DIRECT PREPARATION OF 1,2:3,5-DI-O-CYCLOHEXYLIDENE-α-D-XYLOFURANOSE FROM CORNCOBS AND ITS CONVERSION TO 1-O-ACETYL2,3,5-TRI-O-BENZOYL-D-RIBOFURANOSE

Article abstract of DOI:10.1135/cccc19941884

A novel synthesis of 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose (I) has been described starting from 1,2:3,5-di-O-cyclohexylidene-α-D-xylofuranose (II), obtained directly from the crude xylose syrup originated from corncobs.Partial acid hydrolysis of II gave 1,2-O-cyclohexylidene-α-D-xylofuranose (III).Selective benzoylation of primary C-5 hydroxyl group of III followed by tosylation of C-3 hydroxyl group afforded IV in an overall yield of 67percent.Mild acid methanolysis of IV gave the corresponding methyl xylofuranosides V which further benzoylated to afford 2,5-di-O-benzoyl derivatives VI in 65percent yield.Solovolysis of VI in 95percent DMF gave a mixture of 2,5- and 3,5-di-O-benzoylribofuranosides VII, which were subsequently converted into the corresponding tribenzoates VIII.An acetolysis of VIII afforded I in an overall yield of 96percent related to VI.

Full text of DOI:10.1135/cccc19941884

1884
Popsavin M., Popsavin V., Vukojevic, Miljkovic:
DIRECT PREPARATION OF 1,2:3,5-DI-O-CYCLOHEXYLIDENE-
α-D-XYLOFURANOSE FROM CORNCOBS AND ITS CONVERSION
TO 1-O-ACETYL-2,3,5-TRI-O-BENZOYL-D-RIBOFURANOSE
Mirjana POPSAVIN, Velimir POPSAVIN, Nada VUKOJEVIC and Dusan MILJKOVIC
Institute of Chemistry,
Faculty of Sciences, University of Novi Sad,
Trg Dositeja Obradovica 3, 21000 Novi Sad, Yugoslavia
Received December 2, 1993
Accepted May 8, 1994
A novel synthesis of 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose (I) has been described starting
from 1,2:3,5-di-O-cyclohexylidene-α-D-xylofuranose (II), obtained directly from the crude xylose
syrup originated from corncobs. Partial acid hydrolysis of II gave 1,2-O-cyclohexylidene-α-D-xylofu-
ranose (III). Selective benzoylation of primary C-5 hydroxyl group of III followed by tosylation of
C-3 hydroxyl group afforded IV in an overall yield of 67%. Mild acid methanolysis of IV gave the
corresponding methyl xylofuranosides V which were further benzoylated to afford 2,5-di-O-benzoyl
derivatives VI in 65% yield. Solvolysis of VI in 95% DMF gave a mixture of 2,5- and 3,5-di-O-
benzoylribofuranosides VII, which were subsequently converted into the corresponding tribenzoates
VIII. An acetolysis of VIII afforded I in an overall yield of 96% related to VI.
1-O-Acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose (I) represents an important starting ma-
terial for numerous syntheses of ribonucleosides1 as well as certain C-nucleosides2 with
potential antitumor and/or antiviral properties. Although commercially available, com-
pound I is usually prepared from D-ribose3. In this paper we want to report a new
synthesis of I starting from crude D-xylose syrup obtained by acid hydrolysis of the
xylan fraction from corncobs.
It is well known that D-xylose can be suitably prepared from corncobs or a similar
natural waste material containing large amounts of xylan or hemicellulose-B. The
method used here is a modification of that described by Whistler and BeMiller4. It
assumes a previous treatment of corncobs with 1% aqueous sodium hydroxide to
remove lignin and acidic impurities. Hydrolysis of such pre-treated corncobs is carried
out as described4, but the yeast fermentation step as well as the crystallization step was
omitted since the crude xylose syrup was immediately treated5 with cyclohexanone in
presence of concentrated sulfuric acid. By this modification, highly crystalline 1,2:3,5-
di-O-cyclohexylidene-α-D-xylofuranose (II) was obtained. Partial acid hydrolysis of II,
under the conditions similar to those already reported6, gave 1,2-O-cyclohexylidene-α-
D-xylofuranose (III).
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1885
Derivative IV was conveniently prepared7 by “one pot” procedure including selective
benzoylation of primary C-5 hydroxyl group in III, followed by esterification of the
remaining C-3 hydroxyl group with tosyl chloride in pyridine.
Compound IV upon reflux in dry methanol in presence of trichloroacetic acid gave
the corresponding methyl xylofuranoside V as an 1 : 1 anomeric mixture. Further treat-
ment of V with benzoyl chloride afforded the corresponding 2,5-di-O-benzoylxylofu-
ranosides VI. Although an analytical sample of VI, obtained by recrystallization from
EtOH, showed as a single spot in TLC and had a sharp melting point (136 °C), it also
represented a mixture of anomers with an α : β anomeric ratio of 3 : 2 (according to
1
NMR). Both α- and β-anomers in the mixture were fully characterized by H and
1
13C NMR data (see Experimental). The H assignments were carried out by spin-de-
coupling experiments, while the 13C assignments were performed by 2D chemical shift
correlation method.
The subsequent important step leading towards the target ribofuranosyl acetates I
included the C-3 epimerization of xylofuranosides VI. This was achieved by a solvo-
lysis of VI in wet N,N-dimethylformamide at 150 °C, in presence of CaCO3 as a proton
acceptor. The resulting mixture of 2,5- and 3,5-di-O-benzoylribofuranosides VII (most
likely formed via cyclic benzoxonium ion8) was subsequently treated with benzoyl
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Popsavin M., Popsavin V., Vukojevic, Miljkovic:
chloride in pyridine to give known9 methyl 2,3,5-tri-O-benzoylribofuranosides VIII. A
treatment of crude VIII with a mixture of acetic acid–acetic anhydride–concentrated
sulfuric acid afforded the desired ribofuranosyl acetates I as a mixture of anomers. By
crystallization of the mixture from EtOH, the pure β-anomer of I was obtained in an
overall yield of 45% (from VI). After evaporation of mother liquor an oily mixture
remained containing the α-anomer of I as the predominant component. By integration
of the signals at δ 6.73 d (H-1α) and δ 6.44 s (H-1β), the α : β anomeric ratio in the
mother liquor was determined as 20 : 3. All three steps concerning the conversion of VI
to I were carried out successively, whereupon the intermediates VII and VIII were used
in the subsequent steps without any purifications. The final product I (α + β) was
obtained in an overall yield of 96% related to the intermediate VI.
Both α- and β-anomers I represent suitable intermediates for preparation of various
N- and C-nucleosides1,2
.
EXPERIMENTAL
Melting points were determined on Büchi SMP 20 apparatus and were not corrected. Optical rota-
tions were measured on automatic polarimeter Polamat A (Zeiss, Jena) at 23 °C in chloroform solu-
tions if not stated otherwise. 1H (250 MHz) and 13C (62.5 MHz) NMR spectra were recorded on
Bruker AC 250 E instrument in deuteriochloroform with tetramethylsilane as an internal standard.
Chemical shifts are given in ppm (δ-scale) and coupling constants (J) in Hz. Thin-layer chromato-
graphy (TLC) was performed on DC Alufolien Kieselgel 60 F254 (Merck). Column chromatography
was carried out on Kieselgel 60. The extracts were dried with Na2SO4 if not stated otherwise.
1,2:3,5-Di-O-cyclohexylidene-α-D-xylofuranose (II)
A suspension of grounded corncobs (85 g) in 1% aqueous NaOH (500 ml) was refluxed for 2.5 h.
The precipitate was collected, washed with hot water and hydrolyzed with boiling 7% aqueous
H2SO4 (500 ml) for 2.5 h. The reaction mixture was filtered and solution neutralized with CaCO3.
The precipitate was filtered off and aqueous solution concentrated under reduced pressure to a pale
yellow syrup (23.7 g). So obtained crude D-xylose was treated with cyclohexanone (40 ml) and con-
centrated H2SO4 (3 ml) in ether (100 ml). The reaction mixture was stirred at room temperature for
24 h and then transferred into a separatory funnel to remove the aqueous phase. The etheral solution
was washed with saturated NaHCO3, dried (Na2CO3) and evaporated to a yellow syrup. Crystal-
lization from hexane followed by recrystallization from aqueous ethanol (20% of water) afforded
pure II (18 g, 21%) as colourless needles, m.p. 104 – 105 °C (ref.5 m.p. 102.5 – 103 °C, ref.10 m.p.
105 °C).
1,2-O-Cyclohexylidene-α-D-xylofuranose (III)
A suspension containing finely powdered compound II (34.14 g, 184.43 mmol) in 50% aqueous
acetic acid (500 ml) was stirred at 100 °C until the solution became clear (20 – 30 min). After cool-
ing to 30 °C, the solution was neutralized with solid NaHCO3 and extracted with chloroform. The
extract was dried and evaporated to a yellow syrup (23.36 g). After crystallization from benzene–
hexane, the pure product III (19.1 g, 75%) was obtained as colourless needles, m.p. 89 – 89.5 °C
(ref.10 m.p. 91 – 92 °C), and [α]D −11.6° (c 0.9, water); ref.10 [α]D −12.4° (c 0.89).
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5-O-Benzoyl-1,2-O-cyclohexylidene-3-O-p-toluenesulfonyl-α-D-xylofuranose7 (IV)
To a solution of compound III (1.039 g, 4.52 mmol) in dry pyridine (10 ml), benzoyl chloride (0.58 ml,
5 mmol) was added during 0.5 h at −20 °C. The reaction mixture was left at this temperature for 48 h
and then at room temperature for 24 h. Finally, tosyl chloride (2.58 g, 13.55 mmol) was added and
the resulting mixture kept at room temperature for additional 72 h. The reaction mixture was poured
into ice and diluted HCl (1 : 1) and extracted with chloroform. The combined extracts were washed
with water, saturated NaHCO3, dried and evaporated. Upon crystallization from ethanol the pure
compound IV was obtained (1.46 g, 67%) in a form of colourless crystals, m.p. 104 – 106 °C, [α]D
1
−65.22° (c 1.2). H NMR spectrum: 1.28 – 1.84 m, 10 H (cyclohexylidene ring); 2.26 s, 3 H (CH3, Ts);
4.27 dd, 1 H, J(5a,5b) = 12.3, J(4,5a) = 6.7 (H-5a); 4.41 dd, 1 H, J(4,5b) = 6 (H-5b); 4.55 ddd, 1 H,
J(3,4) = 2.9 (H-4); 4.82 d, 1 H, J(1,2) = 3.7 (H-2); 4.96 d, 1 H (H-3); 6.0 d, 1 H (H-1); 7.12 – 8.16 m,
9 H (Bz and Ts). 13C NMR spectrum: 21.53 (CH3, Ts), 23.44, 23.78, 24.75, 35.63 and 36.22 (5 × CH2,
cyclohexylidene), 60.95 (C-5), 76.44, 81.59 and 82.83 (C-2, C-3 and C-4), 104.42 (C-1), 113.38 (qC
from cyclohexylidene), 127.78, 128.3, 129.39, 129.71, 130.02, 132.58, 133.17 and 145.52 (C-atoms
from aromatic rings), 163.9 (C=O, Bz). For C25H28O8S (488.3) calculated: 61.44% C, 5.78% H,
6.57% S; found: 61.69% C, 6.08% H, 6.79% S.
Methyl 5-O-Benzoyl-3-O-p-toluenesulfonyl-D-xylofuranosides (V)
A solution of compound IV (0.15 g, 0.31 mmol) and trichloroacetic acid (0.64 g, 3.91 mmol) in dry
methanol (2 ml) was refluxed for 32 h. The reaction mixture was poured into cold water, neutralized
(NaHCO3) and extracted with chloroform. The extract was dried and evaporated to give a crude mix-
ture as a yellow oil. After chromatographic purification on a column of silica gel (toluene–ethyl ace-
tate 4 : 1), the pure V was obtained (0.082 g, 63%) as an anomeric mixture (α : β = 1 : 1; according
to NMR) that moved as a single spot in TLC with different solvents. 1H NMR spectrum: 2.21 and
2.4 2 s (2 × CH3, Ts); 2.41 and 2.6 2 d (2 × OH); 3.35 and 3.5 2 s (2 × CH3O); 4.36 – 5.01 m (H-2,
H-3, H-4, H-5a, H-5b and H-1β); 5.04 d, J(1,2) = 4.8 (H-1α); 7.2 – 8.09 m (Bz and Ts). 13C NMR
spectrum: 22.5 (2 overlapping CH3 from 2 × Ts), 56.1 and 56.8 (2 × CH3O), 62.5 (C-5α), 63.6 (C-5β),
75.0, 76.9, 78.3, 80.0, 83.6 and 84.3 (C-2, C-3 and C-4), 101.8 (C-1α), 109.4 (C-1β), 128.7 – 145.8
(partially overlapping C-atoms from Bz and Ts), 166.1 (2 overlapping C=O).
Methyl 2,5-Di-O-benzoyl-3-O-p-toluenesulfonyl-D-xylofuranosides (VI)
To a solution of compound V (1.0 g, 2.36 mmol) in dry dichloromethane (10 ml) and dry pyridine
(2 ml) was added benzoyl chloride (1.1 ml, 9.46 mmol) at 0 °C. The mixture was stored at room
temperature for 48 h, then acidified with aqueous HCl (1 : 1) to pH 2 and extracted with dichloro-
methane. The combined extracts were washed with water and saturated aqueous NaHCO3 dried
(Na2CO3) and evaporated. The syrupy residue was crystallized from ethanol to give VI (0.81 g, 65%)
as an anomeric mixture (α : β = 3 : 2), m.p. 132 – 133 °C. An analytical sample of VI obtained by
1
recrystallization from ethanol showed m.p. 136 °C. H NMR spectrum: 2.03 s (CH3, Ts; α-anomer),
2.12 s (CH3, Ts; β-anomer); 3.14 s (α-CH3O), 3.2 s (β-CH3O); 4.52 – 4.7 m (H-4α, H-5aα, H-5aβ,
H-5bα and H-5bβ); 4.86 broad dd (H-4β); 4.99 broad s (H-1β); 5.21 – 5.28 m (H-1α, H-2α and
H-3β); 5.37 d, J(2,3) = 2.1 (H-2β); 5.43 – 5.5 m (H-3α); 7.12 – 8.11 m (Bz and Ts). 13C NMR
spectrum: 21.8 (2 overlapping CH3, Ts), 55.5 and 55.6 (CH3, Ts), 62.2 (C-5α), 63.1 (C-5β), 73.4
(C-4α), 77.3 (C-2α), 78.2 (C-4β), 80.2 (C-2β), 80.4 (C-3β), 80.7 (C-3α), 99.9 (C-1α), 106.9 (C-1β),
128.6 – 145.7 (partially overlapping C-atoms from Bz and Ts), 165.0, 165.4 and 166.1 (4 partially
overlapping C=O). For C27H26O9S (526.3) calculated: 61.56% C, 4.98% H, 6.10% S; found: 61.54% C,
4.93% H, 5.75% S.
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Popsavin M., Popsavin V., Vukojevic, Miljkovic:
1-O-Acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose (I)
To a solution of compound VI (0.704 g, 1.34 mmol) in 95% aqueous N,N-dimethylformamide
(12 ml) was added calcium carbonate (0.2 g, 2 mmol). The reaction mixture was stirred at 150 °C for
16 h, then concentrated under reduced pressure. The remaining mixture was treated with chloroform,
filtered and the solvent was evaporated. Resulting crude mixture of 2,5- and 3,5-di-O-benzoyl deri-
vatives VII was dissolved in dry pyridine (9 ml) and allowed to react with benzoyl chloride (0.59 ml,
5.07 mmol) for 48 h at room temperature. The mixture was poured onto ice, acidified with aqueous
HCl (1 : 1) to pH 2 and extracted with dichloromethane. The extract was washed with water and
saturated NaHCO3, dried and evaporated to afford crude VIII (0.81 g) as an anomeric mixture moving
as a single spot in TLC with different solvents. To stirred and cooled (0 °C) solution of crude VIII
in a mixture of glacial acetic acid (15 ml) and acetic anhydride (3.5 ml) was added concentrated
H2SO4 (0.7 ml). The mixture was stirred at room temperature for 4 h, then poured onto ice (30 g) and
extracted with dichloromethane. The extract was washed with water and saturated NaHCO3, dried
and evaporated. Crystallization of the residue from ethanol gave β-anomer of I (0.301 g, 45%), m.p.
1
130 °C and [α]D + 38.0° (c 1.38); ref.3 m.p. 130 – 131 °C; [α]D + 44.2° (c 1.32). H NMR spectrum:
2.0 s, 3 H (CH3, Ac); 4.53 dd, 1 H, J(5a,5b) = 12.8, J(4,5a) = 5.4 (H-5a); 4.8 m, 2 H, J(4,5b) = 3.7
(H-4 and H-5b); 4.81 dd, 1 H, J(1,2) = 0.9, J(2,3) = 4.7 (H-2); 5.93 dd, 1 H, J(3,4) = 6.7 (H-3); 6.44
broad s, 1 H (H-1); 7.25 – 8.16 m, 15 H (arom. from 3 Bz). The mother liquor was evaporated to give
an oil (0.343 g, 51%) containing α-anomer of I as the major component (α : β = 20 : 3, according
to NMR). 1H NMR spectrum: 2.16 s, 3 H (CH3 from Ac); 4.63 dd, 1 H, J(5a,5b) = 12.2, J(4,5a) =
3.6 (H-5a); 4.73 dd, 1 H, J(4,5b) = 3.2 (H-5b); 4.83 m, 1 H, J(3,4) = 2.6 (H-4); 5.65 dd, 1 H, J(1,2)
= 4.5; J(2,3) = 6.5 (H-2); 5.85 dd, 1 H (H-3); 6.73 d, 1 H (H-1); 7.4 – 8.07 m, 15 H (arom. 3 × Bz).
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