Novel synthesis of 1-thioglycopyranoses via thioiminium salts

Article abstract of DOI:10.1081/CAR-120013495

Methanolysis of a glycosylthioiminium salt, which was prepared from the reaction of acetohalogenosugar with thioacetamide, afforded the corresponding per-O-acetylated 1,2-trans-1-thioglycose in good yield after fractional crystallization. This synthetic method is very convenient in operation and proceeds without loss of acetyl groups, as the reaction is carried out under mild and neutral conditions.

Full text of DOI:10.1081/CAR-120013495

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NOVEL SYNTHESIS OF 1-THIOGLYCOPYRANOSES VIA
THIOIMINIUM SALTS
a
b
b
b
b
Takayoshi Fujihira , Mitsutaka Chida , Haruo Kamijo , Toshio Takido & Manabu Seno
a
Japan Sugar Refiners' Association, Technical Department and Research Laboratory, 5-7
Sanbancho, Chiyoda-ku, Tokyo, 102-0075, Japan
b
Department of Materials Applied Chemistry, College of Science and Technology, Nihon
University, 1-8-14 Kanda Surugadai, Chiyoda-ku, Tokyo, 101-8308, Japan
Version of record first published: 16 Aug 2006
To cite this article: Takayoshi Fujihira, Mitsutaka Chida, Haruo Kamijo, Toshio Takido & Manabu Seno (2002): NOVEL
SYNTHESIS OF 1-THIOGLYCOPYRANOSES VIA THIOIMINIUM SALTS, Journal of Carbohydrate Chemistry, 21:4, 287-292
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JOURNAL OF CARBOHYDRATE CHEMISTRY
Vol. 21, No. 4, pp. 287–292, 2002
NOVEL SYNTHESIS OF 1-THIOGLYCOPYRANOSES
VIA THIOIMINIUM SALTS
1,*
2
Takayoshi Fujihira, Mitsutaka Chida, Haruo Kamijo,
2
2
Toshio Takido, and Manabu Seno
2
1
Japan Sugar Refiners’ Association, Technical Department and Research
Laboratory, 5-7 Sanbancho, Chiyoda-ku, Tokyo 102-0075, Japan
Department of Materials Applied Chemistry, College of Science and
Technology, Nihon University, 1-8-14 Kanda Surugadai, Chiyoda-ku,
Tokyo 101-8308, Japan
2
ABSTRACT
Methanolysis of a glycosylthioiminium salt, which was prepared from the
reaction of acetohalogenosugar with thioacetamide, afforded the correspond-
ing per-O-acetylated 1,2-trans-1-thioglycose in good yield after fractional
crystallization. This synthetic method is very convenient in operation and
proceeds without loss of acetyl groups, as the reaction is carried out under
mild and neutral conditions.
Key Words: Synthesis; 1-Thioglycopyranose; Thioamide; Iminium salt
INTRODUCTION
1-Thioglycopyranoses are used as starting materials for the synthesis of various 1-
thioglycosides; for example, glucosinolates, carbohydrate clusters and alkyl thioglyco-
[1]
[2]
[
sides. The 1-thioglycosides are useful as stable glycosyl donors for the synthesis of
3]
[
4]
oligosaccharides. Tetra-O-acetyl-1-thio-D-glucopyranose is usually prepared by alkali
[5]
hydrolysis of the S-glucopyranosyl isothiouronium bromide prepared from the reaction
*
Corresponding author. Fax: + 81-3-3288-3399; E-mail: fujihira@dream.com
2
87
DOI: 10.1081/CAR-120013495
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288
FUJIHIRA ET AL.
of tetra-O-acetyl-a-D-glucopyranosyl bromide with thiourea. Other 1-thioglycoses are also
[
1,7–10]
prepared by similar methods.
the prolonged time required for decomposition of the thioisouronium salt brings about
It should be noted that, in the reaction with thiourea,
[5]
gradual hydrolysis of acetyl groups. Very recently, the conversion of S-glycosyl
[11]
isothiourea derivatives into thioglycosides without loss of acetyl groups was reported.
We recently described the preparation of 2-(2,3,4,6-tetra-O-acetyl-b-D-glucopy-
ranosylthio)ethaniminium bromide from the reaction of tetra-O-acetyl-a-D-glucopy-
[6]
ranosyl bromide with thioacetamide. It was found in a subsequent study that the
glycosylthioiminium salt affords tetra-O-acetyl-1-thio-b-D-glucopyranose by methano-
lysis. In this paper we report on this novel, simple and effective method for the
synthesis of per-O-acetylated 1,2-trans-1-thioglycoses, including disaccharides.
RESULTS AND DISCUSSION
Per-O-acetylated glycopyranosyl bromides 1a and 1b were synthesized by the
[
7]
literature procedure
[
and other glycopyranosyl bromides 1d–1f were similarly
8]
prepared. Tetra-O-acetyl-b-D-mannopyranosyl chloride 1c is commercially available.
[6]
According to the method previously described, 2-(2,3,4,6-tetra-O-acetyl-b-D-gluco-
pyranosylthio)ethaniminium bromide 2a is prepared from tetra-O-acetyl-a-D-glucopy-
ranosyl bromide 1a and thioacetamide in a melt state without solvent or under reflux in
dry benzene. As this thioiminium salt was gradually hydrolyzed in the presence of
moisture in air, the glycosylthioiminium salt, which is an adduct of acetohalogenosugar
and thioacetamide, was predicted to be easily decomposed by the addition of a
nucleophilic reagent. It was found that 2a was decomposed by the addition of methanol
for a short time (ca. 10 min.) at 20°C to give tetra-O-acetyl-1-thio-b-D-glucopyranose.
This synthetic method is applicable to other sugars 1b–1f (see Scheme 1). In the case
of monosaccharides 1a–1c, freshly prepared and dried (anhydrous conditions)
acetohalogenosugar and thioacetamide were stirred just above the melting temperature
(ca. 120°C) in a dry nitrogen or argon stream. Although the starting materials
(acetohalogenosugar and thioacetamide) were soluble in a warm nonpolar organic
solvent (e.g., benzene), the reaction products were barely soluble. The products are
mainly the thioiminium salts 2a–2c as indicated by FAB-MS data; the fragment ion
À
+
peaks of m/z 406 ([M-Br ] ) and 331 (pyranosyl ring cation) were clearly observed.
[6]
In the case of disaccharides 1d–1f, the reaction was complete (the reaction mixture
became solid and viscous) in approximately 3 h under reflux conditions in a small
amount of dry benzene to give glycosylthioiminium salts. The reaction intermediates
from disaccharides are presumed to be thioiminium salts as with monosaccharides,
although their formation could not be detected by FAB-MS under the present reaction
conditions. Side reactions such as the amino-carbonyl reaction were minimized under
these conditions. When the reaction of disaccharides was carried out without solvent at
an elevated temperature, the amino-carbonyl reaction proceeded to give products of
higher melting points. From this result, we decided to include a small amount of dry
benzene as a solvent in these cases (see Experimental). As shown in Table 1, per-O-
acetylated 1,2-trans-1-thioglycoses synthesized from monosaccharides are tetra-O-
acetyl-1-thio-b-D-glucopyranose 3a (yield 89%), tetra-O-acetyl-1-thio-b-D-galactopy-
ranose 3b (97%) and tetra-O-acetyl-1-thio-a-D-mannopyranose 3c (98%), and from
disaccharides, hepta-O-acetyl-1-thio-b-lactose 3d (75%), hepta-O-acetyl-1-thio-b-mal-

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SYNTHESIS OF 1-THIOGLYCOPYRANOSES
289
Scheme 1. Synthesis of per-O-acetylated 1,2-trans-1-thioglycopyranoses.
tose 3e (73%) and hepta-O-acetyl-1-thio-b-cellobiose 3f (76%). In the methanolysis of
2
e the yield of 3e deposited from the methanol solution was 44%.
1
H NMR coupling constants from 9.6 Hz to 9.9 Hz for H-1 of reducing terminal,
1
except for 3c, were observed for the methanolysis products. Measurements of H and
1
3
C NMR of 3b were carried out on viscous precipitates after methanol was distilled
off, as the crystallization was difficult (Tables 1 and 2). Also, the molecular weights of
these products (3a–3f) were measured by chemical ionization mass spectrometry, the
fragment ion peaks of m/z 365 (M + 1) and 331 (pyranose ring cation) were observed in
the case of monosaccharides (3a–3c) and the fragment ion peaks of m/z 653 (M + 1)
and 619 and 332 (pyranose ring cation) were observed in the case of disaccharides
(3d–3f). From these results, it was confirmed that per-O-acetylated 1,2-trans-1-
thioglycoses were obtained by the present method.
This reaction is considered to proceed in a similar way as the reaction using
thiourea. Glycosylthioiminium salt 2 is formed by the reaction of the acetohalogen-
osugar with thioacetamide by an S 2 type reaction and undergoes nucleophilic attack
N
by methanol to give per-O-acetylated 1,2-trans-1-thioglycose. In the reaction using
d-methanol, the formation of the product 3 having a deuteriated thiol group was
observed. Furthermore, evolution of hydrogen bromide was detected in this reaction
[6]
and suggests the formation of acetonitrile.
The reaction temperature must to be monitored carefully in the preparation of
glycosylthioiminium salts by this method in order to avoid the amino-carbonyl side
reaction. It is necessary for the reaction temperature to be lower than the melting point
of thioacetamide (ca. 114°C) and higher than the melting points of acetohalogenosugar.
The progress of the side-reaction may be detected by observing a change in color of the
reaction mixture; from initial yellow to orange color, and finally brown.

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SYNTHESIS OF 1-THIOGLYCOPYRANOSES
291
1
3
Table 2.
C NMR Chemical Shift Data of 1-Thioglycose 3
Chemical Shift (d, ppm, CDCl3)
3
C-1
C-2
C-3
C-4
C-5
C-6
C-1’
C-2’
C-3’
C-4’
C-5’
C-6’
a
b
c
d
e
f
78.7 73.5 73.6
79.1 70.8 71.5
76.3 71.6 72.0
78.5 73.9 73.5
78.2 74.3 76.1
78.5 73.7 73.2
68.1
67.2
65.2
70.7
72.6
76.7
76.3 62.0
74.9 61.4
76.9 62.6
77.2 58.5 101.1 69.1 71.0 66.6 62.2 60.8
76.5 63.0 95.6 69.9 69.3 67.9 68.6 61.4
77.2 61.5 100.8 71.5 67.7 72.0 72.9 62.1
The reaction of acetohalogenosugars with thiourea affords stable thioisouronium
salts, from which per-O-acetylated 1,2-trans-1-thioglycoses are derived by alkali
hydrolysis. However, the time required for alkali hydrolysis can result in loss of acetyl
groups and careful treatment of pH adjustment is always necessary to obtain a good
yield. In the present synthetic method using thioacetamide instead of thiourea, the
resulting thioiminium salts are easily decomposed even with alcohol, and per-O-
acetylated 1,2-trans-1-thioglycoses are obtained without loss of acetyl groups and also
tedious pH adjustment. Furthermore, per-O-acetylated 1,2-trans-1-thioglycoses are
purified by fractional crystallization from a chilled alcohol solution without the need
for separation by column chromatography. In conclusion, the procedure described here
is a convenient method to prepare per-O-acetylated 1,2-trans-1-thioglycose in good
yield under mild and neutral conditions.
EXPERIMENTAL
1
13
H and C NMR spectra were recorded with a JEOL GX-400 instrument using
tetramethylsilane as a standard. Chemical ionization mass spectra were recorded by direct
inlet probe with a JEOL JMS-AMII 150 instrument using isobutane as a reaction gas.
General method (3a–3c). Freshly prepared and dried (anhydrous conditions)
acetohalogenosugar (2.5 mmol) and thioacetamide (2.7 mmol, 0.2 g) were stirred
mechanically under argon at approximately 120°C for 5 min. Dry methanol (20 mL)
was added after cooling to 20°C, and the mixture was stirred for about 10 min (until
the solid dissolved). Solvent was evaporated under reduced pressure, a slight amount of
methanol was added again, and the mixture cooled to À 18°C. The product separated
by fractional crystallization was filtered and dried.
For the disaccharides (3d–3f), the first step of the reaction was carried out as
follows. Freshly prepared and dried acetohalogenosugar (2.5 mmol) and thioacetamide
(
2.7 mmol, 0.2 g) in dry benzene (below 5 mL) were stirred mechanically at reflux
˚
temperature (ca. 82°C) for 3 h under argon. Molecular sieves (4 A) were included in
this reaction mixture in order to maintain anhydrous conditions. Dry methanol (20 mL)
was added after cooling to 20°C, and the mixture was stirred for about 10 min (until
the solid dissolved). Solvent was evaporated under reduced pressure, and a slight

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amount of methanol was added again and the mixture cooled to À 18°C. The product
separated by fractional crystallization was filtered and dried.
ACKNOWLEDGMENT
We thank Ms. Fujita for measurements of NMR spectra.
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Received July 9, 2001
Accepted April 4, 2002