Direct synthesis of 1,6-anhydro sugars from unprotected glycopyranoses by using 2-chloro-1,3-dimethylimidazolinium chloride

Article abstract of DOI:10.1016/j.tetlet.2009.02.171

Various 1,6-anhydro sugars have been synthesized directly from the corresponding unprotected glycopyranoses in excellent yields by using 2-chloro-1,3-dimethylimidazolinium chloride (DMC) as a dehydrative condensing agent. The reactions took place smoothly under mild reaction conditions in aqueous media. The present method would be a practical tool for synthesis of 1,6-anhydro derivatives of monosaccharides, linear-oligosaccharides, and branched-oligosaccharides.

Full text of DOI:10.1016/j.tetlet.2009.02.171

Tetrahedron Letters 50 (2009) 2154–2157
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Tetrahedron Letters
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Direct synthesis of 1,6-anhydro sugars from unprotected glycopyranoses
by using 2-chloro-1,3-dimethylimidazolinium chloride
*
Tomonari Tanaka, Wei Chun Huang, Masato Noguchi, Atsushi Kobayashi, Shin-ichiro Shoda
Department of Biomolecular Engineering, Graduate School of Engineering, Tohoku University, 6-6-11-514 Aoba, Sendai 980-8579, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Various 1,6-anhydro sugars have been synthesized directly from the corresponding unprotected glyco-
pyranoses in excellent yields by using 2-chloro-1,3-dimethylimidazolinium chloride (DMC) as a dehyd-
rative condensing agent. The reactions took place smoothly under mild reaction conditions in aqueous
media. The present method would be a practical tool for synthesis of 1,6-anhydro derivatives of mono-
saccharides, linear-oligosaccharides, and branched-oligosaccharides.
Received 29 January 2009
Accepted 23 February 2009
Available online 26 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1,6-Anhydro sugars and their derivatives are known to be useful
synthetic intermediates for preparation of various glycosyl com-
pounds such as S-glycosides,1–7 N-glycosides,8 glycosyl halides,9–12
C-glycosides,13–17 and proteoglycans.18 In addition, 1,6-anydro
sugars are important monomers for the cationic ring-opening poly-
merizations, which afford stereoregular linear polysaccharide
derivatives19 or hyperbranched polysaccharide derivatives.20
However, there have been no practical method especially that of
1,6-anhydro oligosaccharides with higher molecular weight in
spite of their utility as precursors for functionalized polymers in
the field of materials science.
The formation of 1,6-anhydro structures has so far been
achieved via chemical processes which involve protection of the
hydroxy groups, activation of the anomeric center, and the removal
of the protecting groups.21 Since each step requires various kinds
of chemical agents as well as organic solvents, the total process be-
comes extremely laborious and time-consuming. It is, therefore,
almost impossible to convert an unprotected oligosaccharide of
higher molecular weight to the corresponding 1,6-anhydro sugar
derivative without damaging the inner glycosidic bonds.
Another classical method for preparation of 1,6-anhydro sugar
is to utilize pyrolysis of polysaccharides.22,23 Thermal degradations
under high pressure or high temperature,24,25 thermal degrada-
tions in supercritical acetone,26 aprotic polar solvents,27 and ionic
liquid,28 and pyrolysis by microwave29,30 have been reported.
These methods, however, can only be applied to synthesis of 1,6-
anhydro monosaccharides, and it is difficult to control the pyroly-
sis conditions in order that a 1,6-anhydro oligosaccharide may be
produced selectively. Furthermore, the purification of the product
from a reaction mixture is extremely difficult.
acetamido-2-deoxy sugars through an intramolecular dehydration
reaction by using 2-chloro-1,3-dimethyl imidazolinium chloride
(DMC)31 as dehydrative condensing agent.32 These findings
prompted us to investigate the possibility of an intramolecular
cyclization between two kinds of hydroxy groups in a saccharide
unit by DMC. The present Letter describes a DMC-mediated intra-
molecular dehydration reaction between the 1-OH and the 6-OH of
various glycopyranoses to afford the corresponding 1,6-anhydro
sugars. The reactions proceed under mild reaction conditions in
aqueous media without using any protecting groups.
It was estimated that DMC would partly be decomposed during
the reaction by the attack of water in aqueous solution, suggesting
that an excess amount of DMC would be needed. We optimized the
amount of DMC using
that when the reaction was carried out in the presence of 10 equiv
of DMC for -glucose, the yield of 1,6-anhydro sugars was almost
D-glucose as a model substrate and found
D
quantitative (Table 1, entry 4). When the amount of DMC de-
creased, the yields decreased significantly (entries 1–3).
It was also predicted that two molecules of hydrogen chloride
would be liberated from one molecule of DMC if the reagent was
completely consumed. We screened the types of bases in order
to optimize the yield of 1,6-anhydro glucose, and found that trieth-
ylamine (Et3N) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) gave
the best results (entries 4 and 5). Other bases, diisopropylethyl-
amine ((i-Pr)2NEt), 2,6-lutidine, pyridine, N-methylmorpholine
(NMM), and sodium hydrogen carbonate (NaHCO3) afforded no
1,6-anhydro glucose (entries 6–10). Next, we carefully investigated
the amount of acid scavenger, and found that at least 3 equiv of
triethylamine against DMC is necessary for the reaction to occur.
Table 2 summarizes the synthesis of various 1,6-anhydro sugars
starting from the corresponding monosaccharides or oligosaccha-
Recently, we have developed a one-step method for synthesis of
sugar oxazolines in aqueous media starting from unprotected 2-
rides. Among the monosaccharides, D-glucose and D-galactose were
successfully converted to the corresponding 1,6-anhydro deriva-
tives almost quantitatively (Table 2, entries 1 and 2). Various
oligosaccharides like lactose, malto-oligosaccharides (DP = 2–7),
* Corresponding author. Tel.: +81 22 795 7230; fax: +81 22 795 7293.
E-mail address: shoda@poly.che.tohoku.ac.jp (S. Shoda).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.171

T. Tanaka et al. / Tetrahedron Letters 50 (2009) 2154–2157
2155
the product appears at 65 ppm lower than that of C-60, 600, 6000
(60 ppm), clearly indicating the formation of a 1,6-anhydro moiety
as a result of intramolecular cyclization (Fig. 1). It is noteworthy
that each carbon atom can be clearly identified as a separated peak
because the anomeric hydroxy group is fixed in the 1,6-anhydro
moiety.
Table 1
Effect of the equivalence (D-Glucose/DMC/base) on the yields of 1,6-anhydro glucose
in aqueous solutionsa
Cl
Cl
CH3
N
+
N
H3C
O
OH
O
OH
DMC
O
On the other hand,
D-mannose, 2-deoxy-D-glucose, and
HO
HO
OH
Base
D2O
2-fluoro-2-deoxy- -glucose gave no dehydrative products (entries
D
OH
OH
OH
3–5), indicating that the existence of 2-hydroxy group and its
configuration are important factors that determine the course of
the formation of 1,6-anhydro structures. The yield of 1,6-anhdyro
Entry Concn of D-glucose (mM) Equiv of DMC Base (equiv)
Yieldb (%)
1
2
3
4
5
6
7
8
9
250
250
250
50
50
50
50
50
50
50
2
3
4
10
10
10
10
10
10
10
Et3N (6)
Et3N (9)
Et3N (12)
Et3N (30)
DBU (30)
29
40
36
Quant.
sugars derived from nigerose (Glca1?3Glc) and laminaribiose
(Glcb1?3Glc) was low, showing that a substituent on the 3 posi-
tion strongly hinders the intramolecular cyclization due to steric
repulsion between the 1-O-substituent and 3-O-substituent (en-
tries 21 and 22). These results were in consistent with the fact that
3-O-methyl-D-glucose cannot be converted to the corresponding
1,6-anhydro derivative (entry 23).
Based on these results, the following reaction mechanism for
DMC-mediated formation of 1,6-anhydro glucose was proposed.
The first step is a nucleophilic attack of b-glucose (1b) to the 2 po-
sition of DMC, giving rise to the intermediate 2b. The 2-hydroxy
group of 2b then attacks the anomeric carbon atom to afford a
1,2-anhydro intermediate 3, which is converted to the 1,6-anhydro
Quant.
(i-Pr)2NEt (30)
2,6-Lutidine (30)
Pyridine (30)
NMM (30)
0
0
0
0
0
10
NaHCO3 (30)
a
The reactions were carried out at 0 °C for 15 min.
b
Determined by 1H NMR by comparing the integrals of the anomeric proton of
D-
glucose and that of 1,6-anhydro glucose.
cello-oligosaccharides (DP = 2–6), and oligoxyloglucan having
1,6-branched linkages, were able to be converted to the corre-
sugar 4 via intramolecular attack of the 6-hydroxy group.
cose (1 ) that is in equilibrium with b-glucose also reacts with
DMC to give the corresponding -intermediate 2 , from which glu-
cose is regenerated by the attack of water via SN2 or SN1 process.
The results that the reaction with -mannose, 2-deoxy- -glucose,
and 2-fluoro-2-deoxy- -glucose did not proceed (Table 2, entries
a-Glu-
a
a
sponding 1,6-anhydro derivatives in good yields (entries 6–20). It
should also be noted that this method is applicable to polysaccha-
rides such as amylose (average MW = 2900) and xyloglucan from
Tamarindus indica (MW > 300,000) (data not shown).
a
a
D
D
D
The following is a typical procedure for synthesis of 1,6-anhy-
dro maltotetraose (entry 9). A mixture of maltotetraose (16.7 mg,
0.025 mmol), DMC (25.4 mg, 0.15 mmol), and Et3N (0.063 mL,
0.45 mmol) in water (0.5 mL) was stirred for 15 min at 0 °C. The
resulting product was purified by using HPLC (column; Amide80
(21.5 ꢀ 300 mm), eluent; water/acetonitrile = 3/2, flow rate;
8 mL/min, column oven; 60 °C, detection; RI) and concentrated in
vacuo to give 1,6-anhydro maltotetraose (14.1 mg, 0.022 mmol,
87%). The 1H NMR spectrum of 1,6-anhydro maltotetraose shows
the anomeric proton at 5.4 ppm characteristic to 1,6-anhydro sug-
ars. The 13C NMR spectrum indicated that the C-6 carbon peak of
3–5) strongly supported the participation of the intermediate 3.
The formation of anhydro moieties of other glycopyranoses can
be explained in a similar manner (see Scheme 1).
In conclusion, we achieved a one-step synthesis of 1,6-anydro
sugars by using DMC as dehydrative agent under mild reaction
conditions. The reaction requires no protection of the hydroxyl
groups and proceeds smoothly in aqueous media. The present
method would be a general and practical tool for synthesis of
1,6-anhydro sugars starting from various glycopyranoses including
oligosaccharides with higher molecular weights.
Table 2
Synthesis of various 1,6-anhydro sugars
Entry
Substrate
(mM)
DMC (equiv)
Et3N (equiv)
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
D
D
D
-Glucose
-Galactose
-Mannose
50
50
50
50
50
250
250
50
50
50
50
50
250
50
50
40
20
50
20
10
10
10
10
10
3
3
6
6
6
10
10
3
6
6
8
10
6
10
10
3
30
30
30
30
30
9
99
99
0
0
2-Deoxy-
2-Fluoro-2-deoxy-
Lactose
D
-glucose
D
-glucose
0
Quant.
89
91
87
70
64
92
Quant.
Quant.
94
Maltose
9
Maltotriose
Maltotetraose
Maltopentaose
Maltohexaose
Maltoheptaose
Cellobiose
18
18
18
30
30
9
18
18
24
30
18
30
30
9
Cellotriose
Cellotetraose
Cellopentaose
Cellohexaose
Panose
Xyloglucan-heptasaccharide
Xyloglucan-nonasaccharide
Nigerose
81
91
Quant.
74
50
97
250
250
50
Traceb
Traceb
Traceb
Laminaribiose
3-O-Methyl-
3
10
9
30
D
-glucose
a
Isolated yield.
b
The reaction was carried out in deuterium oxide solution at 0 °C for 15 min and a trace amount of the product was detected by 1H NMR.

2156
T. Tanaka et al. / Tetrahedron Letters 50 (2009) 2154–2157
6
O
OH
OH
OH
OH
O
6'
6'''
6''
O
O
1
O
1'''
O
1'
1''
O
HO
HO
HO
HO
HO
OH
HO
HO
O
6’
6’’
6’’’
1’’
1
1’’’
6
1’
140.0
130.0
120.0 110.0
100.0
90.0
80.0
70.0
60.0
50.0
40.0
30.0
20.0
ppm
Figure 1. 13C NMR spectrum of isolated 1,6-anhydro maltotetraose in D2O (Table 2, entry 9).
OH
O
OH
O
OH
O
DMC
N
HO
HO
HO
HO
HO
HO
OH
O
+ N
HO
HO
O
Cl
2β
O
3
1β
N
N
DMI
H2O
DMI
OH
O
O
OH
OH
O
HO
HO
DMC
O
N
HO
HO
HO
O
OH
OH
HO
+ N
OH
Cl
DMI
4
1α
2α
Scheme 1. Plausible reaction mechanism of 1,6-anhydro sugar formation.
6. Arndt, S.; Hsieh-Wilson, L. C. Org. Lett. 2003, 4179.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.02.171.
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