An efficient chemoenzymatic route to methyl 4-O-benzyl-2,3-anhydro-β- D-lyxopyranoside from methyl β-D-xylopyranoside

Article abstract of DOI:10.1016/j.carres.2003.10.005

Methyl 4-O-benzyl-2,3-anhydro-β-D-lyxopyranoside, an intermediate for the preparation of methyl β-D-xylopyranoside derivatives modified at C-2, was obtained in five steps in 58% yield. The synthetic sequence starts from methyl β-D-xylopyranoside through two main steps involving regioselective enzymatic acetylation and deacetylation catalyzed by lipase PS.

Full text of DOI:10.1016/j.carres.2003.10.005

Carbohydrate
RESEARCH
Carbohydrate Research 339 (2004) 425–428
Note
An efficient chemoenzymatic route to methyl 4-O-benzyl-2,3-
-lyxopyranoside from methyl b-
anhydro-b-
D
D
-xylopyranoside
a
b
Maria Mastihubova, Vladimır Mastihuba and Peter Biely
ꢀ
ꢀ a,*
ꢀ
aInstitute of Chemistry, Slovak Academy of Sciences, Duꢀbravskaꢀ cesta 9, SK-845 38 Bratislava, Slovakia
bFaculty of Chemical and Food Technology, Slovak University of Technology, SK-812 37 Bratislava, Slovakia
Received 5 September 2003; accepted 9 October 2003
Abstract—Methyl 4-O-benzyl-2,3-anhydro-b-
D
-lyxopyranoside, an intermediate for the preparation of methyl b-
D
D
-xylopyranoside
-xylopyranoside
derivatives modified at C-2, was obtained in five steps in 58% yield. The synthetic sequence starts from methyl b-
through two main steps involving regioselective enzymatic acetylation and deacetylation catalyzed by lipase PS.
ꢀ 2003 Elsevier Ltd. All rights reserved.
Keywords: 2,3-Anhydropyranosides; Lipase PS; Regioselective acetylation; Regioselective deacetylation
2,3-Anhydropentopyranoside derivatives find wide ap-
plication in the synthesis of modified pentopyranoside
compounds due to easy regioselective opening of
the epoxide functionality by various nucleophiles.1
Recently, the interest in modified or regioselectively
requires four steps, which means that the preparation of
2 from 3 involves eight steps.
Use of lipases for the regioselective acylation or de-
acylation of carbohydrate hydroxyl groups at a pre-
parative scale begins to be a standard protection or
deprotection method in carbohydrate chemistry.7 In our
literature search, we have found lipase PS-30 (from
Burkholderia cepacia) to be a very convenient enzyme
capable to operate regioselectively at OH-3 or OH-4 of
xylopyranoside compounds.8;9 Moreover, it is relatively
stable in a large variety of organic solvents and is re-
usable repeatedly for several times.
acylated b-D-xylopyranosides increased due to the de-
velopment of studies focused on substrate specificity and
mode of action of acetylxylanesterases2;3 or xylanases.4
Methyl 2,3-anhydro-b-
methyl 4-O-benzyl-2,3-anhydro-b-
(Fig. 1) are convenient starting materials for the prep-
aration of b- -xylopyranoside derivatives modified at
D
-ribopyranoside (1)5 and
D
-lyxopyranoside (2)
D
C-3 or C-2, respectively. Recently, we have reported a
four-step synthesis of 2 from 1.6 However, the prepa-
In this note, we report a short and efficient chemo-
enzymatic synthesis of methyl 4-O-benzyl-2,3-anhydro-
ration of 1 from methyl b-
D
-xylopyranoside (3) still
b-
D
-lyxopyranoside (2) from the readily available
-xylopyranoside (3). As illustrated in Scheme 1,
methyl b-
D
our route to 2 begins with the known regioselective en-
zymatic O-diacetylation of 3 by lipase PS-30 (Amano).9
We have slightly modified this step by the use of t-BuOH
as a reaction medium instead of the toxic acetonitrile
and in order to increase the solubility of the starting
compound and the rate of the reaction. After 48 h of
shaking, the 3,4-diacetate 4 was formed in 87% yield as
the only diacetylated product. We did not observe any
formation of the corresponding triacetate. Treatment
of 4 with p-toluenesulfonyl chloride in pyridine pro-
vided the C-2-tosylate 5, which was easily purified by
Figure 1. Key anhydropentopyranoside derivatives for the synthesis of
modified pentopyranosides.
* Corresponding author. Tel.: +4212-59410-246; fax: +4212-59410-
222; e-mail: chemjama@savba.sk
0008-6215/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2003.10.005

426
M. Mastihubovꢀa et al. / Carbohydrate Research 339 (2004) 425–428
Scheme 1. Reagents and conditions: (a) Lipase PS-30, vinyl acetate, t-BuOH, 87%; (b) TsCl, Pyr, rt, 88%; (c) Lipase PS-30, toluene, n-BuOH, 89%;
(d) BnOCNHCCl3, CF3SO3H, rt, 91%; (e) NaOCH3, CH3OH, 93%.
crystallisation from ethanol (88%). The key step of this
synthetic sequence is the regioselective deacetylation at
OH-4 of 5 by enzymatic alcoholysis. Fortunately,
treatment of 5 with lipase PS in toluene in the presence
of n-butanol afforded only the 4-O-deacetylated product
6 in high yield, the tosylated group remaining intact.
Mild benzylation of OH-4 of 6 was successfully achieved
with benzyl trichloroacetimidate10 in the presence of
trifluoromethanesulfonic acid giving 7 in 91% isolated
yield. The introduction of a stable benzyl group at C-4
avoids further epoxide-ring migration and formation of
1H spectra were recorded at 300 MHz with a Bruker AM
300 spectrometer and chemical shifts are referred to
Me4Si as internal standard. 13C NMR spectra were re-
corded in CDCl3 at 75 MHz and shifts are referred to
internal CDCl3. Microanalyses were performed with a
Fisons EA 1108 analyzer.
1.2. Methyl 3,4-di-O-acetyl-b-D-xylopyranoside (4)
Vinyl acetate (11.2 mL, 122 mmol, 20 equiv), Lipase PS
ꢁ
(9 g) and 4 A molecular sieves (8 g) were added to a soln
an equilibrium between the
isomerisation product -arabino-3,4-epoxide in solu-
tion. The preparation of methyl 2,3-anhydro-4-O-ben-
zyl-b- -lyxopyranoside (2) was accomplished in 93%
yield by the treatment of tosylate 7 with sodium meth-
oxide in methanol and simultaneous deacetylation.
In summary, we report an efficient and straight-
forward chemoenzymatic synthesis of methyl 4-O-
D
-lyxo-2,3-epoxide and its
of 3 (1 g, 6.1 mmol) in t-BuOH (150 mL). The reaction
mixture was shaken at 40 ꢁC and 200 rpm for 48 h. The
reaction was stopped by filtration of lipase, which was
repeatedly used for about 4 another times in the same
reaction. The filtrate was concentrated and the residue
was purified by column chromatography (1:2 toluene–
EtOAc) to give 4 as white solid, which was washed with
D
D
diethyl ether (1.32 g, 87%): mp 113–114 ꢁC (from
20
EtOAc); ½aꢀ )29 (c 1.0, CHCl3); lit.9 mp 110 ꢁC (tran-
benzyl-2,3-anhydro-b-
D
-lyxopyranoside (2) from methyl
D
b- -xylopyranoside (3). The preparation involves two
D
sition temperature) fi 120 ꢁC; ½aꢀ )32 (c 1.0, CHCl3);
D
main steps catalyzed by the same lipase but under dif-
ferent reaction conditions, that is regioselective 3,4-O-
diacetylation of 3 and regioselective 4-O-deacetylation
of 5. The epoxide 2 is obtained in 58% overall yield from
3 in five steps.
1H NMR (CDCl3): d 2.05 (s, 3H, COCH3), 2.10 (s, 3H,
COCH3), 2.53 (d, 1H, JH–OH;H-2 3.5 Hz, H–OH), 3.34
(dd, 1H, J4;5a 9.4, J5a;5b 11.7 Hz, H-5a), 3.51 (ddd, J1;2
7.1 Hz, J2;3 8.9 Hz, H-2), 3.54 (s, 3H, OCH3), 4.09 (dd,
1H, J4;5b 5.3 Hz, H-5b), 4.25 (d, H-1), 4.94 (dt, 1H, J3;4
8.9 Hz, H-4), 5.09 (t, 1H, H-3). Anal. calcd for
C10H16O7: C, 48.39; H, 6.50. Found: C, 48.35; H, 6.88.
1. Experimental
1.3. Methyl 3,4-di-O-acetyl-2-O-tosyl-b-D-xylopyrano-
side (5)
1.1. General methods
Solvents were distilled in the presence of appropriate
drying agents before use. Lipase PS-30 was a gift from
Amano (Japan). Methyl b-D-xylopyranoside was pur-
Diacetate 4 (4.92 g, 19.8 mmol) was dissolved in pyridine
(30 mL) in the presence of a catalytic amount of 4-
dimethylaminopyridine (0.5 g). p-Toluenesulfonyl chlo-
ride (5.73 g, 30 mmol) was added at 0 ꢁC and the mixture
was stirred at room temperature. After 72 h, the soln
was poured on ice (30 g) and the crude precipitate was
crystallised from 95% EtOH (7.0 g, 88%): mp 152–
chased from a commercial source (Lachema). All reac-
tions were monitored by TLC on Silica Gel 60 (0.25 mm,
E. Merck). Compounds were detected with 1% orcinol
in a 10% (v/v) ethanolic soln of H2SO4. Column chro-
matography was performed on Silica Gel 60 (100–
160 lm). Melting points were determined on a Kofler
hot stage and are uncorrected. Optical rotations were
measured with a Perkin–Elmer 241 polarimeter at 20 ꢁC.
20
1
153 ꢁC; ½aꢀ )24 (c 1.0, CHCl3); H NMR (CDCl3): d
D
2.02 (s, 3H, COCH3), 2.03 (s, 3H, COCH3), 2.44 (s, 3H,
CH3), 3.27 (s, 3H, OCH3), 3.32 (dd, 1H, J4;5a 9.0, J5a;5b
11.8 Hz, H-5a), 4.08 (dd, 1H, J4;5b 5.2 Hz, H-5b), 4.30

M. Mastihubovꢀa et al. / Carbohydrate Research 339 (2004) 425–428
427
(d, J1;2 6.9 Hz, H-1), 4.52 (dd, J2;3 8.9 Hz, H-2), 4.93 (dt,
1H, J3;4 8.8 Hz, H-4), 4.94 (t, 1H, H-3), 7.32 (d, 2H, J
8.1 Hz, H-30,50), 7.78 (d, 2H, J 8.3 Hz, H-20,60); 13C
NMR (CDCl3): d 20.7 (2 · COCH3), 21.6 (CH3), 56.8
(OCH3), 62.2 (C-5), 69.0 (C-4), 70.8 (C-3), 77.9 (C-2),
101.5 (C-1), 2 · 128.00, 2 · 129.5, 134.3, 144.7 (C–Ar),
169.8 (COCH3), 169.9 (COCH3). Anal. calcd for
C17H22O9S: C, 50.74; H, 5.51; S, 7.97. Found: C, 50.87;
H, 5.77; S, 8.18.
4.44 (dd, J2;3 9.3 Hz, H-2), 4.56 (s, 2H, CH2), 5.21 (t, 1H,
H-3), 7.24–7.34 (m, 7H, H–Ph, H-30,50), 7.76 (d, 2H, J
8.3 Hz, H-20,60); 13C NMR (CDCl3): d 20.8 (COCH3),
21.6 (CH3), 56.9 (OCH3), 63.7 (C-5), 72.7 (C-3), 73.0
(CH2), 75.2 (C-4), 78.7 (C-2), 101.8 (C-1), 127.7, 128.0,
128.5, 129.4, 129.6 (7 · CH–Ar), 134.5, 137.5, 144.5
(3 · C–Ar), 169.9 (COCH3). Anal. calcd for C22H26O8S:
C, 58.66; H, 5.82; S, 7.12. Found: C, 58.55; H, 6.12;
S, 7.10.
1.6. Methyl 4-O-benzyl-2,3-anhydro-b-D-lyxopyranoside
(2)
1.4. Methyl 3-O-acetyl-2-O-tosyl-b-D-xylopyranoside (6)
Compound 5 (1 g, 2.5 mmol) was dissolved in toluene
(100 mL), then n-BuOH (0.8 mL) and Lipase PS (5 g)
were added. The reaction mixture was shaken at 40 ꢁC
and 200 rpm until complete disappearance of 5 (about
4–5 days). The reaction was stopped by filtration of the
lipase. The regenerated lipase was used for the same
reaction for another two or three runs. The solvent was
eliminated under diminished pressure and the product was
separated from the starting compound (about 5%) by
column chromatography (2:1 toluene–EtOAc) to give 6
The soln of 7 (2.50 g, 5.6 mmol) in 0.7 M sodium meth-
oxide (22 mL) was stirred overnight at room tempera-
ture. It was then neutralised with 1 M H2SO4 and the
product was extracted with CH2Cl2 (3 · 40 mL). The
organic layer was washed twice with water, dried over
Na2SO4 and concentrated under diminished pressure.
The crude syrup was purified by column chromatogra-
phy (2:1 toluene–EtOAc) to afford epoxide 2 (1.23 g,
20
1
93%) as a colourless oil: ½aꢀ )77 (c 1.0, CHCl3); H
D
NMR (CDCl3): d 3.33 (ddd, 1H, J2;3 3.7, J3;4 1.9 Hz, H-
3), 3.37 (t, 1H, J1;2 2.9 Hz, H-2), 3.46 (s, 3H, OCH3), 3.59
(dt, 1H, J4;5a 3.1, J3;5a 1.6, J5a;5b 12.1 Hz, H-5a), 3.76–3.78
(m, 1H, H-4), 3.80 (dd, 1H, J4;5b 2.1 Hz, H-5b), 4.67 (dd,
2H, CH2), 4.93 (d, 1H, H-1), 7.29–7.37 (m, 5H, H–Ph);
13C NMR (CDCl3): d 50.5 (C-3), 51.5 (C-2), 55.8
(OCH3), 58.6 (C-5), 70.4 (C-4), 72.0 (CH2), 94.9 (C-1),
2 · 127.9, 128.1, 2 · 128.6, 137.6 (C–Ph). Anal. calcd for
C13H16O4: C, 66.09; H, 6.83. Found: C, 65.67; H, 6.97.
as a colourless oil, which precipitated in diethylether as a
20
white solid (0.8 g, 89%): mp 108–110 ꢁC; ½aꢀ )27 (c 1.0,
D
CHCl3); 1H NMR (CDCl3): d 2.10 (s, 3H, COCH3), 2.44
(s, 3H, CH3), 2.74 (d, 1H, JH–OH;H-4 5.9 Hz, H–OH), 3.25
(s, 3H, OCH3), 3.30 (dd, 1H, J4;5a 9.4, J5a;5b 11.8 Hz, H-
5a), 3.79 (m, 1H, H-4), 4.03 (dd, 1H, J4;5b 5.2 Hz, H-5b),
4.28 (d, J1;2 7.1 Hz, H-1), 4.49 (dd, J2;3 8.9 Hz, H-2), 4.94
(t, 1H, J3;4 8.8 Hz, H-3), 7.32 (d, 2H, J 8.1 Hz, H-30,50),
7.79 (d, 2H, J 8.3 Hz, H-20,60); 13C NMR (CDCl3): d 20.8
(COCH3), 21.6 (CH3), 56.8 (OCH3), 65.1 (C-5), 68.9 (C-
4), 75.1 (C-3), 78.0 (C-2), 101.6 (C-1), 2 · 127.9,
2 · 129.4, 134.6, 144.6 (C–Ar), 171.8 (COCH3). Anal.
calcd for C15H20O8S: C, 49.99; H, 5.59; S, 8.90. Found:
C, 50.35; H, 5.95; S, 8.76.
Acknowledgements
This work was supported by a grant from the Slovak
Grant Agency for Science VEGA 2/3079/23. The au-
ꢂ
ꢀ
ꢂ
ꢀ
thors thank A. Karovicova, G. Kosicky, J. Tonka and
K. Paule for NMR spectra, optical rotation measure-
ments, and microanalyses.
1.5. Methyl 3-O-acetyl-4-O-benzyl-2-O-tosyl-b-D-xylo-
pyranoside (7)
Compound 6 (3.6 g, 10 mmol) and benzyl trichloroace-
timidate (3.72 mL, 20 mmol) were dissolved in dry 2:1
cyclohexane–CH2Cl2 (90 mL). After cooling to )5 ꢁC,
trifluoromethanesulfonic acid (0.44 mL, 5 mmol) was
added slowly and the reaction mixture was stirred for 3 h
under N2 at room temperature. Then CH2Cl2 (200 mL)
was added and the soln was washed with aq saturated
NaHCO3, dried over MgSO4 and evaporated. The crude
oil was chromatographed (1:0 fi 5:1 toluene–EtOAc) to
obtain a slowly solidifying product 7 (4.10 g, 91%): mp
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