Stereoselective synthesis of thioxylooligosaccharides from S-glycosyl isothiourea precursors

Article abstract of DOI:10.1016/S0040-4039(01)00775-4

A stereoselective synthesis of thioxylo-di-, -tri-, -tetra- and -penta-saccharides from S-glycosyl isothiourea precursors is described. The synthesis was performed starting from 2,3,4-tri-O-acetyl-β-D-xylopyranosyl isothiouronium bromide using a triethylamine promoted reaction with 1,2,3-tri-O-benzoyl-4-O-trifluoromethanesulphonyl-β-L-arabinopyranose. The resulting 4-thioxylobiose was then converted into the corresponding isothiouronium bromide and used for the synthesis of 4,4′-dithioxylotriose. Higher homologues of the series and their α-methyl glycosides were also prepared.

Full text of DOI:10.1016/S0040-4039(01)00775-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4565–4567
Stereoselective synthesis of thioxylooligosaccharides from
S-glycosyl isothiourea precursors
Farid M. Ibatullin,a,* Konstantin A. Shabalin,a Janne V. Ja¨nisb and Stanislav I. Selivanovc
aBiophysics Division, Petersburg Nuclear Physics Institute, Gatchina 188300, Russia
bDepartment of Chemistry, University of Joensuu, Joensuu, Finland
cChemical Department of Petersburg State University, St. Petersburg, Russia
Received 6 April 2001; revised 30 April 2001; accepted 10 May 2001
Abstract—A stereoselective synthesis of thioxylo-di-, -tri-, -tetra- and -penta-saccharides from S-glycosyl isothiourea precursors is
described. The synthesis was performed starting from 2,3,4-tri-O-acetyl-b-
D
-xylopyranosyl isothiouronium bromide using a
-arabinopyranose. The resulting
triethylamine promoted reaction with 1,2,3-tri-O-benzoyl-4-O-trifluoromethanesulphonyl-b-
L
4-thioxylobiose was then converted into the corresponding isothiouronium bromide and used for the synthesis of 4,4%-dithioxy-
lotriose. Higher homologues of the series and their a-methyl glycosides were also prepared. © 2001 Elsevier Science Ltd. All rights
reserved.
Thio-linked oligosaccharides have recently drawn atten-
tion owing to their potential as competitive inhibitors
for exo- and particularly for endo-glycosidases. Due to
a close similarity to the natural oligosaccharides and
stability to enzymatic cleavage, thiooligosaccharides
have proven to be very convenient and versatile tools
for biochemical and structural investigations of the
carbohydrate processing enzymes.1
S-Glycosyl isothiourea derivatives are known as very
convenient precursors for the stereoselective synthesis
of thioglycosides due to the fixed 1,2-trans-configura-
tion of the thioglycosidic bond, the simplicity of their
preparation from corresponding glycosyl bromides and
thiourea,6 and their ability to be readily converted into
the target compounds.5–7
Although S-glycosyl isothiourea derivatives have also
been utilized for the preparation of thiooligosaccha-
rides, the syntheses were usually performed employing a
two-step procedure, involving cleavage of the S-ami-
dino group, followed by isolation of the corresponding
1-thio-aldose and subsequent coupling with an appro-
priate triflate derivative.8
In recent years, xylanases have attracted considerable
research interest because of their large potential appli-
cation in food and paper pulp industries.2 Xylanases
hydrolyze the b-1,4-linkages between the internal xylose
units of xylan, the major constituent of hemicellulose.
Syntheses of some derivatives of 4-thioxylobiose and
4,4%-dithioxylotriose have been described.1,3 However,
for an efficient productive binding into the active site of
the enzymes, higher oligosaccharides are required.4
Recently, we described a synthesis of methyl 4-thio-a-
cellobioside and methyl 4-thio-a-lactoside derivatives
using a one-pot procedure based on the triethylamine
promoted reaction of methyl 2,3,6-tri-O-benzoyl-4-O-
A systematic synthesis of higher members of this series
or of their methyl glycosides has not been carried out
due to the difficulties involved in the preparation of
suitable intermediates. Here, we present the synthesis of
a series of 1,4-thioxylooligosaccharides from S-glycosyl
isothiourea derivatives using a new efficient approach,
recently developed in our laboratory.5
trifluoromethanesulphonyl-a-D-galactopyranoside with
a corresponding isothiourea derivative in acetonitrile.5
Successful synthesis of these two compounds prompted
us to apply the same approach to the synthesis of
thioxylooligosaccharides.
1,2,3-tri-O-Benzoyl-4-O-trifluoromethanesulphonyl-b-
L
-arabinopyranose 6 has been chosen as the key
monomer for the synthesis of the thioxylooligosaccha-
rides for several reasons. The benzoyloxy group at the
anomeric position can be easily substituted affording a
glycosyl bromide, which, in turn, can be converted into
Keywords: thiooligosaccharides; S-glycosyl isothiourea derivatives.
* Corresponding author. Tel.: +7 (81271) 46056; fax: +7 (81271)
32303; e-mail: ibatullin@omrb.pnpi.spb.ru
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00775-4

4566
F. M. Ibatullin et al. / Tetrahedron Letters 42 (2001) 4565–4567
the corresponding isothiouronium bromide. Moreover,
due to steric reasons the axial 1-benzoyloxy group
decreases the decomposition of triflate 6, leading to
the formation of unsaturated byproducts during the
coupling step. The rate of this side reaction strongly
depends on the glycosidic bond configuration, and
explains the considerably lower yields of corresponding
coupling products with an equatorial substituent at
C-1.9 Indeed, the yield of disaccharide 8 was almost
double in comparison with the yield of corresponding
1,2-di-O-benzoyl-3,4-isopropylidene
2 and 3 in comparable yields. The b-
separated as a crystalline material by crystallization
from 2-propanol. After the removal of the isopropyli-
dene group by heating in 60% acetic acid for 25 min,
L
-arabinopyranose
-anomer 3 was
L
the desired 1,2-di-O-benzoyl-b-L-arabinopyranose 4
was precipitated from the reaction mixture after dilu-
tion with cold water. Selective benzoylation of the OH
group at C-3 in pyridine followed by triflation of the
resulting tri-O-benzoate 5 in CH2Cl2 afforded the
desired 4-O-triflate 6.
4-thioxylobiose derivative prepared from the a-L-
analog of compound 6. For the same reason, the syn-
thesis of thioxylooligosaccharides has been performed
utilizing a stepwise approach. It is also important that
benzoyl protecting groups can be selectively introduced
and easily removed under basic conditions in the final
step to give free thiooligosaccharides.
Synthesis of thioxylooligosaccharides has been per-
formed as described in Scheme 2 using a triethylamine
promoted reaction of the isothiouronium bromides with
triflate 6.
To a suspension of 2,3,4-tri-O-acetyl-b-D-xylopyranosyl
The compound 6 has been prepared (Scheme 1) starting
isothiouronium bromide 7, prepared from a-acetobrom-
oxylose and thiourea by a 10–15 minute reflux in
acetonitrile, compound 6 and triethylamine were added.
The reaction mixture was stirred at room temperature
for one hour to give the thiodisaccharide 8 in 79% yield
after work up.
from 3,4-isopropylidene
L
-arabinopyranose 1, which
can be readily obtained in high yield by acetonation of
-arabinose with 2,2-dimethoxypropane in DMF apply-
ing the procedure described for its
-isomer.10 Benzoyl-
ation of this compound afforded both anomers of
L
D
OH
HO
O
O
O
O
O
b
a
c
R1
R2
O
O
OH
OH
L-Ara
OH
OH
BzO
1
2 R1=OBz, R2=H 42%
3 R1=H, R2=OBz 57%
OH
HO
OH
BzO
OTf
O
O
O
d
f
BzO
BzO
BzO
BzO
OBz
OBz
OBz
4
5
6
Scheme 1. Reaction conditions: (a) Me2C(OMe)2, TosOH, DMF, rt, 1 h, 95%; (b) BzCl/Pyr, 0°C–rt, 2 h; (c) AcOH/H2O (3:2),
95°C, 25 min, 82%; (d) BzCl/Pyr, −20°C, 1 h, 0°C, 2 h, rt, 15 h, 81%; (e) Tf2O, Pyr/CH2Cl2, 0°C–rt, 30 min, 96%.
6, a
NH2
BzO
O
BzO
O
HBr
O
O
O
BzO
S
BzO
S
AcO
AcO
AcO
AcO
S
BzO
S
NH
OAc
OAc
BzO
n
n
OBz
b
7
9
n=0
n=1
8
n=0 79%
OTf
BzO
10 n=1 82%
12 n=2 65%
14 n=3 53%
O
11 n=2
13 n=3
a
BzO
15
OMe
BzO
OH
O
O
O
O
O
BzO
S
HO
S
c
AcO
AcO
HO
HO
S
BzO
S
HO
O
OAc
OH
OH
OMe
BzO
n
n
OMe
16 n=0 71% 20 n=2 60%
18 n=1 70% 22 n=3 67%
17 n=0 21 n=2
19 n=1 23 n=3
Scheme 2. Reaction conditions: (a) Et3N/CH3CN or /CH3CN–DMF, rt, 60 min; (b) i. HBr/AcOH, rt, 15 min; ii. SC(NH2)2/
CH3CN, reflux, 10 min; (c) NaOMe/MeOH, rt, overnight.

F. M. Ibatullin et al. / Tetrahedron Letters 42 (2001) 4565–4567
4567
Due to possible decomposition of triflates 6 and 15
under the basic conditions by elimination of the triflate
group as described above, 10–40% molar excess of these
compounds was used in the coupling reactions.
4. Sulzenbacher, G.; Driguez, H.; Henrissat, B.; Schu¨lein,
M.; Davies, G. Biochemistry 1996, 35, 15280–15287.
5. Ibatullin, F. M.; Selivanov, S. I.; Shavva, A. G. Synthesis
2001, 419–422.
6. (a) Horton, D. Methods Carbohydr. Chem. 1963, 2, 433–
437 and references cited therein; (b) Bonner, W. A.;
Kahn, J. E. J. Am. Chem. Soc. 1951, 73, 2241–2245; (c)
Horton, D.; Wolfrom, M. L. J. Org. Chem. 1962, 27,
1794–1800; (d) Chipowsky, S.; Lee, Y. C. Carbohydr.
Res. 1973, 31, 339–346.
Compound 8 was easily converted into a glycosyl bro-
mide by 15 minute treatment with hydrogen bromide in
acetic acid/CH2Cl2 using a standard protocol.11 A 15
minute reflux of the resulting bromide and thiourea in
acetonitrile afforded isothiourea derivative 9.
&
7. (a) Cerny´, M.; Paca´k, J. Chem. Listy 1958, 52, 2090–
&
Reaction of compound 9 with triethylamine and triflate
6 in acetonitrile gave thiotrisaccharide 10 in 82% yield.
The compound was then converted into isothiouronium
bromide 11 according to the reaction sequence
described for 9, and treated with Et3N and 6 to give
thioxylotetrasaccharide 12 in 65% yield. Due to the low
solubility of compound 11 in acetonitrile, the reaction
was carried out in an acetonitrile–DMF mixture. To
reduce oxidation of the 1-thio group, the reaction was
performed in the presence of dithiothreitol (DTT) (1
equivalent).
2093; (b) Cerny´, M.; Vrkoc, J.; Staneˇk, J. Coll. Czech.
&
Chem. Commun. 1959, 24, 64–69; (c) Cerny´, M.; Paca´k, J.
Coll. Czech. Chem. Commun. 1959, 24, 2566–2570; (d)
&
Cerny´, M.; Staneˇk, J.; Paca´k, J. Monatsh. Chem. 1963,
94, 290–294; (e) Claeyssens, M.; De Bruyne, C. K. Carbo-
hydr. Res. 1972, 22, 460–463.
8. (a) Wang, L.-X.; Lee, Y. C. J. Chem. Soc., Perkin Trans.
1 1996, 581–591; (b) Countour-Galcera, M.-O.; Ding, Y.;
Ortiz-Mellet, C.; Defaye, J. Carbohydr. Res. 1996, 281,
119–128.
9. Moreau, V.; Norrid, J. Chr.; Driguez, H. Carbohydr. Res.
1997, 300, 271–277.
Conversion of 12 into isothiourea derivative 13 fol-
lowed by reaction with Et3N, DTT and 6 in DMF/ace-
tonitrile afforded thioxylopentasaccharide 14 in 53%
yield (Scheme 2).
10. Kiso, M.; Hasegawa, A. Carbohydr. Res. 1976, 52, 95–
101.
11. (a) Nicholas, S. D.; Smith, F. Nature 1948, 161, 349; (b)
Haynes, L. J.; Newth, F. W. Adv. Carbohydr. Chem.
Biochem. 1955, 10, 207–256.
Similarly, reaction of isothiouronium bromides 7, 9, 11
12. All synthesized compounds gave satisfactory elemental
analyses and were characterized by NMR spectroscopy.
Assignments in 1H and 13C spectra of final thioxy-
looligosaccharides were performed using a combination
of 1D and 2D homo- and heteronuclear chemical shift
correlation techniques including DEPT-135, COSY-45,
DQF-COSY, HMQC, COLOC, NOESY and J-resolved
spectroscopy at 300 MHz Bruker DPX-300. Compound
17: 13C NMR (D2O, 125 MHz) l 100.21 (C-1), 84.65
(C-1%), 77.45 (C-3%), 72.98 (C-2), 72.46 (C-2%), 70.14 (C-3),
69.39 (C-4%), 69.14 (C-5%), 62.11 (C-5), 55.52 (OCH3),
45.70 (C-4). Compound 19: 13C NMR (D2O, 125 MHz) l
100.19 (C-1), 84.68, 84.56 (C-1%, C-1%%), 77.44 (C-3%%), 74.36
(C-3%), 73.83 (C-2%), 72.98 (C-2), 72.44 (C-2%%), 70.14 (C-3),
70.04 (C-5%), 69.37 (C-4%%), 69.12 (C-5%%), 62.10 (C-5), 55.53
(OCH3), 45.64, 45.54 (C-4, C-4%). Compound 21: 13C
NMR (D2O, 125 MHz) l 100.19 (C-1), 84.69, 84.60,
84.56 (C-1%, C-1%%, C-1%%%), 77.43 (C-3%%%), 74.32 (C-3%, C-3%%),
73.82 (C-2%, C-2%%), 72.96 (C-2), 72.43 (C-2%%%), 70.12 (C-3),
70.06 (C-5%, C-5%%), 69.37 (C-4%%%), 69.13 (C-5%%%), 62.11
(C-5), 55.52 (OCH3), 45.64, 45.52, 45.48 (C-4, C-4%, C-4%%).
Compound 23: 13C NMR (D2O, 125 MHz) l 100.19
(C-1), 84.70, 84.60, 84.58, 84.54 (C-1%, C-1%%, C-1%%%, C-1%%%%),
77.43 (C-3%%%%), 74.32 (C-3%, C-3%%, C-3%%%), 73.80 (C-2%, C-2%%,
C-2%%%), 72.95 (C-2), 72.42 (C-2%%%%), 70.12 (C-3), 70.08
(C-5%, C-5%%, C-5%%%), 69.36 (C-4%%%%), 69.13 (C-5%%%%), 62.12
(C-5), 55.52 (OCH3), 45.63, 45.50, 45.46 (C-4, C-4%, C-4%%,
C-4%%%).
and 13 with methyl 2,3-di-O-benzoyl-4-O-triflyl-b-L-
arabinopyranoside 15 afforded a-methyl glycosides 16
(71% yield), 18, 20 and 22 in 70, 60 and 67% overall
yields, correspondingly, from compounds 8, 10 and 12.
The final thioxylooligosaccharides 17, 19, 21 and 23
were obtained after removal of the protecting groups
from the acylated precursors using a solution of
NaOMe in MeOH.12
In summary, an efficient approach for the synthesis of
1-4-thioxylooligosaccharides from isothiourea precur-
sors is described. Very mild reaction conditions and
short reaction times, high yields of the products in
combination with the availability of the reagents used
are evidently advantageous for the approach in com-
parison with all the known methods of 1,2-trans-
thiooligosaccharide synthesis.13
References
1. Driguez, H. In Topics in Current Chemistry; Driguez, H.;
Thiem, J., Eds.; Berlin: Springer Verlag, 1997; Vol. 187,
pp. 86–116 and references cited therein.
2. Kulkarni, N.; Shendye, A.; Rao, M. FEMS Microbiol.
Rev. 1999, 23, 411–456 and references cited therein.
3. (a) Defaye, J.; Driguez, H.; John, M.; Schmidt, J.;
Ohleyer, E. Carbohydr. Res. 1985, 139, 123–132; (b)
Comtat, J.; Defaye, J.; Driguez, H.; Ohleyer, E. Carbo-
hydr. Res. 1985, 144, 33–34.
13. Fairweather, J. K.; Driguez, H. In Oligosaccharides in
Chemistry and Biology: A Comprehensive Handbook;
Ernst, B.; Hart, G.; Sinay¨, P., Eds.; Wiley/VCH, 2000;
pp. 531–564.
.