Selective monodeacetylation of methyl 2,3,5-tri-O-acetyl-D- arabinofuranoside using biocatalyst

Article abstract of DOI:10.1016/j.tetlet.2005.05.120

Methyl arabinofuranoside 1 was fully acetylated to methyl 2,3,5-tri-O-acetyl-d-arabinofuranoside 2 and it was regioselectively deacetylated using enzymes. Rhizopus oryzae esterase gave methyl 3,5-di-O-acetyl-d-arabinofuranoside 3, regioselectively. This protected 3 was deoxygenized to 3,5-di-O-acetyl-d-2-deoxyarabinofuranoside 7 using hypophosphorous acid.

Full text of DOI:10.1016/j.tetlet.2005.05.120

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5063–5065
Selective monodeacetylation of methyl
2,3,5-tri-O-acetyl-D-arabinofuranoside using biocatalyst
Sook Jin Jun,b Man Sik Moon,b So Ha Lee,a Chan Seong Cheonga,* and Kwan Soo Kimb
aLife Sciences Division, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Korea
bDepartment of Chemistry, Yonsei University, Shinchon 134, Seoul 120-749, Korea
Received 16 April 2005; revised 4 May 2005; accepted 16 May 2005
Abstract—Methyl arabinofuranoside 1 was fully acetylated to methyl 2,3,5-tri-O-acetyl-D-arabinofuranoside 2 and it was regio-
selectively deacetylated using enzymes. Rhizopus oryzae esterase gave methyl 3,5-di-O-acetyl-D-arabinofuranoside 3, regioselectively.
This protected 3 was deoxygenized to 3,5-di-O-acetyl-D-2-deoxyarabinofuranoside 7 using hypophosphorous acid.
Ó 2005 Elsevier Ltd. All rights reserved.
Carbohydrates containing polyhydroxyl groups are
inexpensive and have the important biological and phys-
ical functions. Their inherent stereochemistries have
been utilized to construct the applied molecular scaffolds
such as pharmaceuticals,1 surfactants2 and functional
polymers.3 But these compounds are difficult to manip-
ulate regioselectively because of their similar reactivities.
Thus selective protection/deprotection steps are needed,
conventionally.4 Methyl arabinofuranoside 1 and its C-2
functionalized analogue are useful for the synthesis of
polysaccharides such as arabinogalactan and lipoara-
binomannan.5 Especially, 2-deoxyarabinofuranoside
can be used as precursor for the synthesis of various
nucleosides as antiviral agent. To do this work, the C-
2deoxygenation of compound 1 should be performed
regioselectively. As estimated, there is no major product
as mono-deacetylation in case of using inorganic acids
or bases. Biocatalysts have been used to synthesize the
various organic compounds under the aqueous or non-
aqueous media6 and their reaction specificity can differ-
entiate the similar hydroxyl groups, regioselectively.
Wong and co-workers7 used hydrolases in the synthesis
of furanose, pyranose and other derivatives by the regio-
selective protection and deprotection method. This letter
was focused on the regioselective deacylation of mono-
5-di-O-acetyl-D-2-deoxyarabinofuranoside 7 as precur-
sor for the synthesis of chiral synthons.
To select ones for C-2selective deprotection of com-
pound 2, various enzymes were screened and these
hydrolyzed products 3, 4 and 5 were mixtures as pre-
sented in Table 1. At first, the blank test was tested in
the aqueous phosphate buffer solution (pH 7) without
enzyme. In this reaction, compound 2 was hydrolyzed
at C-2moderately although the reaction was long
(62h). In enzymatic reaction as Scheme 1, most of them
hydrolyzed it at the secondary alcohol C-2ester except
the lipase from Candida rugosa, which was acting at
the primary alcohol C-5 ester. These results might come
from the favourable substrate–enzyme complex8 in addi-
tion to the result of blank test. Pig liver esterase com-
pletely hydrolyzed it within 1 h and C-2hydrolyzed
compound 3 was obtained at 70%. For our purpose,
esterases from Rhizopus oryzae, pig liver and lipases
from hog pancreas and R. oryzae were adequate. But
Table 1. Distributions of product from hydrolysis of compound 2
Enzyme
Reaction
time (h)
2
(%) (%) (%) (%)
3
4
5
Rhizopus oryzae lipase (LRO)
Candida rugosa lipase (CRL)
Pig liver esterase (PLE)
Hog pancreas lipase (HPL)
Wheat germ lipase (LWG)
Rhizopus niveus lipase (LN)
Rhizopus oryzae esterase (ERO)
Blank
38
13
1
3253
6
1
2
saccharide, 2,3,5-tri-O-acetyl-D-arabinofuranoside
2
1
70
44
33
17
86
279
26
9
using biocatalysts and the product 3,5-di-O-acetyl-D-
arabinofuranoside 3 was chemically transformed to 3,
—
25
51
69
4
3
3
—
—
1
0.5
83
7
7
3
Keywords: Arabinose; 2-Deoxyarabinofuranoside; Enzyme; Resolution.
*
3
Corresponding author. Tel.: +820295 85153; fax: +820295 85189;
e-mail: c2496@kist.re.kr
6274
9
5
3
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.120

5064
S. J. Jun et al. / Tetrahedron Letters 46 (2005) 5063–5065
OH
HO
O
OMe
OH
1
Pyridine / (Ac)2O
OAc
AcO
OAc
OH
OAc
Enzyme, 30 oC
AcO
+
AcO
HO
+
O
O
O
O
OMe
pH 7, phosphate buffer
OMe
OMe
OMe
OAc
OH
OAc
OAc
2
5
3
4
Scheme 1. Enzymatic deacetylation of 2,3,5-tri-O-acetyl-D-arabinofuranoside 2.
the reaction rate of two lipases were relatively low and
gave the unwanted by-products 4 and 5. Therefore, the
two esterases from R. oryzae and pig liver were confined
to optimize the reaction condition.
the 3,5-di-O-acetyl-D-arabinofuranoside 3. This is a pro-
tected precursor for the 2-deoxygenized compound 7.
Scheme 2 shows the procedure to synthesize compound
7 by free radical deoxygenation. The original method
was developed by Barton and McCombie9 and many
other researches have modified it. Generally, in this
reaction, tri-n-butyltin hydride (nBu3SnH) was used as
the reducing agent. But in our substrate 3, the resulted
major product was methyl 2,3,5-tri-O-acetyl-2-O-butyl-
D-arabinofuranoside by n-butyl group transfer from
nBu3SnH. Thus we used hypophosphorous acid instead
of tin derivative.10
During the investigation, the solvent effect was highly
critical to obtain the C-2deacetylated compound 3.
We used the solvents as additive and the composition
was 9/1 (aqueous phosphate buffer/organic solvent).
The results from using the various solvents are shown
in Table 2. In most solvents, compound 3 was obtained
predominantly by ERO and PLE. Especially, in dimeth-
ylsulfoxide, n-hexane and t-butanol, the esterase ERO
almost gave compound 3.
The coupling reaction between compound 3 and 1,10-
thiocarbonyldiimidazole occurred smoothly under the
1,2-dichloroethane reflux and nitrogen atmosphere as
shown in Scheme 2. There were no side products and
Therefore, we used the aqueous buffer solution/dimethyl
sulfoxide (9/1) as solvent and R. oryzae esterase to get
Table 2. Solvent effects on hydrolysis of 2,3,5-tri-O-acetyl-D-arabinofuranoside 2 by ERO and PLE
Solventa
2 (%)
3 (%)
4 (%)
5 (%)
ERO
PLE
ERO
PLE
ERO
PLE
ERO
PLE
Dimethyl sulfoxide
N,N-Dimethyl formamide
t-Butanol
—
100
94.6
88.4
75
—
0.9
—
0.9
2.7
0.8
—
—
—
1.7
6.7
4.3
53.5
59.5
7.6
38.1
37.9
15.6
1.1
Acetone
91.276.7
8.7
88.5
—
—
6
—
.7
12
Tetrahydrofuran
Methylene chloride
n-Hexane
89.1
2.5
20.9
55.1
—
69.4
—
0.8
2.3
0.9
28.2
—
0.8
5.2
6
3.7
63.6
93.274.4
33
14.2 —
—
Only buffer solution
90.1
0.7
4.8
—
1.3
a Solvent was used as additive (9/1 = aqueous buffer solution/organic solvent).
S
N
N
OH
O
AcO
AcO
O
O
1.1'-thiocarbonyldiimidazole
1,2-dichloroethane / reflux
OMe
OMe
OAc
OAc
3
6
H3PO2, trimethylamine
1,2-dimethoxyethane / AIBN
reflux
HO
AcO
O
O
aqueous NaOH / methanol
OMe
OMe
OH
OAc
7
8
Scheme 2. 2-Deoxygenation of the protected compound 3.

S. J. Jun et al. / Tetrahedron Letters 46 (2005) 5063–5065
5065
7. (a) Hennen, W. J.; Sweers, H. M.; Wang, Y. F.; Wong, C.
H. J. Org. Chem. 1988, 53, 4939–4945; (b) Terreni, M.;
Salvetti, R.; Linati, L.; Fernandez-Lafuente, R.; Fernan-
dez-Lafuente, G.; Bastida, A.; Guisan, J. M. Carbohydr.
Res. 2002, 337, 1615–1621; (c) Khan, R.; Gropen, L.;
Konowicz, P. A.; Matulova, M.; Paoletti, S. Tetrahedron
Lett. 1993, 34, 7767–7770.
8. (a) Grochulski, P.; Bouthillier, F.; Kazlauskas, R. J.;
Serreqi, A. N.; Schrag, J. D.; Ziomek, E.; Cygler, M.
Biochemistry 1994, 33, 3494–3500; (b) Tuomi, W. V.;
Kazlauskas, R. J. J. Org. Chem. 1999, 64, 2638–2647; (c)
Goj, O.; Annegret, A.; Haufe, G. Tetrahedron: Asymmetry
1997, 8, 399–408.
9. Barton, D. H.; McCombie, S. W. J. J. Chem. Soc., Perkin
Trans. 1 1975, 1574–1585.
10. (a) Takamatsu, S.; Katayama, S.; Hirose, N.; Naito, M.;
Izawa, K. Tetrahedron Lett. 2001, 42, 7605–7608; (b)
Mathe, C.; Imbach, J. L.; Gosselin, G. Carbohydr. Res.
2000, 323, 226–229.
the purified product 6 was obtained in 90% yield as a
syrup. This protected product was subjected to radical
deoxygenation. Compound 6 and trimethylamine in
dimethoxyethane were stirred and 50% aqueous hypo-
phosphorous acid was added. The reaction mixture
was heated until reflux, then a,a0-azobisisobutyronitrile
(AIBN) in dimethoxyethane was added dropwise in
three portions. After 2h, the starting material disap-
peared completely.11 This method was free of methyl
2,3,5-tri-O-acetyl-2-O-butyl-D-arabinofuranoside and
the work-up procedure, and the yield was up to 60%.
Finally, this compound 7 was hydrolyzed to compound
8 quantitatively and identified with the reported
spectral data.
In conclusion, we obtained the protected 2-D-deoxy-
ribose from naturally abundant D-arabinose as moderate
yield. D-Arabinose was chemically transformed to
methyl 2,3,5-tri-O-acetyl-D-arabinofuranoside 2 and C-
2regioselective deacetylation was performed using
R. oryzae esterase. This enzyme showed very high regio-
selectivity and 2-deacetylated product was obtained
quantitatively as compound 3. Finally, it was deoxyge-
nized by free radical reaction and the products 7 and 8
will be on going to prepare nucleoside antiviral agents
and chiral drug intermediates.
11. (a) Synthesis of compound 6: A solution of methyl 2,3-di-
O-acetyl-D-arabinofuranoside 3 (100 mg, 0.4 mmol) and
1.10-thiocarbonyldiimidazole (140 mg, 0.81 mmol) in
anhydrous 1,2-dichloroethane (3 ml) was refluxed under
nitrogen atmosphere for 3 h. After cooling to room
temperature, the solvent was removed under the reduced
pressure. The residue was chromatographed on a column
of silica gel with a stepwise gradient of ethyl acetate/n-
22
hexane to give compound 6 as a syrup (130 mg, 90%). ½aꢀD
1
+56.9 (c 0.93, CHCl3); H NMR (CDCl3): d 2.07 (s, 3H),
2.15 (s, 3H), 3.46 (s, 3H), 4.26–4.32 (m, 2H), 4.47–4.51 (m,
1H), 5.16 (s, 1H), 5.21–5.23 (m, 1H), 5.69 (d, 1H,
J = 1.32Hz), 7.05–7.06 (m, 1H), 7.61–7.62 (m, 1H); 13C
NMR d 20.6, 20.7, 55.1, 62.8, 76.3, 80.2, 88.7, 105.8, 117.9,
131.1, 136.9, 170, 170.5; (b) Synthesis of compound 7: To
a solution of compound 6 (50 mg, 0.14 mmol) in dimeth-
oxyethane (2.5 ml) were added triethylamine (0.23 ml,
1.7 mmol) and 50% aqueous hypophosphorous acid
(0.15 ml, 1.4 mmol). The reaction mixture was refluxed
with heating and AIBN (14 mg, 0.08 mmol) dissolved in
dimethoxyethane (1.5 ml) was added in three portions.
After stirring for 2h at reflux, the reaction mixture was
cooled to room temperature. The organic layer was
concentrated under the reduced pressure and the residue
was chromatographed on a column of silica gel with an
eluent solvent ethyl acetate/n-hexane to give compound 7
Acknowledgements
This work was supported by a grant of Ministry of
Science and Technology.
References and notes
1. Patel, R. N. Enzyme Microb. Technol. 2002, 31, 804.
2. Weingarten, S.; Theim, J. Org. Biomol. Chem. 2004, 2, 962.
3. Milkereit, G.; Morr, M.; Theim, J.; Vill, V. Chem. Phys.
Lipids 2004, 127, 47.
4. Sureshan, K. M.; Shashidhar, M. S.; Praveen, T.; Das, T.
Chem. Rev. 2003, 103, 4477–4504.
5. (a) Cociora, O. M.; Lowary, T. L. Tetrahedron 2004, 60,
1481–1489; (b) Lowary, T. L. Curr. Opinion in Chem. Biol.
2003, 7, 749–756.
6. Koskinen, A. M. P.; Klivanov, A. M. Enzymatic Resolu-
tions in Organic Media; Blackie: London, 1996, p 140.
24
as syrup (82mg, 60%). ½aꢀD +121 (c 0.4, CHCl3); 1H NMR
(CDCl3): d 1.96–2.02 (m, 1H), 2.07 (s, 6H), 2.33–2.42 (m,
1H), 3.37 (s, 3H), 4.16 (dd, 1H, J = 4.7, 11.4 Hz), 4.92(s,
1H), 5.03 (m, 1H), 5.10 (m, 1H); 13C NMR d 20.8, 21.0,
39.0, 55.1, 63.9, 73.9, 80.5, 104.9, 170.6, 170.9.