A mild and convenient indium(III) chloride-catalyzed synthesis of thioglycosides

Article abstract of DOI:10.1016/S0008-6215(03)00355-0

The efficiency of glycosidation reactions generally involves a high chemical yield, as well as high/complete stereo- and regioselectivity. All these depend on the compatibility of the reactivity of glycosyl donors and acceptors. Among glycosyl donors, thi

Full text of DOI:10.1016/S0008-6215(03)00355-0

Carbohydrate Research 338 (2003) 2237Á2240
/
www.elsevier.com/locate/carres
Note
A mild and convenient indium(III) chloride-catalyzed synthesis of
thioglycosidesꢀ
Saibal Kumar Das,* Joyita Roy, Kalusani Anantha Reddy, Chandrasekhar Abbineni
Department of Discovery Chemistry, Discovery Research, Dr. Reddy’s Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500 049, India
Received 6 March 2003; accepted 16 July 2003
Abstract
The efficiency of glycosidation reactions generally involves a high chemical yield, as well as high/complete stereo- and
regioselectivity. All these depend on the compatibility of the reactivity of glycosyl donors and acceptors. Among glycosyl donors,
thioglycosides are widely used because of their high degree of stability in many organic reactions. Although there are number of
methods available for the preparation of thioglycosides, all of them have one or more disadvantages, especially concerning the time
factor and cumbersome workup procedures. Here we report a convenient and high-yielding method for the preparation of
thioglycosides.
# 2003 Elsevier Ltd. All rights reserved.
Keywords: Indium(III) chloride; Thioglycoside; Thiols; Stereoselectivity
O-Glycosylation, which is crucial for attaching a sugar
to other sugar moieties or aglycons, is an important
chemical reaction. From a synthetic standpoint, the
efficiency of the O-glycosylation reaction generally
involves both a high chemical yield and high/complete
stereo- and regioselectivity. All these depend on the
general compatibility of the reactivity of glycosyl donors
and acceptors. Among glycosyl donors, thioglycosides
are widely used because of their high degree of stability
in many organic reactions. These are also useful
intermediates for the preparation of glycosyl fluorides,1
which are also useful glycosyl donors. There are many
methods available in the literature for thioglycoside
preparation.2 But all of them have one or another
disadvantage such as cumbersome workup, cost of
production, use of heavy metal salts like ZnCl2/ZnI2,
which are also difficult to get rid of. Moreover, the use
of a huge excess of thiols as reagents as well as solvent or
the use of CHCl3-like carcinogenic solvents are also
among a few drawbacks to be mentioned. Above all,
these conditions generally require a longer time for the
completion of the reaction.
Recently, indium(III) halides have emerged as useful
Lewis acid catalysts in organic synthesis.3 The unique
feature of indium(III) chloride is its compatibility with
both organic and aqueous media, facts which have
widely attracted chemists to this reagent. Because of low
catalyst loading, moisture compatibility and easy re-
moval from the reaction mixture by water wash, InCl3
has been used by sugar chemists in both O- and C-
glycosylation reactions in carbohydrate field.4 Intrigued
by the widespread use of this particular catalyst and cost
effectiveness, we wanted to explore the utility of InCl3
for the synthesis of different thioglycosides, which, to
our knowledge, has not yet been reported. In this report,
we present a novel method for the preparation of
thioglycosides using indium(III) chloride. An example
is shown in the Scheme 1 below.
For our studies we chose per-O-acetylglycopyranoses
as substrates and acetonitrile as the solvent of choice
because of its known assistance for stereospecific 1,2-
trans-glycosylations. Initially, we tried to develop the
reaction via the addition of a thiol to a stirred solution
of per-O-acetylglycopyranose in acetonitrile and InCl3
(20 mol%). However, the reaction was found to proceed
slowly. The reaction was incomplete even after 72 h by
ꢀ DRL Publication No. 268.
* Corresponding author. Tel.: ꢀ
/
91-40-23045439; fax: ꢀ91-
/
40-23045438.
E-mail address: saibalkumardas@drreddys.com (S.K. Das).
0008-6215/03/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0008-6215(03)00355-0

2238
S.K. Das et al. / Carbohydrate Research 338 (2003) 2237Á
/2240
Scheme 1.
using as high as 50 mol% InCl3. When a catalytic
amount of TiCl4 was added as co-activator along with
20 mol% (40 mol% for mannose pentaacetate) of InCl3,
the reactions were complete within short time with high
A summary of thioglycosides prepared using this
method is illustrated in Table 1. The choice of amount
of InCl3 and TiCl4 was found to be perfect for all the
glycose acetates, excepting mannose pentaacetate where
additional amounts of both the reagents had to be used.
All the yields reported are isolated yields, and the
structures of each of the compounds was deduced based
on 1H NMR spectroscopy, chemical-ionization mass
spectrometry (CIMS) or electrospray-ionization mass
spectrometry (ESIMS), and IR spectroscopy, which
were found to be in accordance with the literature
data.5 Spectral and physical characterization data of the
new compounds were satisfactory. The anomeric ratios
yields. Lonn synthesised2j ethyl 3,4,6-tri-O-acetyl-2-
¨
deoxy-2-phthalimido-1-thio-b-D-glucopyranoside using
only TiCl4 (1.3 equiv) as promoter, and the reaction
also took a longer time to complete.
However, when we performed the reaction on per-O-
acetylglucopyranose using TiCl4 (0.2 equiv) and etha-
nethiol (3 equiv) in the absence of InCl3, the reaction
remained incomplete even after 24 h at room tempera-
ture, yielding only 11% of ethyl 2,3,4,6-tetra-O-acetyl-1-
1
thio-b-
D
-glucopyranoside. When the same conditions
were determined by HPLC and H NMR spectroscopy.
were applied with an increased amount of TiCl4 (1.0
equiv), the reaction was complete within 3 h affording
only 37% of the said product. In both the cases, a
substantial amount of starting material was found to be
decomposed. (Details are not provided in the Experi-
mental.)
It was observed that the pentaacetate derivatives of
glucose and galactose showed high b-selectivity apart
from good to excellent yields. The yields of tri-O-acetyl-
thiofucosides were high, and the selectivities were also
moderate. For mannose pentaacetate the conversion
rates were slow, and the yields were low because of
Table 1
Experimental data for 1-thioglycosides prepared from different sugar acetates
Starting sugar acetate
Thiogly. formed InCl3 (mol%) TiCl4 (equiv) Yield (%) a/b (min) Time Reference
b-
b-
b-
a-
a-
D
-Galactose
-Glucose
p-Toluoyl
Phenyl
Ethyl
20
20
20
0.2
0.2
0.2
75
84
98
ꢀ
/
95% b
25 5a
25 5b
25 5c
ꢀ
/
95% b
a
1:19
D
p-Toluoyl
Phenyl
Ethyl
20
20
20
0.2
0.2
0.2
80
82
72
1:19
25 5a
75 2k
25 5c
ꢀ95% b
/
a
1:19
L-Fucose
p-Toluoyl
Phenyl
Ethyl
20
20
20
0.2
0.2
0.2
86
82
70
1:6
1:4
1:19a
10 5ab
10 5db
10 5e
D-Mannose
p-Toluoyl
Phenyl
Ethyl
40
40
40
0.5
0.5
0.5
43
44
30
ꢀ
/
95% a 180 5f
19:1 180 5g
95% a 180 2d
ꢀ
/
L-Rhamnose
p-Toluoyl
Phenyl
Ethyl
20
20
20
0.2
0.2
0.2
78
80
72
4:1
2:1
9:1
20
6
20 5h
20 5i
2-Deoxy-2-phthalimido-b-
D
-Glucose
p-Toluoyl
Phenyl
Ethyl
20
20
20
0.2
0.2
0.2
24
57
60
ꢀ
/
95% b 180
6
40 5j
40 2j
ꢀ
/
95% b
95% b
ꢀ
/
a
Only from NMR spectrum.
For major anomer.
b

S.K. Das et al. / Carbohydrate Research 338 (2003) 2237Á
/2240
2239
degradation, although the reactions are highly stereo-
selective. Anomeric selectivity for the rhamnose thiogly-
cosides has been observed to be slightly low. This could
be attributed to its high reactivity, which forced the
formation of kinetically controlled b-thioglycosides to a
larger extent. The yields of tri-O-acetyl-2-deoxy-2-
PerkinÁ
ionization, ESI, capillary voltage between ꢀ
4500 V). The IR spectra were recorded using PerkinÁ
Elmer 1650 FTIR spectrophotometer. Melting points
were measured in glass capillaries on a Buchi 535 digital
¨
melting point apparatus and are uncorrected. All
/
Elmer Sciex model API 3000 (electrospray-
/5000 and
ꢁ
/
/
phthalimido-1-thio-b-
ate, although, as expected, the outcomes are stereose-
lective. p-Tolyl
2-deoxy-2-phthalimido-b-
D
-glucopyranosides were moder-
chromatography solvents were distilled before use. Silica
gel (100Á200 mesh, SRL, India) was used for column
/
D
-
chromatography.
glucopyranoside was obtained in only 24% yield prob-
ably because of the steric interaction of phthalimido
group with the p-tolyl group. When the reactions of
1.2. General procedure
tetra-O-acetyl-2-deoxy-2-phthalimido-b-
ose were conducted at 0Á5 8C, the main product isolated
was the 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-b-
D-glucopyran-
/
To a stirred solution of per-O-acetylglycopyranose (0.5
mmol) in acetonitrile (2 mL), thiol (3 equiv) and InCl3
(for amount, see Table 1) were added at room tempera-
ture, followed by the addition of TiCl4 (for amount, see
Table 1), and the reaction was monitored by TLC. At
the end point the reaction mixture was diluted with
EtOAc and washed successively with satd aq Na2CO3
and brine, dried (Na2SO4) and concentrated. Filtration
of the crude products through a short column of silica
gel afforded the respective thioglycosides as anomeric
mixtures.
D
-
glucopyranosyl chloride,6 and no thioglycoside could
be detected. This observation gives an idea about the
plausible mechanism of the reaction. It seems that
product formation is guided by the neighboring group,
either through direct participation or through the steric
bulk, thereby allowing the nucleophile to attack from
the b face. It is therefore presumed that in this TiCl4-
mediated InCl3-promoted reaction per-O-acetyl-glyco-
syl chlorides are the intermediates, which on further
attack by the sulfur nucleophile give rise to 1,2-trans-
products. In fact, when these reactions were performed
at 10 8C with fucose tetraacetate, the reactions were
complete within 15 min providing the respective thio-
glycosides. This fact can be attributed to the high
1.2.1. p-Methylphenyl 2,3,4-tri-O-acetyl-1-thio-a-L-
rhamnopyranoside. Syrup; IR (KBr): 2984, 1751, 1493,
1434, 1373, 1223, 1107, 1055, 981, 907 cmꢁ1
.
reactivity of the 2,3,4-tri-O-acetyl-b-
L
-fucopyranosyl
1H NMR (CDCl3): d 1.27 (d, 3 H, J 6.2 Hz, H-6),
2.00, 2.07 and 2.16 (3s, 9 H, 3Ac), 2.32 (s, 3 H, Me),
chloride, obtained from fucose tetraacetate, in the
presence of InCl3, thereby affording the final thioglyco-
sides even at 10 8C.
4.06Á4.22 (m, 1 H, H-5), 5.13 (t, 1 H, J 9.9 Hz, H-4),
/
5.39 (br s, 1 H, H-2), 5.56 (dd, 1 H, J 10.2 and 3.2 Hz,
H-3), 5.93 (br s, 1 H, H-1), 7.12 (d, 2 H, J 7.5 Hz, Ph),
7.35 (d, 2 H, J 8.3 Hz, Ph). 13C NMR (CDCl3): d 16.71,
20.15, 20.22, 20.29, 67.4, 69.1, 70.68, 71.47, 88.87 (C-1),
129.5, 129.6 (2C), 132.1 (2C), 137.77, 169.29, 169.37 and
In summary, our present methodology has the
following advantages: (a) the promoter is used in
catalytic amount; (b) cost-effective inexpensive reagents
are employed; (c) short reaction times are involved; (d)
good yields are obtained; (e) usually easy workups are
involved, and (f) moderate-to-high stereoselectivities are
observed. To conclude, we have developed a general,
mild, and time-saving approach to prepare varieties of
thioglycosides.
169.49. CIMS: m/z 397 (Mꢀꢀ
1).
/
1.2.2. p-Methylphenyl
phthalimido-1-thio-b- -glucopyranoside. Solid; mp 160Á
162 8C (EtOAcÁpetroleum ether); [a]D 408 (c 0.58,
3,4,6-tri-O-acetyl-2-deoxy-2-
D
/
/
ꢀ
/
CHCl3). IR (KBr): 2924, 1750, 1624, 1384, 1229, 1037,
912 cmꢁ1. 1H NMR (CDCl3): d 1.84, 2.03 and 2.11 (3s,
1. Experimental
9 H, 3Ac), 2.34 (s, 3 H, Me), 3.84Á/3.93 (m, 1 H, H-5),
1.1. General instrumentation procedures
4.11Á4.30 (m, 2 H, H-6), 4.33 (t, 1 H, J 10.5 Hz, H-4),
/
5.13 (t, 1 H, J 9.8 Hz, H-3), 5.66 (d, 1 H, J 10.7 Hz, H-
1), 5.79 (dd, 1 H, J 10.3 and 9.3 Hz, H-2), 7.08 (d, 2 H, J
8.3 Hz, Ph), 7.31 (d, 2 H, J 8.3 Hz, Ph), 7.77 (dd, 2 H, J
5.9 and 2.9 Hz, Ph), 7.88 (dd, 2 H, J 5.5 and 3.4 Hz, Ph).
13C NMR (CDCl3): d 20.34, 20.56, 20.70, 21.12, 53.60,
62.17, 68.71, 71.64, 75.83, 83.09 (C-1), 123.64 (3C),
126.95, 129.61 (3C), 133.89 (3C), 134.32, 138.71, 166.89,
The 1H NMR spectra were recorded with tetramethylsi-
lane (TMS, d 0.00) as the internal standard on a Varian
Gemini 200- or 400-MHz FTNMR spectrometer. 13C
NMR spectra were recorded with CDCl3 (d 77.00) as
the internal standard at 50 MHz on a Varian Gemini
200-MHz FTNMR spectrometer. Mass spectra were
either measured on Hewlett-Packard 5989A mass spec-
trometer (chemical ionization, CI, 20 eV) or on a
167.76, 169.40, 170.03 and 170.55. ESIMS: m/z 559.2 (/
MꢀNHꢀ4 ); 564.2 (MꢀNaꢀ).
/

2240
S.K. Das et al. / Carbohydrate Research 338 (2003) 2237Á2240
/
(b) Ghosh, R. Indian J. Chem. 2001, 40B, 550Á
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Acknowledgements
We express our esteemed gratitude to Dr K. Anji Reddy
and Dr R. Rajagopalan and Professor J. Iqbal for their
continued encouragement in this work. We thank the
members of Analytical Research Department for the
spectral analysis. Professor N. Roy, Indian Association
for the Cultivation of Science, Calcutta is gratefully
acknowledged for providing some literature assistance.
/
/
/
(d) Das, S. K.; Reddy, K. A.; Roy, J. Synlett., 2003, in
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