A common access to 2- and 3-substituted methyl β-D-xylopyranosides

Article abstract of DOI:10.1016/S0040-4039(01)01957-8

2-Deoxy-, 3-deoxy-, 2-deoxy-2-fluoro- and 3-deoxy-3-fluoro- derivatives of methyl β-D-xylopyranoside diacetates were prepared by a new common route via 2,3-anhydropentosides. The stereo- and regioselective introduction of fluorine or hydrogen was accompli

Full text of DOI:10.1016/S0040-4039(01)01957-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 9065–9067
A common access to 2- and 3-substituted methyl
b- -xylopyranosides
D
Ma´ria Mastihubova´* and Peter Biely
Institute of Chemistry, Slovak Academy of Sciences, 842 38 Bratislava, Slovakia
Received 27 September 2001; accepted 17 October 2001
Abstract—2-Deoxy-, 3-deoxy-, 2-deoxy-2-fluoro- and 3-deoxy-3-fluoro- derivatives of methyl b-
prepared by a new common route via 2,3-anhydropentosides. The stereo- and regioselective introduction of fluorine or hydrogen
was accomplished by epoxide ring opening of methyl 2,3-anhydro-b- -ribopyranoside and methyl 2,3-anhydro-4-O-benzyl-b-
lyxopyranoside. Methyl 2,3-anhydro-4-O-benzyl-b- -lyxopyranoside was originally obtained in three simple steps from readily
available methyl 2,3-anhydro-4-O-benzyl-b- -ribopyranoside. © 2001 Elsevier Science Ltd. All rights reserved.
D-xylopyranoside diacetates were
D
D-
D
D
Acetylxylan esterases (EC 3.1.1.72, AcXEs) are microbial
enzymes which deacetylate partially acetylated 4-O-
etates in which the formation of hypothetical 2,3-ortho-
ester intermediate is eliminated. Such analogues include,
e.g. 2-deoxy-, 3-deoxy-, 2-deoxy-2-fluoro- and 3-deoxy-3-
methyl-
Previous investigations of the mode of action of AcXEs
using diacetates of methyl b-
-xylopyranosides1,2
D-glucuronoxylan, the major plant hemicellulose.
fluoro- derivatives of methyl b-D-xylopyranoside diacet-
D
ates. These compounds also will be useful to evaluate the
role of OH-groups at positions 2 and 3 in the enzyme–
substrate interactions.
showed that AcXEs deacetylate efficiently positions 2
and 3 if the adjacent OH-group is non-esterified. These
results led to the hypothesis that deacetylation of posi-
tions 2 and 3 involves a common ortho-ester intermediate
in which the acetyl group is loosely bound to both
OH-groups. The verification of the hypothesis requires
There are many synthetic methods for preparation of
differently substituted deoxy3 and deoxy-fluoro4 deriva-
tives of carbohydrates. All of them require a variety of
different suitably protected starting compounds.
substrate analogues of methyl b-
D
-xylopyranoside diac-
O
O
OCH3
OCH3
a
BnO
HO
O
O
2
1
b
O
O
+
BnO
AcO
BnO
OCH3
OCH3
HO
OH
OAc
3b
3a
c, d
O
OCH3
BnO
O
4
Scheme 1. Reagents and conditions: (a) BnBr, NaH, THF, rt, 2.5 h, 88%; (b) CH3COONa (10 equiv.), CH3COOH, 140°C, 3 h,
91% 3a+3b (66% for 3a); (c) TsCl, Py, rt, 48 h; (d) 0.7 M MeONa/MeOH, rt, overnight, (87% from 3a).
Keywords: epoxide ring opening; regioselectivity; reduction; hydrofluorination; acetylxylan esterase.
* Corresponding author. Tel.: +421 2 59410239; fax: +421 2 59410222; e-mail: chemjama@savba.sk
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01957-8

9066
M. Mastihubo6a´, P. Biely / Tetrahedron Letters 42 (2001) 9065–9067
The epoxide ring opening of anhydroglycosides as ver-
satile intermediates for reactions with a wide range of
nucleophiles, is a well-established reaction. Factors
leading to stereo- and regioselectivity in carbohydrate
epoxide ring opening have been frequently investigated.
Usually, the trans-diaxial opening products are formed
exclusively (the Fu¨rst–Plattner rule).
We further investigated the possibility of transforming
the new methyl 2,3-anhydro-4-O-benzyl-b- -lyxopyran-
oside (4) into corresponding -xylopyranosides substi-
tuted at position 2. The reduction under the same
conditions as for -ribo-2,3-epoxide 1 was not so
straightforward and afforded -xylo and -arabino
D
D
D
D
D
products in the proportion 1.8:1 (Table 1). After
column chromatography on silica gel methyl 4-O-ben-
Here we report the synthesis of diacetates of methyl
zyl-2-deoxy-b-
D
-threo-pentopyranoside (7a) and methyl
b-D-xylopyranoside substituted at positions 2 and 3 by
4-O-benzyl-3-deoxy-b-
D
-erythro-pentopyranoside (7b)
hydrogen or fluorine. The derivatives were synthesized
by routes that involve regioselective nucleophilic epox-
ide ring opening in 2,3-anhydropentoside 1 and 4. The
were obtained in 53 and 29% yield, respectively. When
epoxide 4 was treated by Bu4N+H2F3 /KHF2 under the
−
SL–PTC conditions, the product of elimination 911 was
methyl 2,3-anhydro-b-
prepared by slight modification of an already reported
synthesis from
-arabinose5 and, after 4-O-benzyla-
tion,6 it was transformed in three steps into a methyl
2,3-anhydro-4-O-benzyl-b-
-lyxopyranoside (4)7 (Scheme
1). The key step of this transformation was the epoxide
ring opening of 4-O-benzylated -ribo-2,3-epoxide 2 to
D
-ribopyranoside (1) was readily
isolated from the reaction mixture in the highest yield
(56%, Fig. 1). Its precursor, 3-deoxy-3-fluoro-b-
arabinopyranoside 8b, was obtained in 15% yield and
the desired 2-deoxy-2-fluoro-b- -xylopyranoside 8a in
D-
D
D
D
only 6% yield. Hydrofluorination of 4 with KHF2 in
ethane-1,2-diol at 180°C also showed a lower degree of
regioselectivity, but satisfactorily afforded 2-deoxy-2-
D
3-acetate 3a by sodium acetate in acetic acid at 130°C.
The reaction proceeded with high regioselectivity
because only xylosides 3a and 3b were formed (91%
overall chemical yield). Due to the acetyl migration
caused by high reaction temperature and by the pres-
ence of acetic acid, only 66% of 3-acetate 3a was
fluoro-b- -xylopyranoside 8a (36%), which is inaccessi-
D
ble using the DAST method due to the occurrence of
side reactions at the glycosidic bond (Scheme 2).4,12
Compounds 7a and 8a were debenzylated by catalytic
hydrogenation (Pd/C) and the resulting deoxy- and
deoxy-fluoro-b-D-xylopyranosides were eventually per-
O-acetylated to afford the desired AcXE substrates.
isolated.
D
-lyxo-2,3-Epoxide 4 was obtained after tosy-
lation of 3a and alkaline treatment in 87% yield. The
4-O-benzyl group of 4 avoids the possibility of equi-
librium of the first produced
the -arabino-3,4-epoxide formed by epoxide migra-
tion.
D-lyxo-2,3-epoxide with
D
In conclusion, efficient and simple parallel routes for
preparation of 2- or 3-deoxy and deoxy-fluoro deriva-
tives of methyl b-D-xylopyranosides from D-arabinose
In the next stage, the epoxides 1 and 4 were converted
to deoxy and deoxy-fluoro analogues 5, 6a, 7a and 8a8
by a regioselective epoxide opening in 2,3-anhydropen-
toside 1 and 4, either by reduction or hydrofluorina-
are described. This approach is applicable for prepara-
tion of different 2- or 3-derivatives of xylopyranosides
depending on used nucleophiles. The described com-
pounds are currently used as enzyme substrates to
elucidate the mechanisms of deacetylation by acetylxy-
lan esterases. Details of the synthesis and results of
biochemical studies will be reported in due course.
tion.
Previous
studies5b,6,9
indicated
that
D
-ribo-2,3-epoxide 1 or 2 could be regioselectively
transformed to 3-substituted xylopyranosides by prefer-
ential nucleophilic attack at position 3. As an extension
of these results, we observed that this reaction proceeds
regioselectively also with small nucleophiles like H− and
F− (Table 1). Reduction of 2,3-anhydro-b-
D
-ribopyran-
oside 1 by LiAlH4 in THF under room temperature
gave only methyl 3-deoxy-b- -erythro-pentopyranoside
5. When -ribo-2,3-epoxide 1 was hydrofluorinated
with Bu4N+H2F3 and KHF2 at 130°C under solid–liq-
uid PTC,10 the minor 2-deoxy-2-fluoro-b-
-arabinopy-
ranoside (6b) was isolated in a 6% yield beside 70%
O
D
BnO
OMe
OH
D
−
9
D
yield of the desired 3-deoxy-3-fluoro-b-
D
-xylopyran-
Figure 1. The structure of isolated major eliminated product
9.
osides 6a (Table 1).
Table 1. The yields of products resulting from the epoxide ring opening of 1 and 4
Epoxide
Reaction condition
Product yields (%)
Ratio of products xylo/arabino
1
1
4
4
4
a
b
a
b
c
5 (74)
6a (70)
7a (53)
8a (6)
–
1/0
11.7/1
6b (6)
7b (29)
8b (15)
8b (35)
1.8/1
a
8a (36)
1/1
a The elimination reaction product 9 was isolated in 56%.

M. Mastihubo6a´, P. Biely / Tetrahedron Letters 42 (2001) 9065–9067
9067
O
HO
a
OCH3
OCH3
O
OH
OCH3
5
b
HO
O
F
O
O
+
HO
HO
1
OCH3
F
OH
6a
6b
OH
HO
O
O
+
BnO
HO
BnO
BnO
OCH3
OCH3
OCH3
c
O
OCH3
7a
7b
d
BnO
O
4
HO
O
F
O
+
BnO
HO
OCH3
8a
8b
F
−
Scheme 2. Reagents and conditions: (a) LiAlH4, THF, rt, 40 h; (b) n-Bu4N+H2F3 (3 equiv.), KHF2 (6 equiv.), 130°C, 12 h; (c)
KHF2, (HOCH2)2, 180°C, 3 h.
Acknowledgements
6.1 Hz, H-2), 3.85 (ddd, J4,5b 4.1 Hz, H-4), 3.95 (ddd,
H-5b), 4.36 (d, H-1). 6a (1H NMR, 300 MHz, CDCl3): l
2.42 (bs, 1H, OH), 2.58 (bs, 1H, OH), 3.30 (dd, 1H, J4,5a
9.4, J5a,5b 11.6 Hz, H-5a), 3.55 (s, 3H, OCH3), 3.61 (ddd,
1H, J1,2 6.9, J2,3 7.9, J2,F 12.9 Hz, H-2), 3.88–4.00 (m, 1H,
H-4), 4.06 (ddd, 1H, J4,5b 5.6 Hz, J5b,F 5.8 Hz, H-5b),
4.22 (d, 1H, H-1), 4.38 (ddd, J3,4 8.1, J3,F 52.0 Hz). 7a
(1H NMR, 300 MHz, CDCl3): l 1.78 (dt, 1H, J1,2a=J2a,3
4.2, J2a,2b 14.1 Hz, H-2a), 2.27 (dt, 1H, J1,2b=J2b,3 3.5,
H-2b), 3.43 (s, 3H, OCH3), 3.36–3.45 (m, 1H, H-3), 3.58
(dd, 1H, J4,5a 3.6, J5a,5b 12.6 Hz, H-5a), 3.87 (dt, 1H, J3,4
4.2 Hz, H-4), 4.05 (dd, 1H, H-5b), 4.65 (dd, 2H, CH2),
4.72 (t, 1H, H-1), 7.29–7.37 (m, 5H, H-Ph). 8a (1H NMR,
300 MHz, CDCl3): l 3.06 (bs, 1H, OH), 3.23 (dd, 1H,
J4,5a 9.7, J5a,5b 11.7 Hz, H-5a), 3.41–3.57 (m, 1H, H-4),
3.52 (s, 3H, OCH3), 3.82 (ddd, 1H, J2,3 8.5, J3,4 8.4, J3,F
15.2 Hz, H-3), 3.94 (ddd, 1H, J4,5b 5.0 Hz, H-5b), 4.15
(ddd, 1H, J2,F 50.5 Hz, H-2), 4.34 (dd, 1H, J1,2 7.2, J1,F
3.7 Hz, H-1), 4.67 (dd, 2H, CH2), 7.35 (m, 5H, Ph).
9. (a) Petra´kova´, E.; Kova´c, P. Carbohydr. Res. 1982, 101,
141–147; (b) Wright, J. A.; Taylor, N. F. Carbohydr. Res.
1967, 3, 333–339; (c) Lugemwa, F. N.; Denison, L. J.
Carbohydr. Chem. 1997, 16, 1433–1443.
This work was supported by a grant from the Slovak
Grant Agency for Science VEGA 2-7136/20.
References
1. Biely, P.; Coˆte´, G. L.; Kremnicky´, L.; Greene, R. V.;
Dupont, C.; Kluepfel, D. FEBS Lett. 1996, 396, 257–260.
2. Biely, P.; Coˆte´, G. L.; Kremnicky´, L.; Greene, R. V.;
Tenkanen, M. FEBS Lett. 1997, 420, 121–124.
3. (a) Collins, P. M.; Ferrier, R. J. Monosaccharides: Their
Chemistry and Their Roles in Natural Products; John
Wiley
& Sons: Chichester, 1995; pp. 206–217; (b)
Kirschning, A.; Jesberger, M.; Scho¨ning, K.-U. Synthesis
2001, 507–540; (c) Marzabadi, C. H.; Franck, R. W.
Tetrahedron 2000, 56, 8385–8417.
4. Dax, K.; Albert, M.; Ortner, J.; Bernhard, J. P. Carbo-
hydr. Res. 2000, 327, 47–86.
5. (a) Hough, L.; Jones, J. K. N. J. Chem. Soc. 1952,
4349–4351; (b) Allerton, R.; Overend, W. G. J. Chem.
Soc. 1951, 1480–1484.
6. Kova´c, P.; Alfo¨ldi, J. Chem. Zvesti 1978, 32, 519–523.
7. 4 (1H NMR, 300 MHz, CDCl3): l 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).
10. (a) Landini, D.; Penso, M. Tetrahedron Lett. 1990, 31,
7209–7212; (b) Hager, M. W.; Liotta, D. C. Tetrahedron
Lett. 1992, 33, 7083–7086; (c) Lundt, I.; Albanese, D.;
Landini, D.; Penso, M. Tetrahedron 1993, 49, 7295–7300.
11. For 9: (1H NMR, 300 MHz, CDCl3): l 2.21 (d, J2,OH 9.1
Hz, H-OH), 3.54 (s, 3H, OCH3), 3.98 (dt, 1H, J3,5a 1.3,
J5a,CH 1.2, J5a,5b 15.2 Hz, H-5a), 4.15 (dt, 1H, J3,5b 1.3,
2
J5b,CH 1.4 Hz, H-5b), 4.31 (m, 1H, H-2), 4.66 (d, 1H, J1,2
2
8. All synthesized compounds gave satisfactory elemental
analyses and were characterized by NMR spectroscopy.
For example: 5 (1H NMR, 300 MHz, D2O): l 1.58 (dt,
1H, J2,3a=J3a,4 9.1, J3a,3b 12.8 Hz, H-3a), 2.26 (ddt,
3.6 Hz, H-1), 4.78 (dd, 2H, CH2), 4.84 (bd, 1H, J2,3 3.4
Hz, H-3), 7.29–7.37 (m, 5H, H-Ph).
12. (a) Ok, K.-D.; Takagi, Y.; Tsuchiya, T.; Umezawa, S.;
Umezawa, H. Carbohydr. Res. 1987, 169, 69–81; (b)
Kova´c, P.; Yeh, H. J. C.; Glaudemans, P. J. Carbohydr.
Res. 1987, 169, 23–34.
J2,3b=J3b,4 4.4, J3b,5b 1.8 Hz, H-3b), 3.38 (dd, J4,5a 7.8,
J5a,5b 11.3 Hz, H-5a), 3.50 (s, 3H, OCH3), 3.52 (ddd, J1,2