Synthesis of 1,2,3-tri-O-acetyl-5-deoxy-D-ribofuranose from D-ribose

Article abstract of DOI:10.1016/S0008-6215(02)00464-0

A practical route towards the synthesis of 1,2,3-tri-O-acetyl-5-deoxy-D-ribofuranose from D-ribose is described. The key steps include deoxygenation of methyl 2,3-O-isopropylidene-5-O-sulfonyloxy-β-D-ribofuranoside by reductive displacement employing hydride reagents. Subsequent total hydrolysis followed by acetylation led to the title compound in 56% overall yield from D-ribose. The sequence is simple, inexpensive, high yielding and clearly suitable for multi-gram preparations.

Full text of DOI:10.1016/S0008-6215(02)00464-0

Carbohydrate Research 338 (2003) 303–306
www.elsevier.com/locate/carres
Synthesis of 1,2,3-tri-O-acetyl-5-deoxy-
-ribose
D-ribofuranose from
D
Pothukuchi Sairam,* Ramachandra Puranik, Bhatraju Sreenivasa Rao,
Ponnapalli Veerabhadra Swamy, Sharad Chandra
Critical Care Di6ision, Dr Reddy’s Laboratories Ltd., IDA Bollaram, Hyderabad, Andhra Pradesh 500 016, India
Received 31 May 2002; accepted 3 November 2002
Abstract
A practical route towards the synthesis of 1,2,3-tri-O-acetyl-5-deoxy-
include deoxygenation of methyl 2,3-O-isopropylidene-5-O-sulfonyloxy-b-
hydride reagents. Subsequent total hydrolysis followed by acetylation led to the title compound in 56% overall yield from
-ribose. The sequence is simple, inexpensive, high yielding and clearly suitable for multi-gram preparations. © 2003 Elsevier
D
-ribofuranose from
D-ribose is described. The key steps
D
-ribofuranoside by reductive displacement employing
D
Science Ltd. All rights reserved.
Keywords: 1,2,3-tri-O-acetyl-5-deoxy-D-ribofuranose; Lithium tri-t-butoxyaluminum hydride (LTTBA); Sodium bis-(methoxyethoxy) aluminium
hydride (SMEAH)
1. Introduction
2. Results and discussion
5-Deoxy-
D
-ribose is key constituent of several nu-
There are two major synthetic routes available in litera-
ture for the synthesis of this intermediate. The first one
focuses on preparing a methyl 2,3-O-isopropylidene-5-
cleosides, which exhibit a variety of biological func-
tions. For example 5%-deoxy-iodotubercidin (1)1 is a
nucleoside derivative of 5-deoxy-
D-ribose. Compound 1
halo-b-
propylidene-b-
dehalogenation employing either palladium-on-char-
D
-ribofuranoside3–5 from methyl 2,3-O-iso-
is a good inhibitor of adenosine kinase, which provides
basis for the design of new therapeutic agents for the
treatment of inflammatory disease. The prodrug strat-
egy involving tumor-selective delivery of 5-fluorouracil
by sequential conversion of a fluoropyrimidine carba-
mate, capecitabine (2)2 also requires the tri-O-acetyl
D
-ribofuranoside,6 followed by reductive
coal, or Adams platinum catalyst, yielding 5-deoxy-D-
ribose.4,7 The other route follows the direct
deoxygenation of a methyl 2,3-O-isopropylidene-5-O-
sulfonyloxy-b-
placement using
5-deoxy-
-ribose.11 Other modification of this general
D
-ribofuranoside,8–10 by reductive dis-
derivative of 5-deoxy-
tyl-5-deoxy- -ribofuranose, for its synthesis. Our in-
D-ribose, namely 1,2,3-tri-O-ace-
a
hydride reagent to give
D
D
volvement with this latter compound as a starting
material, in a linear synthetic route, required examina-
tion and modification of existing chemistry to enable a
practical bulk synthesis of this compound (Fig. 1).
* Corresponding author
E-mail address: sairam@drreddys.com (P. Sairam).
Fig. 1.
0008-6215/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(02)00464-0

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P. Sairam et al. / Carbohydrate Research 338 (2003) 303–306
Scheme 1. Reagents: (i) SnCl2·2H2O, Conc.H2SO4, acetone, MeOH; (ii) Mesyl chloride, pyridine, CH2Cl2 (Compound 5); OR
tosyl chloride, pyridine, CH2Cl2 (Compound 6); OR triflic anhydirde, pyridine, CH2Cl2 (Compound 7); (iii) NaBH4, Me2SO
(compound 5,6,7); OR SMEAH, THF (compound 5,6,7); OR LTTBA, THF (compound 5,6,7); (iv) 0.04N H2SO4; Ac2O, pyridine.
Table 1
Percentage yields of isolated products (4 and 8) obtained by reaction of compounds 5, 6, and 7 with hydride reagents
Hydride reagent
Compound (5)
Compound (6)
Compound (7)
4
8
4
8
4
8
NaBH4
SMEAH
LTTBA
–
70
75
80
–
–
–
45
70
89
50
20
70
30
–
20
50
95
approach required additional steps, which render them
unattractive candidates for a large-scale process.12,13
Opting the later method, in the present article, we
report a comparative study of deoxygenation of three
different sulfonyloxy-activated sugar derivatives using
three different hydride reagents, two of which are being
employed for the first time for such a conversion.
yield from D-ribose (Scheme 1). The best yield
reported14 earlier for the synthesis of title compound
was 52%, and involved hazardous operations like
bromination and catalytic hydrogenation.
The main drawback of displacement of sulfonyloxy
activated sugar hydroxyl groups by hydride reagents is
that they often undergo OꢀS cleavage15 to give back the
starting compounds. The results of reduction by differ-
ent hydride reagents of compounds 5, 6, and 7 yielded
either the 5-deoxy sugar derivative 8 or the product of
OꢀS cleavage, namely the 5-hydroxy sugar derivative 4,
and are summarized in Table 1.
Commercially available
D-ribose (3) is converted into
methyl 2,3-O-isopropylidene-b-D-ribofuranoside (4) by
a known method.6 The hydroxyl group at C-5 carbon
of compound 4 was activated using three different
sufonyl protecting agents 6iz, methanesulfonyl chlo-
ride,8 p-toluenesulfonyl chloride,9 and trifluoro-
methanesulfonic anhydride10 to give compounds 5, 6,
and 7. Compounds 5, 6, and 7 were independently
reduced by three different hydride reagents, namely,
sodium borohydride (NaBH4),11 lithium tri-t-butoxya-
luminum hydride (LTTBA), and sodium bis(-
methoxyethoxy) aluminium hydride (SMEAH), to yield
3. Conclusion
We have successfully developed an efficient four-step
process for the synthesis of 1,2,3-tri-O-acetyl-5-deoxy-
D-ribofuranose. The reaction conditions are opera-
methyl
2,3-O-isopropylidene-5-deoxy-b-D-ribofura-
tionally simple, robust, and amenable to multi-gram
scale. The most favored method of activating the pro-
tected ribose 4 would be p-toluenesulfonyl chloride to
give 6, as two other sulfonylating reagents gave either
lower yields or were labile and difficult to handle.
noside (8). Further simplification of reported
procedures4,5 adopted for total hydrolysis and subse-
quent acetylation yielded the desired intermediate 1,2,3-
tri-O-acetyl-5-deoxy- -ribofuranose (9) in 56% overall
D

P. Sairam et al. / Carbohydrate Research 338 (2003) 303–306
305
Subsequent deoxygenation of the activated sugar
derivative 6 was best achieved by using NaBH4 which
yields compound 8 in high yields in simple and cost-ef-
fective way. Total hydrolysis of 8 followed by acetyla-
tion yields the title compound.
4.4. Preparation of methyl-2,3-O-isopropylidene-5-O-to-
syl-b- -ribofuranoside (6)
D
Compound 4 (350 g, 1.71 mol) dissolved in CH2Cl2 and
pyridine on reaction with p-toluenesulfonyl chloride
(630 g, 3.3 mol) yielded 6 (546 g, 89% yield) as a white
solid. 1H NMR data were in agreement with those
reported in the literature.9
4. Experimental
4.5. Preparation of methyl-2,3-O-isopropylidene-5-O-
trifluoromethanesulfonyl-b-D-ribofuranoside (7)
4.1. General methods
Melting points were determined with a Bu¨chi 535 ap-
paratus and are uncorrected. IR spectra were recorded
on Perkin–Elmer 1650 FTIR. 1H NMR (200 MHz) and
13C NMR (50 MHz) spectra were taken with a Varian
Gemini FT-NMR instrument in CDCl3 and Me2SO-d6
using Me4Si as internal standard. Mass spectra were
recorded on a, Hewlett-Packard model-5989 instrument
with a direct insertion probe at 20 eV. Gas chro-
matograms were taken with a Shimadzu GC 17A in-
strument. TLC was performed on Silica Gel 60 F254 230
mesh (E. Merck); detection was executed by spraying
with a solution of Ce(NH4)2(NO3)6, (NH4)6Mo7O24, as
well as H2SO4 in water and subsequent heating on a hot
plate.
Following the procedure just mentioned, compound 4
(1 g, 4 mmol) in CH2Cl2 (10 mL) containing pyridine
(0.7 mL, 9 mmol) on reaction with trifluoromethanesul-
fonic anhydride (1.2 mL, 73 mmol) at 0 °C for 4 h
yielded 7 (0.8 g, 50%) as an colourless oil. Due to
thermal decomposition at room temperature, no spec-
tral evidence could be obtained.10
4.6. Preparation of methyl-2,3-O-isopropylidene-5-de-
oxy-b-D-ribofuranoside (8)
Compound 5 (10.0 g, 35 mmol) in Me2SO (50 mL), was
reacted with NaBH4 (6.1 g, 175 mmol) for 12 h at
80–85 °C. The mixture was cooled and 5% aqueous
AcOH (100 mL) was added. The mixture was extracted
with CH2Cl2, washed with water, dried (Na2SO4), con-
centrated, and purified by column chromatography
(10% EtOAc in petroleum ether) to yield 8 (5.3 g, 80%).
The NMR data were in agreement with those reported
in the literature;13 [h]D23 −110° (c 2, EtOH) [lit5 [h]D23
−109° (c 2, EtOH)]; IR (neat): 2985, 2938, 1210, 1101,
4.2. Preparation of Methyl-2,3-O-isopropylidene-b-D-ri-
bofuranoside (4)
A mixture of
D-ribose (3, 250 g, 1.66 mol) and
SnCl2·2H2O (375 g, 1.66 mol) were suspended in ace-
tone (5 L) and methanol (1.3 L) with catalytic amount
of conc.H2SO4 (18.7 g, 186 mmol) and heated at 40–
45 °C for 20 h. The mixture was filtered, and the filtrate
was neutralized (pH 6–7) with NaHCO3 solution. The
resulting solution was once again filtered through a
Celite bed and evaporated to remove acetone and
MeOH. The aqueous solution thus obtained was ex-
tracted with EtOAc, washed with brine, dried (Na2SO4)
and evaporated in vacuo to yield 4 (300 g, 88% yield).
1H NMR data were in agreement with those reported in
the literature.6
1
1057, 870 cm−1; H NMR (CDCl3): d 1.25 (d, 3 H, J5,4
7, H-5), 1.45 and 1.29 (2s, each 3 H, CMe2), 3.31 (s, 3
H, OMe), 4.32 (q, 1 H, J4,5 7, H-4), 4.49 (d, 1 H, J2,1 6,
H-2), 4.61 (d, 1 H, J3,2 6, H-3), 4.92 (s, 1 H, H-1); 13C
NMR(CDCl3, 50 MHz): 110 (C-1), 108 (C, CMe2), 84
(C-2), 83 (C-3), 81 (C-4), 52 (CH3, OCH3), 25 and 23
(Me2, CMe2), 19 (C-5); mass spectrum: m/z 173 (M+−
CH3). The structure was also established by the absence
of methylene carbon in DEPT. Similarly, 5 (5.0 g, 17
mmol) in THF (50 mL), was treated with SMEAH
(70% solution in toluene; 26 mL, 85 mmol) and refluxed
for 12 h. The mixture was extracted with CH2Cl2 and
worked up using 1N HCl to give exclusively compound
4 (2.5 g, 70%). Compound 5 in THF (50 mL) reacted
with LTTBA (30% solution in THF, 50 mL, 9 h) and
processed as just described also yielded compound 4
(0.54 g, 75%) exclusively.
4.3. Preparation of methyl-2,3-O-isopropylidene-5-O-
mesyl-b-D-ribofuranoside (5)
Compound 4 (2 g, 9 mmol) in CH2Cl2 (20 mL) and
pyridine (6 mL, 73 mmol) was added to methanesul-
fonyl chloride (2 mL, 25 mmol) and stirred at 0–5 °C
for 16 h. The reaction mixture was successively washed
with 1N HCl, water, NaHCO3, brine. The organic layer
was dried (Na2SO4) and concentrated to yield a syrupy
mass, which was further crystallized from Et2O to give
Compound 6 (300.0 g, 0.83 mol) in Me2SO (2.2 L)
was allowed to react with NaBH4 (127 g, 3.4 mol;
80–85 °C; 3 h). Work up with 5% aqueous AcOH,
yielded compound 8 (140 g, 89% yield) upon distillation
(bp 65–70 °C, 0.2 mmHg). Similarly 6 (5.0 g, 13 mmol)
in THF (50 mL) on reaction with SMEAH (70% solu-
1
5 (1.8 g, 65% yield) as a white solid. H NMR data was
in agreement with those reported in the literature.8

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P. Sairam et al. / Carbohydrate Research 338 (2003) 303–306
tion in toluene, 20 mL, 69 mmol, 12 h, reflux) followed
by column chromatography (10% EtOAc–petroleum
ether) gave 8 (1.3 g, 50%) and 4 (1.3 g, 45%). However
compound 6 (5.0 g, 13 mmol) in THF (100 mL) when
treated with LTTBA (30% solution in THF, 55 mL, 65
mmol, reflux, 16 h) and work up using procedures
mentioned earlier provided 8 (0.5 g, 20%) and 4 (2.0 g,
70%).
compound 9 (56 g, 81%) as a syrupy mass. The
anomeric mixture (1.0 g) partially crystallized from
hexane to yield the crude b anomer, which was further
crystallized from Et2O–hexane to yield the pure b
anomer (0.6 g) as white solid, mp: 63–64 °C [lit4 64–
65 °C]; [h]2D3 −27.0° (c, 2 in CHCl3) [lit4 [h]2D3 −26.9°
(c, 2 in CHCl3)].
Compound 7 (1.0 g, 2.9 mmol) in Me2SO (10 mL)
was treated with NaBH4 (0.6 g, 14 mmol, rt, 2 h). Work
up with 5% aq. AcOH yielded 8 (0.1g, 20% yield) and
4 (0.42 g, 70%). Similarly 7 (10.0 g, 30 mmol) in THF
(100 mL) on reaction with SMEAH (70% solution in
toluene, 50 mL, 148 mmol, −40 °C; 1 h) provided 8
(2.8 g, 50%) and 4 (1.8 g, 30%). Furthermore 7 (10.0 g,
30 mmol) in THF (100 mL), when treated with LTTBA
(30% solution in THF, 125 mL, 147 mmol; 0 °C 1 h)
using similar work up procedures mentioned earlier for
LTTBA reactions, yielded 8 (5.35 g, 95%) exclusively.
References
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4.7. Preparation of 1,2,3-tri-O-acetyl-5-deoxy-D-ribo-
furanose (9)
Compound 8 (50 g, 0.26 mol) in 0.04N H2SO4 (500 mL)
was heated to 80–90 °C for 3 h. The mixture was
cooled to rt, neutralized with solid Na2CO3, and evapo-
rated to dryness. The residue was dissolved in pyridine
(800 mL), treated with Ac2O (210 mL, 2.2 mol), and
stirred at rt for 16 h. Saturated NaHCO3 (5 L) was
poured into the reaction mixture, and extracted with
CH2Cl2 (1×3 L, 2×2 L). The combined organic phase
was washed with water (2×1 L), dried (Na2SO4), and
concentrated in vacuo to 600 mL. To this solution silica
gel (65 g) and activated charcoal (6.5 g), were added
and the solution was stirred for 1 h at rt. The solution
was then filtered, and the filtrate evaporated in vacuo to
provide a mixture of the two anomers of the title