by a JASCO DIP-1000 digital polarimeter. Thin-layer
and column chromatography were carried out on Merck coated plates 60F254
and silica gel 60N. Methyl b-L-arabinopyranoside was synthesized from L-
arabinose according to a literature procedure for corresponding D-isomer.27)
Methyl 3,4-O-Isopropylidene-b-L-arabinopyranoside (2) To the mix-
ture of methyl b-L-arabinopyranoside 1 (16.4 g, 100 mmol) and 2,2-
dimethoxypropane (38.6 ml, 300 mmol) in dry dimethylformamide (DMF)
(130 ml) was added Amberlyst 15 (1 g, Hϩ form) and the whole was stirred
at room temperature for 18 h. After filtration of the resin, the solvent was
evaporated and the residue was coevaporated with m-xylene to give suffi-
ciently pure colorless syrup of 2. (23.04 g, quant.): 1H-NMR (CDCl3) d:
1.36, 1.53 (3H each, 2s), 2.43 (1H, br), 3.44 (3H, s), 3.78 (1H, m), 3.93,
3.94 (2H, 2s), 4.15—25 (2H, m), 4.71 (1H, d, Jϭ3.5 Hz). MS (secondary
ion (SI)-MS) m/z: 205 (Mϩϩ1). High resolution (HR)-MS m/z: 205.1093
(Calcd for C9H17O5: 205.1075).
Methyl 3,5-O-Isopropylidene-b-L-threo-pentopyranosid-2-ulose (3)
Oxalyl chloride (13.23 ml, 151.6 mmol) dissolved in dry dichloromethane
(350 ml) was placed in a 3-neck flask equipped with a thermometer and a
dropping funnel under Ar atmosphere. The contents of the flask were cooled
to Ϫ60 °C and a solution of DMSO (23.4 ml, 331 mmol) in dry dichloro-
methane (138 ml) was added dropwise over 15 min. Stirring was continued
at Ϫ60 °C for 10 min, then a solution of 2 (28 g, 137 mmol) in dry dichloro-
methane (138 ml) was added dropwise into the flask for 15 min. The reaction
mixture was stirred for 15 min, and triethylamine (95.9 ml, 689 mmol) was
added over 10 min with stirring at Ϫ60 °C. The cooling bath was removed
and distilled water was added at room temperature. Stirring was continued
for 10 min and the organic layer was separated. The aqueous layer was re-ex-
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