CL-150201
Received: March 6, 2015 | Accepted: March 25, 2015 | Web Released: April 9, 2015
Metal-catalyzed Stereoselective and Protecting-group-free Synthesis of 1,2-cis-Glycosides
Using 4,6-Dimethoxy-1,3,5-triazin-2-yl Glycosides as Glycosyl Donors
Tomonari Tanaka,*1 Naoya Kikuta,1 Yoshiharu Kimura,1 and Shin-ichiro Shoda2
1Department of Biobased Materials Science, Graduate School of Science and Technology, Kyoto Institute of Technology,
Matsugasaki, Sakyo-ku, Kyoto 606-8585
2Department of Biomolecular Engineering, Graduate School of Engineering, Tohoku University, Aoba, Sendai, Miyagi 980-8579
(E-mail: t-tanaka@kit.ac.jp)
4,6-Dimethoxy-1,3,5-triazin-2-yl glycosides, glycosyl donors
prepared in one step from free saccharides without protection of the
hydroxy groups, were stereoselectively and equivalently converted
to the corresponding 1,2-cis-glycosides by using a catalytic amount
of metal catalyst. This reaction was successfully applied not only to
monosaccharides, but also to di- and oligosaccharides.
A typical procedure for preparing DMT-glycoside involves
stirring an aqueous solution of the free saccharide, 2-chloro-
4,6-dimethoxy-1,3,5-triazine (CDMT), and N-methylmorpholine
(NMM) for 24 h at room temperature (Scheme 1). The resulting
products were purified by silica gel column chromatography. The
nucleophilic substitution reaction between the anomeric hydroxy
group of the free saccharide and CDMT occurred smoothly in the
presence of a base in aqueous media since the acidity of the
hemiacetal anomeric hydroxy group is much higher than that of
other hydroxy groups and water;14 the reaction afforded the corre-
sponding DMT-glycoside. D-Glucose (Glc), maltose (Mal), meli-
biose (Mel), and maltopentaose (Glc5), which have an equatorial
hydroxy group at the 2-position, provided DMT-β-glycosides,
whereas DMT-α-glycoside was obtained from D-mannose (Man),
which has an axial hydroxy group at the 2-position.15
The development of chemical glycosylation reactions for the
efficient production of carbohydrates and for specific biological
applications has been an important pursuit in chemical research
since the first report on glycosylation by Fischer in 1893.1
Fischer glycosylation is the simplest and most direct route for
the synthesis of unprotected alkyl glycosides in the presence of an
acidic catalyst at high temperatures in an alcohol solvent, and
remains one of the most popular methods owing to its simplicity
and versatility.2 A critical issue in chemical glycosylation is
stereoselectivity at the anomeric position.3 It is well known
that anomeric effect,4 neighboring group participation,5 solvent
effect of nitrile solvents,6 and through-space effect7 are efficient
approaches for stereoselective glycosylation, and several glycosyl
donors, e.g., thioglycoside,8 glycosyl iodide,9 and glycosyl
trichloroimidate,10 stereoselectively provide glycosyl products in
conjunction with activators under appropriate reaction conditions.
However, the synthesis of these glycosyl donors from free
saccharides requires multistep processes, including protection of
all the hydroxy groups, activation or selective deprotection at the
anomeric position, and the introduction of leaving groups.
The synthesis of alkyl glycosides using DMT-glycosides as
glycosyl donors was conducted in various anhydrous alcohol
OR2
O
OCH3
N
N
N
R1O
HO
O
OH
OCH3
OR2
O
OCH3
N
N
N
DMT-β-Glc : R1 = R2 = H
31%
40%
57%
R1O
HO
Cl
DMT-β-Mal : R1 = α-Glc, R2 = H
DMT-β-Mel : R1 = H, R2 = α-Gal
OH
OH
OCH3
OH
DMT-β-Glc5 : R1 = (α-Glc)4, R2 = H 48%
CDMT
H2O
NMM
HO
HO
HO
OH
O
HO
OH
O
HO
OCH3
HO
N
N
O
N
We recently reported that free saccharides can be directly
converted to the corresponding 4,6-dimethoxy-1,3,5-triazin-2-yl
(DMT)-glycosides in water without protecting the hydroxy groups,
using a dehydrative condensing agent, 4-(4,6-dimethoxy-1,3,5-
triazin-2-yl)-4-morpholinium chloride (DMT-MM).11 The resulting
DMT-glycosides were recognized by the corresponding glycosi-
dases and acted as efficient glycosyl donors for enzymatic glycosyl-
ation catalyzed by glycosidases, e.g., endo-β-1,4-glucanase, α-N-
acetylglucosaminidase, α-N-acetylgalactosaminidase, α-L-arabino-
furanosidase, and exo-chitosanase.12 However, little has been
reported regarding chemical glycosylation using 1,3,5-triazin-2-yl
glycosides as glycosyl donors.13 Fujimoto et al. reported a chemi-
cal glycosylation using a protected DMT-glycoside and a molar
equivalent of Lewis acid, but the reaction was not stereoselective.
Schmidt et al. also reported chemical glycosylations using several
1,3,5-triazin-2-yl glycosides, for example, 4,6-dichloro-, 4-chloro-
6-methoxy-, and 4-chloro-6-diisopropylamino-1,3,5-triazin-2-yl
glycosides. In this letter, we report a metal-catalyzed stereoselective
glycosylation reaction using DMT-glycosides prepared in one step
and then used as glycosyl donors. This reaction is applicable not
only to monosaccharides, but also to di- and oligosaccharides.
OCH3
DMT-α-Man 44%
Scheme 1. Synthesis of DMT-glycosides from free saccharides.
OR2
O
OCH3
N
R1O
HO
O
N
N
OH
OCH3
OR2
O
DMT-β-Glc : R1 = R2 = H
R1O
HO
DMT-β-Mal : R1 = α-Glc, R2 = H
DMT-β-Mel : R1 = H, R2 = α-Gal
DMT-β-Glc5 : R1 = (α-Glc)4, R2 = H
HO
OR
metal catalyst
ROH
HO
HO
HO
OH
O
HO
HO
HO
OH
O
OCH3
N
N
N
OR
O
OCH3
DMT-α-Man
Scheme 2. Metal-catalyzed synthesis of alkyl glycosides using DMT-
glycosides.
© 2015 The Chemical Society of Japan