Protection-free synthesis of glycosyl dithiocarbamates in aqueous media by using 2-chloroimidazolinium reagent

Article abstract of DOI:10.1016/j.tetlet.2016.06.106

Glycosyl dithiocarbamates (GDTCs) have been synthesized directly from the corresponding unprotected sugars and dithiocarbamate salts in good yields by using 2-chloro-1,3-dimethylimidazolinium chloride (DMC) as condensing agent in aqueous media. The three-component one-pot synthesis of GDTCs starting from unprotected sugars, carbon disulfide, and secondary amines has also been successfully demonstrated. This is the first report on the direct synthesis of GDTCs from unprotected sugars without using any protecting groups.

Full text of DOI:10.1016/j.tetlet.2016.06.106

Tetrahedron Letters 57 (2016) 3529–3531
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Protection-free synthesis of glycosyl dithiocarbamates in aqueous
media by using 2-chloroimidazolinium reagent
⇑
Gefei Li, Masato Noguchi, Haruka Kashiwagura, Yuuki Tanaka, Kazunari Serizawa, 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:
Glycosyl dithiocarbamates (GDTCs) have been synthesized directly from the corresponding unprotected
sugars and dithiocarbamate salts in good yields by using 2-chloro-1,3-dimethylimidazolinium chloride
(DMC) as condensing agent in aqueous media. The three-component one-pot synthesis of GDTCs starting
from unprotected sugars, carbon disulfide, and secondary amines has also been successfully
demonstrated. This is the first report on the direct synthesis of GDTCs from unprotected sugars without
using any protecting groups.
Received 18 May 2016
Revised 20 June 2016
Accepted 23 June 2016
Available online 25 June 2016
Keywords:
Ó 2016 Elsevier Ltd. All rights reserved.
Glycosyl dithiocarbamate
2-Chloro-1,3-dimethylimidazolinium
chloride
Direct anomeric activation
Unprotected sugar
Protection-free synthesis
Glycosyl dithiocarbamates (GDTCs) are greatly important pre-
cursors in the synthesis of various kinds of carbohydrate deriva-
tives.1–5 In addition, as an important class of pharmaceutical
product, GDTCs display significant anti-bacterial6 and anti-tuber-
cular7 activities. The most widely used synthetic pathway for
accessing the GDTCs relies on the nucleophilic displacement of
acetylated glycosyl bromides with dithiocarbamate salts (DTC
salts) under basic conditions.8,9 As an alternative to utilizing DTC
salts, in some cases, carbon disulfide (CS2), and secondary amines
(R2NH) were employed to prepare designed N-substituted
GDTCs.10,11 More recently, an in situ conversion of perbenzylated
glycals to the GDTCs by the reaction with Et2NH and CS2 was
demonstrated by Wei and co- workers.12 However, the tedious
process including the protection-deprotection of the hydroxy
groups has been an obvious defect which constrains the synthesis
of GDTCs on a larger and more practical scale. In addition, these
reactions cannot be applied to a higher oligosaccharide having an
acid labile inner glycosidic bond, because the use of a strong acid
like HBr for preparation of glycosyl bromides in some cases causes
the cleavage of the inner glycosidic bonds of oligosaccharides. The
development of a facile method for synthesis of glycosyl dithiocar-
bamates under milder conditions has, therefore, been an urgent
topic in organic synthesis.
glycosyl azides,13 aryl thioglycosides,14–16 sugar oxazolines,17,18
and 1,6-anhydro sugars19 directly from the corresponding
unprotected sugars by using 2-chloro-1,3-dimethylimidazolinium
chloride (DMC) as a condensing agent, avoiding the protecting-
deprotection procedures. All these reactions can be carried out
under extremely mild reaction conditions in aqueous media. In
the present communication, we describe the first protection-free
synthesis of glycosyl dithiocarbamates (GDTCs) via the DMC-
mediated anomeric activation of unprotected sugars where DTC
salts behave as a nucleophile in aqueous media. To the best of
our knowledge, this is the first report on the direct synthesis of
GDTCs starting from unprotected sugars.
In a typical procedure, DMC was added to a solution of
D-glucose, sodium N,N-dimethyldithiocarbamate, and triethy-
lamine in a mixture of water and acetonitrile at À15 °C. The result-
ing mixture was stirred for one hour at the same temperature and
concentrated in vacuo. The residue was directly subjected to the
1HNMR analysis in order to evaluate the yield of the corresponding
b-
D
-glucopyranosyl dimethyldithiocarbamate.
Three kinds of commercially available DTC salts (Table 1, A, B,
and C) as well as synthesized DTC salt (Table 1, D)20 were used
in the DMC-mediated nucleophilic substitution with -glucose,
D
giving rise to the corresponding 1,2-trans glucopyranosyl dithio-
carbamates in good yields (Table 1, entries 1–3). The stereo-selec-
tive formation of b-products was confirmed by the coupling
constants of the doublet signals derived from the anomeric protons
(J1,2 = 9.8–11.0 Hz). In case of using a 2-pyrrolidone derivative as
In our previous works, we have developed a series of novel
methods for synthesis of useful synthetic intermediates such as
⇑
Corresponding author.
http://dx.doi.org/10.1016/j.tetlet.2016.06.106
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

3530
G. Li et al. / Tetrahedron Letters 57 (2016) 3529–3531
Table 1
Direct synthesis of glycosyl dithiocarbamates from unprotected sugars by using DMC
Cl
C
l
N
N
DMC
)
(OH n
(
O
)
H
n
,
dithocarbamate salts (DTC salts)
O
O
NR1R2
S
3
Et N, H2O/MeCN
OH
Na
S
S
NH4
S
NH4
Na
S
S
S
S
S
S
N
C
N
D
O
N
N
A
B
Entry
Sugar
DTC saltsa (equiv)
DMCa (equiv)
Et3Na (equiv)
H2O/MeCN
Temp. (°C)
Time (h)
Yieldb [%] ( /b)b
a
1
2
3
4
5
A (2)
B (2)
C (2)
D (2)
A (2)
2
2
2
3
4
9
9
9
9
2/3
1/1
1/1
1/1
1/1
À15
À15
À15
À10
À15
À15
À10
0
0
0
À15
À10
0
0
0
1.0
1.0
1.0
0.5
1.0
80 (b only)
70 (b only)
79 (b only)
50 (b only)
D
-Glucose
16
67 (a only)
D-Mannose
D-Galactose
D-Xylose
6
7
A (2)
A (2)
2
2
9
9
1/1
1/1
1.0
1.0
21 (b only)
70 (b only)
8
9
2-Deoxy-glucose
2-O-Propyl-glucose
N-Acetylglucosamine
Melibiose
Lactose
Maltose
Chitobiose
Maltotriose
Maltopentaose
A (5)
A (5)
A (4)
A (2)
A (2)
A (4)
A (3)
A (6)
A (4)
3
3
3
2
2
2
3
3
2
9
9
9
9
6
9
9
9
9
1/1
1/1
1/0
1/1
1/1
1/1
3/1
1/1
1/1
1.0
1.0
1.0
1.0
1.5
1.0
1.0
1.0
1.0
42 (45/55)
68 (15/85)
67 (b only)
72 (b only)
55 (b only)
70 (b only)
60 (4/96)
10c
11
12
13
14
15
16
80 (b only)
45 (b only)
À10
a
b
c
Relative to unprotected sugar.
Determined by 1H NMR.
After one hour, trifluoroacetic acid was added.
nucleophile, the yield was considerably decreased (entry 4). This
result can be explained by the reduced nucleophilicity of the thio-
late anion D due to the existence of the electron-withdrawing
pyrrolidone moiety.
Next, other monosaccharides were treated with DTC salt A by
using DMC as condensing agent under a similar reaction condition
The DMC-mediated direct synthesis of GDTCs by using dithio-
carbamate salts as a nucleophile has successfully been expanded
to a three-component one-pot synthesis of GDTCs starting from
unprotected sugars, dialkylamines, and CS2 without isolating the
DTC salts as synthetic intermediate. It was found that a simple
mixing of CS2, a dialkylamine and an unprotected sugar gave the
desired products in good yields with DMC as the condensing agent
(Table 2). A typical experimental procedure for synthesis of meli-
biosyl diethyldithiocarbamate is as follows: CS2 and Et2NH were
mixed firstly with Et3N, forming the intermediate of the corre-
sponding DTC salt. Thereafter, an aqueous solution of melibiose
(Table 1, entries 5–10). The
a-type product was obtained in fairly
good yield in case of using -mannose as the result of the neighbor-
D
ing participation of the axial hydroxy group at the C-2 position
(entry 5). The hydrolysis of the resulting glycosyl dithiocarbamate
to the hemiacetal was observed in the reaction with
due to the low stability of galactosyl DTC species (entry 6). When
2-deoxy-glucose and 2-O-propyl- -glucose were used, a mixture
of and b glycosyl dithiocarbamates was obtained, because no
D-galactose
D
Table 2
a
One-pot reaction of carbon disulfide, amines and unprotected sugars for the synthesis
neighboring participation exists due to the lack of the hydroxy
group at the C-2 position (entries 8 and 9). When N-acetylglu-
cosamine was employed, 1,2-oxazoline derivative was formed in
more than 40% yield as the by-product via an intramolecular
cyclization of the 2-acetamido group,17,18 resulting in low yield
of the desired GDTC (data not shown). To facilitate the conversion
of the 1,2-oxazoline to the GDTC by a ring-opening substitution by
DTC salt, the reaction mixture was further treated by an aqueous
solution of trifluoroacetic acid (1 M) in order to activate the oxazo-
line moiety by protonation on the nitrogen atom of the oxazolines
ring, which greatly improved the yield of 2-acetoamide-2-deoxy-b-
glucopyranosyl dithiocarbamate (entry 10).
The present method could also be applied to disaccharides and
oligosaccharides (entries 11–16). Various oligosaccharides
including an acid labile inner glycosidic bond like melibiose could
be converted to the corresponding b-dithiocarbamates stereoselec-
tively under mild reaction conditions without affecting the inner
glycosidic bonds. In case of using maltopentaose as unprotected
sugars, an intramolecular nucleophilic attack of the hydroxy group
at C-6 took place as a side reaction, giving rise to the corresponding
1,6-anhydro sugar (35% yield), which caused the decrease of the
yield of maltopentaosyl dithiocarbamate (entry 16).
a
of glycosyl dithiocarbamates by using DMC
㻱㼠 㻺㻴
㻟
(OH)
n
R1R2NH, Et3N
MeCN,
S
S
Sugar
O
CS2
R R N
2
1
S
NR R
1
2
DMC, Et3N, 0.5 h
MeCN/H2O, -15 㼻C
㼻→
C
0
rt, 0.5h
S
Entry
Sugar
Amine
Yieldb [%] ( /b)b
a
1
2
3
Diethylamine
Piperidine
Morpholine
84 (b only)
83 (b only)
82 (b only)
D-Glucose
4
5
6
Di-i-propylamine
t-Butylamine
Diethylamine
trace
-
72 (b only)
D
-Mannose
-Galactose
7
Diethylamine
43 (b only)
D
8
Melibiose
Maltose
Glucosamine
Diethylamine
Diethylamine
None
84 (b only)
77 (b only)
—
9
10c
a
All the reactions were carried out using 3 equiv of CS2, R1R2NH, and DMC for
unprotected sugars. Equivalency of Et3N: entries 1 and 2: 3 equiv; entry 3: 5 equiv;
entry 6: 12 equiv; entries 7–9: 9 equiv.
b
Determined by 1H NMR.
Compound B1 was obtained in 45% yield.
c

G. Li et al. / Tetrahedron Letters 57 (2016) 3529–3531
3531
OH
In summary, a one-step direct synthetic approach was estab-
lished for the preparation of various kinds of glycosyl dithiocarba-
mates starting from unprotected sugars and dithiocarbamate salts
(DTC salts) by using DMC as a dehydrative condensing agent. It is
to be noted that the reaction requires no protection of hydroxy
groups and proceeds under extremely mild conditions in aqueous
media. The present novel method would be a general and practical
tool for the synthesis of various glycosyl dithiocarbamates, which
can be applicable to not only unprotected monosaccharides but
also complex oligosaccharides without affecting their inner glyco-
sidic bonds. Varied DTC structures were gained by the one-pot
reaction with CS2 and secondary amines. Further application of
the resulting unprotected dithiocarbamates to radical reactions
as well as the elucidation of a detailed reaction mechanism is
now in process in our laboratory.
OH
O
O
HO
HO
HO
HO
N
O
S
H
O
HN
C
S
B1
Figure 1. DMC-mediated formation of a cis-fused bicyclic thiocarbamate by the
reaction of -glucosamine with CS2.
D
and DMC was added and the resulting mixture was stirred for
another half an hour at À15 °C.
Several kinds of secondary amines such as Et2NH, piperidine,
and morpholine afforded the corresponding glycosyl dithiocarba-
mates in good yields (entries 1–3 and 6–9). The use of diisopropy-
lamine gave no desired product (entry 4). This result is in
consistent with the fact that the nucleophilic attack of the nitrogen
atom of diisopropylamine to CS2 becomes disadvantageous due to
the bulky isopropyl groups, affording only small amount of the
corresponding DTC salt.21
Acknowledgments
This work was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science,
and Technology, Japan.
When tert-butylamine was utilized as a primary amine, the
desired product could not be obtained (entry 5). It is well known
that DTC salts of primary amines are easily converted to the corre-
sponding dehydrated products of isothiocyanates by a dehydrative
condensing agent.22 In the present study, it is assumed that since
the reaction was carried out in an aqueous media, the resulting
isothiocyanates were immediately decomposed by the intermolec-
ular attack of water molecule. In case of using glucosamine as a
primary amine, the desired cyclic dithiocarbamate could not be
detected. Instead of it, the formation of a novel compound,
O-glycoside B1 was confirmed by NMR analysis (Fig. 1).23 The
formation of the by-product B1 can be explained by an intramolec-
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.06.
106.
References and notes
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ular attack of the anomeric hydroxy group with
the resulting isothiocyanate moiety.
a-configuration to
The stereo-selective formation of b-gluco-type dithiocarbamate
can be explained by assuming the initial formation of a formami-
dinium glycosyl intermediate having a b-configuration as the
result of a nucleophilic substitution of the hemiacetal of an
unprotected sugar with the chlorine on the 2 position of DMC by
the assistance of Et3N as a general base. The resulting formami-
dinium type glycosyl intermediate is immediately converted to
the 1,2-anhydro intermediate by the intramolecular nucleophilic
substitution of the 2-hydroxy group, by liberating 1,3-dimethylim-
idazolidin-2-one (DMI). Since the resulting 1,2-anhydro sugar has a
ring strain due to the epoxide moiety, an intermolecular attack of a
DTC salt takes place smoothly from the b-side of the pyranose ring,
giving rise to the corresponding b-dithiocarbamate. The another
plausible mechanism which involves the SN2 type nucleophilic
attack of DTC salt to the formamidinium intermediate having an
a
-configuration formed by the reaction of
not be excluded. The neighboring participation of the hydroxy
group at the C-2 position is also possible in case of -mannose,
where the product is -glycosyl dithiocarbamate as a result of
a-glucose and DMC can-
18. Noguchi, M.; Fujieda, T.; Huang, W. C.; Ishihara, M.; Kobayashi, A.; Shoda, S.
Helv. Chim. Acta 2012, 95, 1928.
19. Tanaka, T.; Huang, W. C.; Noguchi, M.; Kobayashi, A.; Shoda, S. Tetrahedron Lett.
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D
a
SN2 attack of DTC salt to the 1,2-anhydro-mannose intermediate.
The participation of these 1,2-anhydrosugar intermediate is
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consistent with the results that 2-deoxy-
pyl- -glucose gave an anomeric mixture of glycosyl dithiocarba-
mates due to the absence of neighboring participation.
D-glucose and 2-O-pro-
D