Tetrahedron Letters 50 (2009) 2154–2157
Tetrahedron Letters
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.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.171