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

Article abstract of DOI:10.1246/cl.150201

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.

Full text of DOI:10.1246/cl.150201

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.
846 | Chem. Lett. 2015, 44, 846–848 | doi:10.1246/cl.150201
© 2015 The Chemical Society of Japan

Table 1. Synthesis of alkyl glycosides using DMT-glycosides
Yieldc
/%
Time Temp.
/h /ºC
α/βc
Entry
Substrate
ROHa
Catalystb
OH
O
OCH3
N
α only
α only
α only
α only
α only
1
2
3
4
5
6
7
8
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
[CuI(CH3CN)4]PF6
2
1
1
r.t.
quant.
quant.
quant.
quant.
35
N
HO
HO
O
N
OH
OCH3
[AgI(CH3CN)4]BF4
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
30
DMT-β-Glc
[PdII(CH3CN)4](BF4)2
bis(2,4-pentanedionato)Pd(II)
72
bis(2,4-pentanedionato)Cu(II) 120
[CuI(CH3CN)4]PF6
[CuI(CH3CN)4]PF6
[CuI(CH3CN)4]PF6
3
4
5
quant. 96/4
quant. 95/5
quant. 96/4
i-PrOH
tert-BuOH
[CuI(CH3CN)4]PF6
[CuI(CH3CN)4]PF6
[CuI(CH3CN)4]PF6
[AgI(CH3CN)4]BF4
[PdII(CH3CN)4](BF4)2
3
4
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
90
90
87
84
87
86
30/70
30/70
30/70
27/73
32/68
30/70
HO
HO
HO
OH
O
9
10
11
12
13
14
MeOH
EtOH
OCH3
N
N
O
N
OCH3
i-PrOH
MeOH
MeOH
5
DMT-α-Man
1
1
MeOH/MeCNd [CuI(CH3CN)4]PF6
22
[CuI(CH3CN)4]PF6
[CuI(CH3CN)4]PF6
OH
O
α only
15
16
MeOH
EtOH
5
5
r.t.
r.t.
quant.
HO
HO
OH
O
OCH3
N
N
HO
O
HO
quant. 94/6
N
O
OH
OCH3
DMT-β-Mal
17
18
MeOH
EtOH
[CuI(CH3CN)4]PF6
[CuI(CH3CN)4]PF6
2
2
r.t.
r.t.
quant.
OH
O
HO
α only
HO
OCH3
N
HO
HO
HO
O
quant. 97/3
N
N
O
O
OH
OCH3
DMT-β-Mel
19
MeOH
[CuI(CH3CN)4]PF6
24
r.t.
quant.
OH
O
α only
O
H
HO
OH
O
OCH3
HO
N
N
4 O
HO
N
O
OH
OCH3
DMT-β-Glc5
c
aAll reactions were conducted in a large excess of alcohol. b0.1 equiv. Determined by 1H NMR measurements of the reaction mixture. dSolvent was
MeOH/MeCN = 1/1 (v/v).
solvents in the presence of a catalytic amount of metal catalyst
(Scheme 2 and Table 1). An excess of alcohol was added to a
mixture of DMT-glycoside and 0.1 equiv of metal catalyst under
nitrogen atmosphere and stirred at room temperature. The metal
catalyst was removed by using a metal scavenger at the completion
of the reaction; after filtering, the filtrate was evaporated in vacuo
and subjected to NMR analysis to determine the yield and α/β ratio.
The treatment of 4,6-dimethoxy-1,3,5-triazin-2-yl β-D-glucopyra-
noside (DMT-β-Glc) with methanol in the presence of tetrakis-
(acetonitrile)copper(I) hexafluorophosphate ([CuI(CH3CN)4]PF6),
tetrakis(acetonitrile)silver(I) tetrafluoroborate ([AgI(CH3CN)4]-
BF4), or tetrakis(acetonitrile)palladium(II) tetrafluoroborate
Chem. Lett. 2015, 44, 846–848 | doi:10.1246/cl.150201
© 2015 The Chemical Society of Japan | 847

([PdII(CH3CN)4](BF4)2) for 1-2 h yielded α-methyl glucopyrano-
side stereoselectively and quantitatively (Entries 1-3). The product
was isolated by silica gel column chromatography and analyzed
by NMR spectroscopy. The anomeric proton signal is a doublet
with J1,2 = 3.6 Hz, indicating an α-glucoside. The use of bis(2,4-
pentanedionato)palladium(II) or bis(2,4-pentanedionato)copper(II)
as catalyst required longer reaction times to obtain the product
(Entries 4 and 5). The α-alkyl glucosides ethyl, i-propyl, and tert-
butyl were obtained stereoselectively following reaction for several
hours, catalyzed by with [CuI(CH3CN)4]PF6 in primary, secondary,
and tertiary alcohols (Entries 6-8). This stereoselective synthesis
of alkyl glycosides catalyzed by Cu(I) using DMT-glycosides as
glycosyl donors was applicable not only to monosaccharides, but
also to the di- and oligosaccharides Mal, Mel, and Glc5 (Entries 15-
19). Application of the classic Fischer method to Mel, a
disaccharide with an acid-labile α-1,6 bond, resulted in complete
destruction of the glycosidic bond by the acid catalyst.16 In contrast,
the present method using a metal catalyst under neutral conditions
allowed even an acid-labile oligosaccharide to be glycosylated
without cleavage of the inner glycosidic bond and clearly indicated
that the anomeric position of the oligosaccharide could be activated
in a regiospecific manner.
We next attempted the synthesis of β-mannoside using 4,6-
dimethoxy-1,3,5-triazin-2-yl α-D-mannopyranoside (DMT-α-Man).
Use of [CuI(CH3CN)4]PF6 as a catalyst in methanol provided
the β-enriched product (α/β ratio = 30/70) and the JC,H
coupling constant of the anomeric carbon in the main product
was 160.0 Hz as determined by 13C NMR spectroscopy (Entry 9
and Figure S12). It is well known that the JC,H couplings of β- and
α-mannopyranosyl anomeric carbons are around 160 and 170 Hz,
respectively.17 NOESY NMR analysis also indicated that the main
product was β-mannoside, as the anomeric proton showed cross-
peaks with the 2-, 3-, and 5-position protons. The JC,H of the
anomeric carbon in the minor product was 169.0 Hz, indicating
α-configuration (Figure S14). The use of other alcohols (ethanol
and i-propanol) and other metal catalysts (Ag(I) and Pd(II)) also
provided product α/β ratios of approximately 30/70 (Entries 10-
14). The addition of acetonitrile slowed the reaction but did not
affect the α/β ratio of the product. The use of Lewis acids, such
as trimethylsilyl trifluoromethanesulfonate (TMSOTf), AgCl, and
ZnCl2, also provided β-enriched product but did not affect the α/β
ratio of the product (data not shown).
Although the detailed reaction mechanism remains unclear,
the preferential formation of 1,2-cis-glycoside suggests that the
reaction proceeds via a stereospecific SN2-type mechanism. It
is assumed that the nitrogen atom in the triazine ring or the
glycosidic oxygen is protonated by the metal, and the anomeric
center is activated. DMT-β-glycosides were almost completely
converted to α-glycosides. In contrast, DMT-α-Man provided
β-enriched mannoside, suggesting that an SN2-type reaction
preferentially occurred at the anomeric position of DMT-α-Man;
the mixture of β- and α-mannosides indicated that an SN1-type
reaction occurred nonpreferentially via an oxocarbenium ion
intermediate.
In conclusion, the stereoselective synthesis of alkyl glycosides
using DMT-glycosides as glycosyl donors, directly prepared from
free saccharides in water, was achieved by using a catalytic
amount of metal catalyst and provided 1,2-cis-glycosides, such as
α-glucoside and β-mannoside, by using 1,2-trans-glycosides, e.g.,
DMT-β-Glc and DMT-α-Man. It is noteworthy that the present
method is applicable not only to monosaccharides, but also to
di- and oligosaccharides and may provide a new approach for
glycosylation reactions in synthetic carbohydrate chemistry.
Supporting Information is available electronically on J-STAGE.
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2-yl-2-O-(4,6-dimethoxy-1,3,5-triazin)-α-D-glucopyranoside and 4,6-di-
methoxy-1,3,5-triazin-2-yl-2-O-(4,6-dimethoxy-1,3,5-triazin)-β-D-manno-
pyranoside etc., which were removed by column chromatography.
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848 | Chem. Lett. 2015, 44, 846–848 | doi:10.1246/cl.150201
© 2015 The Chemical Society of Japan