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Chemistry Letters Vol.38, No.5 (2009)
Direct Transformation of Unprotected Sugars to Aryl 1-Thio-ꢀ-glycosides
in Aqueous Media Using 2-Chloro-1,3-dimethylimidazolinium Chloride
Tomonari Tanaka, Takeshi Matsumoto, Masato Noguchi, Atsushi Kobayashi, and Shin-ichiro Shodaꢀ
Department of Biomolecular Engineering, Graduate School of Engineering, Tohoku University,
6-6-11-514 Aoba, Sendai 980-8579
(Received February 25, 2009; CL-090193; E-mail: shoda@poly.che.tohoku.ac.jp)
Aryl 1-thioglycosides have directly been synthesized in
Table 1. Direct synthesis of aryl thioglycosides from unpro-
tected sugarsa
good yields from the corresponding unprotected sugars and
thiols without protection of the hydroxy groups by using 2-
chloro-1,3-dimethylimidazolinium chloride (DMC) as dehydra-
tive condensing agent. The reaction proceeded in a mixed sol-
vent of water and acetonitrile under mild reaction conditions,
leading to the predominant formation of ꢀ-anomers.
Cl
Cl
+
N
H3C
CH3
N
R SH
DMC
O
O
OH
S
R
Et3N
H2O / MeCN
OH
OH
Entry Sugar
H2O/MeCN, RSH (equiv)
Yield/%b
Temp/°C
(β/α)
There has been a growing research interest in thioglycosides
in carbohydrate chemistry.1 Aryl 1-thioglycosides are useful pre-
cursors of glycosyl fluorides, glycosyl bromide, and glycosyl
sulfoxides.2 Thioglycoside derivatives are also employed as ef-
ficient glycosyl donors or glycosyl acceptors for chemical or en-
zymatic glycosylations.3 In addition, they are stable O-glycoside
analogues, which can be utilized as enzyme inhibitors in various
biochemical studies.4
In general, thioglycoside derivatives are synthesized by the
reaction of a peracetylated sugar with a thiol in the presence of a
Lewis acid,5 or by substituting the bromine of an acetobromo-
glucose with a thiolate anion.6 Thioglycosides can also be pre-
pared by treating 1-thiosugars with an electrophile like alkyl
halides.7 All of these procedures require multistep reactions
including protection and deprotection of the hydroxy groups.
Direct methods for preparation of thioglycosides from hemiace-
tals have been demonstrated in trifluoroacetic acid. However,
these methods show poor selectivity concerning the anomeric
configuration and are accompanied by the formation of dithio-
acetals as by-products.8
In a series of our investigation of the direct activation of
unprotected sugars,9 we have recently reported the synthesis of
1,6-anhydrosugars10 via an intramolecular dehydration reaction
in aqueous media by using 2-chloro-1,3-dimethylimidazolinium
chloride (DMC).11 The reaction proceeds via a reactive inter-
mediate that is formed as a result of a preferential attack of
the anomeric hydroxy group toward DMC.12 Then, an intramo-
lecular nucleophilic attack of the 6-hydroxy group to the anome-
ric carbon gives rise to the 1,6-anhydrosugar.
We postulated that if the reaction is carried out in the pres-
ence of a thiol, a direct introduction of a thioaryl group to the
anomeric carbon would be possible, affording the corresponding
1-thioglycoside. The present paper describes a DMC-mediated
intermolecular dehydration reaction between the anomeric
hydroxy group of unprotected sugars and aromatic thiols to give
the corresponding aryl 1-thioglycosides.
1
2
3
4
5
6
7
8
9
D-Glucose
D-Glucose
D-Glucose
D-Glucose
D-Glucose
Cellobiose
Lactose
1/1, −15
1/1, 0
(5)
quant. (6.7/1)
93 (4.5/1)
90 (10/1)
90 (β)
SH
SH
SH
(7)
(3)
(5)
(5)
(5)
(5)
(5)
(5)
Me
1/1, 0
MeO
1/1, r.t.
1/1, 0
O2N
SH
SH
SH
SH
N
N
N
91 (β)
4/1, 0
quant.(β)
quant.(β)
quant.(β)
quant.(β)
4/1, 0
N
N
Laminaribiose 4/1, 0
Melibiose
4/1, 0
SH
SH
aThe reactions were carried out using 3 equiv of DMC and 10
equiv of Et3N. The reaction time: 1 h. bDetermined by 1H NMR
by comparing the integrals of the anomeric proton of the product
and that of unprotected sugar in D2O.
(Et3N) is effective for promotion of the reaction. It was also pre-
dicted that a considerable amount of 1,6-anhydrosugar would be
formed as by-product. Interestingly, the addition of acetonitrile
greatly reduced the formation of 1,6-anhydroglucose, leading
to the preferential formation of thioglycoside.13
Table 1 summarizes the synthesis of various aryl 1-thio-
glycosides by the reaction of unprotected sugars and aromatic
thiols. In case of using benzenethiol, p-toluenethiol, and 4-
methoxybenzenethiol, the corresponding ꢀ-thioglycosides were
obtained preferentially (Entries 1–3). When 4-nitrobenzenethiol
and 2-pyridinethiol were reacted with D-glucose in the presence
of DMC, the corresponding thioglycosides having ꢀ-configura-
tion were exclusively obtained (Entries 4 and 5). The present
reaction could successfully be applied to disaccharides (Entries
6–9). Cellobiose (ꢀ-1,4), laminaribiose (ꢀ-1,3), melibiose (ꢁ-
1,6) have been transformed to the corresponding 2-pyridyl thio-
glycosides in excellent yields without affecting the inner glyco-
sidic bonds.
It was predicted that more than 2 equivalents of base would
be necessary to scavenge hydrogen chloride liberated and to ac-
tivate a hydroxy group in the course of the reaction. We screened
various bases as well as their equivalency using D-glucose as a
model substrate, and finally found that the use of triethylamine
The following is a typical procedure for synthesis of thiogly-
coside (Entry 5). DMC was added to a mixture of D-glucose,
Et3N, and 2-pyridinethiol in water/acetonitrile (1/1 (v/v)),
and the reaction mixture was stirred for 1 h at 0 ꢁC. After re-
moving the solvent, the residue was purified by using silica
Copyright Ó 2009 The Chemical Society of Japan
Tanaka, Tomonari
