InBr 3 -Catalyzed Synthesis of Aryl 1,2- trans -Thio(seleno)glycosides

Article abstract of DOI:10.1055/s-0036-1588507

InBr ₃ is demonstrated to be an efficient catalyst for reactions of fully acetated aldoses with aryl mercaptans or selenophenol at room temperature, rapidly furnishing the corresponding thioglycosides or selenoglycosides with exclusively 1,2- t

Full text of DOI:10.1055/s-0036-1588507

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–D
letter
A
en
T. Ma et al.
Letter
Synlett
InBr3-Catalyzed Synthesis of Aryl 1,2-trans-Thio(seleno)glycosides
O
Teng Ma
10% InBr3
O
AcO
S
SH
AcO
OAc
Changwei Li
Haijing Liang
Zhaoyan Wang
Lan Yu*
r.t., air, CH2Cl2
R
R
up to 98% yield, 19 examples
O
10% InBr3
O
SeH
AcO
Se
AcO
OAc
r.t., air, CH2Cl2
Weihua Xue*
up to 98% yield, 9 examples
School of Pharmacy, Lanzhou University,
Lanzhou, 730000, P. R. of China
xuewh@lzu.edu.cn
Received: 25.05.2017
Accepted after revision: 23.06.2017
Published online: 20.07.2017
quential assembly of complex oligosaccharides. Thus,
synthesis of these organosulfur compounds with high effi-
ciency is of great value.
DOI: 10.1055/s-0036-1588507; Art ID: st-2017-w0399-l
Considerable effort has been directed toward the devel-
opment of general and selective methods for preparing
thioglycosides. Preparation of thioglycosides is accom-
plished by metal-catalyzed coupling reaction of aryl halides
with nucleophilic thioglycosylating reagents,6–8 although
these nucleophiles are relatively inaccessible and their
preparation requires tedious synthetic procedures and la-
borious chromatographic processes. The most commonly
used strategy for the construction of S-glycosidic bonds in-
volves treatment of peracetated aldoses with commercially
available aryl mercaptans in the presence of Lewis acids.
Diverse Lewis acids such as FeCl3,9 ZiCl4,10 Et2O·BF3,11 and
Abstract InBr3 is demonstrated to be an efficient catalyst for reactions
of fully acetated aldoses with aryl mercaptans or selenophenol at room
temperature, rapidly furnishing the corresponding thioglycosides or
selenoglycosides with exclusively 1,2-trans-stereoselectivity. This bro-
mide is an air- and moisture-stable Lewis acid and therefore the reac-
tions can be performed in air atmosphere making the procedure simple
to perform.
Key words InBr3, thioglycosides, selenoglycosides, stereoselectivity,
aldose acetates
The synthesis and application of carbohydrate deriva-
tives remains a subject of great interest because of the re-
markable biological relevance of carbohydrate motifs.
Among them, thioglycosides represent a valuable class of
functional compounds, in which a sulfur atom has replaced
the glycosidic oxygen atom. These glycomimetics exhibit
apparent advantages over their parent molecules because
they increase the metabolic stability and might lead to the
rational design of new generations of therapeutic agents.1
Additionally, a large number of naturally occurring antibi-
otics2 and antitumor compounds possess thioglycoses as
crucial structural moieties.3 As thioglycosides are usually
stable under many protecting group transformations, mul-
tifunctional derivatives can be produced relatively easily.
Moreover, thioglycosides are readily converted into other
glycosyl donors that are commonly used in oligosaccharide
synthesis, including halides,4 fluorides, and sulfoxides.5 In
particular, thioglycosides, featuring tunable reactivity de-
pendent on different protecting groups, have been estab-
lished to be attractive building blocks for the one-pot se-
12
Cu(OTf)2 have been reported to enable the conversion;
nevertheless, in most instances, high loading — often a stoi-
chiometric amount — is required to achieve satisfactory
yields. Especially, these Lewis acid catalyzed reactions usu-
ally give a mixture of α,β-anomers. To date, examples of
glycosylating aryl mercaptans under the catalysis of transi-
tion metals remain scarce. MoO2Cl2 was first found to be an
effective catalyst for reaction of fully acetated aldoses with
thiols.13 FeI3 was then reported to be an alternative promot-
er.14 Unfortunately, the strong sensitivity of these halides to
moisture and air rendered the preparation and handling of
them fairly difficult. Phenyl selenoglycosides constitute an-
other category of useful glycosyl donors. They can be selec-
tively activated in the presence of thioglycosides, which
make them attractive in oligosaccharide synthesis.15 Analo-
gous to thioglycosides, they are mostly prepared from acid-
activated reaction of peracetylated aldoses with phenylsele-
nol. A potentially promising alternative protocol relies on
the phenylselenolate anion generated in situ from the re-
duction of phenyldiselenide with reducing agents16 and its
subsequent nucleophilic attack toward glycosyl bromides.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

B
T. Ma et al.
Letter
Synlett
Although these methods sometimes provide satisfactory
yields, they suffer from laborious workup and high con-
sumption of excess reagents. To our knowledge, examples of
catalytic reactions that can be used to access selenoglyco-
sides under mild conditions remain unknown. Therefore,
there remains a need to develop an efficient catalyst that
overcomes the above drawbacks.
Indium species are widely applied to mediate various
reactions, producing diverse synthetic intermediates as
well as many natural bioactive products. Another distinc-
tive advantage of using indium compounds is that both in-
dium metal and its derivatives are less toxic or even non-
toxic.17 Among a legion of readily accessible indium re-
this reaction performed much better within 2 h, and com-
pound 1a was isolated in an excellent yield (entries 4 and
5). Although InI3 is tolerant of water, its highly hygroscopic
nature is inconvenient. In contrast, InBr3 has high stability
to air and moisture and is comparatively inexpensive, so
this reagent was selected as the optimal catalyst in the pro-
tocol. A reduction of its loading to 5 mol% led to a slightly
lower yield (entry 6). We also noted that the α-isomer of a
was unreactive and that the substitution of alkylthiols for
p-thiocreso did not lead to the formation of 1a.
The thioglycosylation reaction could be performed on a
gram scale. Treating a solution of a (3.90 g, 10.0 mmol) and
p-thiocresol (1.49 g, 12.0 mmol) in CH2Cl2 (50 mL) with cat-
alytic InBr3 (354 mg, 1.0 mmol) for approximately 4 h, fur-
nished 1a in 93% yield.
agents, InBr3 is
a remarkably air- and water-stable
crystalline solid. Moreover, it has been found to be an effec-
tive catalyst for the synthesis of important functional mole-
cules.18 Based on our previous work, herein we report In-
Br3-promoted condensation of peracetylated aldoses with
some simple arylthiols or selenophenol. In most cases, the
reactions proceed smoothly to furnish thio(seleno)glyco-
sides.
With the optimal conditions in hand, the use of a range
of commercially available arylthiols bearing substituents
and various readily accessible aldosyl donors in the reac-
tions was explored. As shown in Scheme 1, all of the ex-
pected thioglycosides were obtained within 2 h. Among
them, 1,2,3,4,6-penta-O-acetyl-β-D-glucose led to exclusive
formation of the corresponding β-thioglycoside 2a–d. Simi-
lar results were observed in the case of β-D-galactopyrano-
syl peracetates, and the expected β-configured product 2e–h
were isolated in almost quantitative yield. β-Ribofuranose
tetraacetates also reacted in excellent yields (1i–k) with re-
tention of β-configuration. Again, the procedures could be
also applied to β-disaccharides (1l–m), with no detectable
amounts of byproducts formed from cleavage of O-glycosid-
ic bonds being observed and no unexpected α-thioglyco-
sides were generated. Furthermore, peracetated β-pyrano-
sides derived from pentoses such as a xylose were subject-
ed to highly efficient thioglycosylation under the same
conditions, giving the pure β-thioglycosides 1n–o. Thus,
these 1,2-trans-aldosyl acetates showed high reactivity, and
the yields of the corresponding products were apparently
not affected by substituents including electron-drawing or
electron-donating groups on the arylthiols.
Attention was also paid to the anomeric selectivity and
the isolated yields resulting from peracetated 1,2-trans-
mannose under the same conditions. Disappointingly, it
was found to be an unreactive donor. Its 1,2-cis-isomer was
inseparable from an anomeric mixture, so a mixture of iso-
mer (α/β ratio of 4:1) was used for further examination.
Equally, only α-thioglycosides were formed, albeit in low
yields (1p–q). The results from mannose are similar to ob-
servations reported by Weng.14 Besides the above D-aldoses,
common L-rhamnose was investigated in our study; curi-
ously, protocols reported by Chen13 and Weng did not pro-
vide experimental details on this. Alike to mannose, its de-
rivatives from the entire acetylation exist anomerically as
α-form. α-L-Rhamnopyranosyl tetraacetates underwent
thioglycosylation to produced moderate yields of the α-gly-
coside 1r–s as the only product, respectively.
Table 1 Catalyst Optimization for the Thioglycoside Synthesisa
OAc
OAc
O
In salt
AcO
AcO
O
S
SH
AcO
AcO
OAc
CH2Cl2
OAc
OAc
a
1a
Entry
In salt (mol%)
Time (h)
Yield (%)b
1
2
3
4
5
6
In(OTf)3 (10)
In(NTf)3 (10)
InCl3 (10)
InBr3 (10)
InI3 (10)
24
24
24
2
52
39
26
97
98
92
2
InBr3 (5)
2
a The reactions were performed using a (0.1 mmol), p-thiocresol (0.12
mmol) and catalyst in CH2Cl2 (2 mL) at r.t. under air.
b Isolated yield.
We initially ran the reaction of 1,2,3,4,6-penta-O-ace-
tyl-β-D-glucopyranose (a) with p-thiocresol. The desired
transformation was examined using a variety of indium
species (10% mol) in CH2Cl2 at room temperature for 2 h
(Table 1). Treatment of the reaction with In (OTf)3 gave the
desired product 1a in 52% yield (entry 1), but the reaction
did not proceed to completion even after 24 h. This obser-
vation prompted us to screen other indium salts to promote
glycosylation. The switch of the counterion to NTf– de-
creased the yield to 39% (entry 2). Activation of the glyco-
sylation with InCl3 was less effective in the reaction for 24
h, giving a yield of 26% (entry 3). Further optimization of
the reaction conditions with InBr3 and InI3 revealed that
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

C
T. Ma et al.
Letter
Synlett
ranoside used in reaction, 80% yield of pure α-selenoglyco-
side (2h) was obtained. In our protocol 1,3,4,6-tetra-O-ace-
tyl-2-deoxy-2-phthalimido-β-D-glucopyranoside is an in-
active donor for thioglycosylation, but its phenyl β-D-
selenoglycopyranoside could be obtained in low yield of
32% (2i) after stirring for 24 h.
10%InBr3
Aryl thiol
Aryl 1,2-trans-thioglycoside
Peracetylated aldose
OAc
1
OAc
O
OAc
AcO
O
S
O
AcO
AcO
AcO
S
S
AcO
AcO
OAc
OAc
OAc
Cl
1H NMR spectroscopic data of these sulfur and selenium
compounds showed that, in all the reactions, 1,2-trans-gly-
cosides are exclusively generated without observable con-
tamination of 1,2-cis-isomers during our study, which
made the chromatographic purification straightforward.
The sole formation of the 1,2-trans isomer of these glyco-
sides in the can be explained by neighboring-group partici-
pation.
1a, 94%
1b, 96%
1c, 97%
OAc
O
OAc
OAc
AcO
AcO
AcO
Cl
AcO
AcO
S
O
O
S
S
AcO
OAc
OAc
OAc
OCH3
1d, 95%
1e, 94%
OAc
1f, 96%
OAc
O
AcO
AcO
AcO
AcO
AcO
Cl
SeH
O
O
S
S
10%InBr3
S
Phenyl 1, 2-trans-selenoglycoside
Peracetylated aldose
OAc
OAc
2
AcO
S
OAc
OCH3
OAc
OAc
O
OAc
OAc
AcO
1g, 93%
1h, 95%
1i, 98%
O
Se
O
AcO
AcO
OAc
OAc
AcO
Se
Se
O
O
S
OAc
OAc
AcO
OAc
2c, 97%
2a, 98%
2b, 96%
OAc
F
AcO
OAc
OAc
AcO
O
1j, 98%
1k, 97%
AcO
AcO
O
OAc
O
OAc
O
OAc
O
Se
AcO
AcO
AcO
OAc
AcO
O
OAc
O
AcO
AcO
OAc
O
Se
AcO
AcO
AcO
OAc
O
O
AcO
S
S
AcO
2d, 97%
OAc
2e, 93%
OAc
OAc
1l, 92%
1m, 94%
F
OAc
O
AcO
O
OAc
AcO
AcO
OAc
O
AcO
O
AcO
AcO
AcO
AcO
AcO
AcO
S
O
S
AcO
AcO
AcO
O
O
AcO
OAc
Se
OAc
Se
S
OAc
2f, 95%
1n, 96%
F
2g, 10%
1p, 12%
1o, 97%
Cl
OAc
O
Se
OAc
O
S
S
AcO
AcO
O
AcO
AcO
Se
AcO
O
O
AcO
AcO
AcO
Cl
AcO
NPhth
2i, 32%
OAc
2h, 83%
AcO
AcO
OAc
1r, 78%
S
OAc
1q, 9%
1s, 83%
Scheme 2 Reactions of peracetylated aldoses with phenylselenol.
Reagents and conditions: peracetylated aldose (0.1 mmol), selenoglyco-
side (0.12 mmol), InBr3 (3 mg) and CH2Cl2 (2 mL), r.t. under air, >2 h.
Isolated yields based on aldoses.
Scheme 1 Reactions of peracetylated aldoses with aryl thiols. Reagent
and conditions: peracetylated aldose (0.1 mmol), aryl thiol (0.12 mmol),
InBr3 (3 mg), CH2Cl2 (2 mL), r.t. under air for 2 h. Isolated yields based on
aldose.
Phenylselenol is much more nucleophilic than thiophe-
nol, so we envisaged that phenylselenol could be glycosylat-
ed. The reactions with phenylselenol are shown in Scheme
2. The best results were observed when pure β-aldosyl ace-
tate was used as donor. Selenoglycosidation of these donors
required a slightly shorter time to provide selenoglycosides
(2a–f) with the anticipated complete β-stereoselectivity in
excellent yields. No reaction was observed with α-mannose
pentacetate donor. Re-examination of its anomeric mixture
only afforded a low yield of selenomannoside with a single
α-configuration (2g). With fully acetylated α-L-rhamnopy-
In conclusion, we have developed an efficient method
for the formation of S- and Se-glycosidic bonds catalyzed by
InBr3. This method provides rapid access to thioglycosides19
and selenoglycoside20 with 1,2-trans-diastereoselectivity.
Moreover, the InBr3 catalyst is affordable and air- and mois-
ture-stable, thus facilitating operation on the bench top.
Given these advantages, we believe the method presented
herein should find broad application in glycochemistry.
Further exploration of the protocol for In-mediated glycosi-
dation is being pursued in our laboratory.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

D
T. Ma et al.
Letter
Synlett
Funding Information
(16) (a) Mukherjee, C.; Tiwari, P.; Misra, A. K. Tetrahedron Lett. 2006,
47, 441. (b) Crich, D.; Suk, D.-H.; Sun, S. Tetrahedron: Asymmetry
2003, 14, 2861.
(17) For a review on the application and nature of indium reagents,
see: Shen, Z.-L.; Wang, S.-Y.; Chok, Y.-K.; Xu, Y.-H.; Loh, T.-P.
Chem. Rev. 2013, 113, 271.
(18) For selected examples, see: (a) Sakai, N.; Annaka, K.;
Konakahara, T. Org. Lett. 2004, 6, 1527. (b) Takita, R.; Yakura, K.;
Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 13760.
(c) Harada, S.; Takita, R.; Ohshima, T.; Matsunaga, S.; Shibasaki,
M. Chem. Commun. 2007, 948. (d) Wang, P.; Song, S.; Miao, Z.;
Yang, G.; Zhang, A. Org. Lett. 2013, 15, 3852.
We gratefully acknowledge financial support from the National Sci-
ence Foundation of China (21402075, 51501080 and 21675070) and
the Fundamental Research Funds for the Central Universities, Lan-
zhou University (lzujbky-2015-307, lzujbky-2016-146, and lzujbky-
2017-62)
N
oaitn
a
l
S
ecin
c
e
F
o
u
n
d
oaitn
of
C
h
n
i
a
2(
1
4
0
2
0
7
5
N)oaitn
a
l
Secince
F
o
u
n
d
oaitn
of
C
h
n
i
a
5(
1
5
0
1
0
8
0
N)oaitn
a
l
S
ecin
c
e
F
o
u
n
d
oaitn
of
C
h
n
i
a
2(
1
6
7
5
0
7
0)
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588507.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
(19) InBr3-Catalyzed Reaction of Fully Acetylated Aldose with
Aryl Thiol; Typical Procedure: To a solution of β-ribofuranose
tetraacetate (0.1 mmol) and 4-fluorobenzenethiol (0.12 mmol)
in CH2Cl2 (2 mL) was added InBr3 (0.01 mmol) and the reaction
mixture was stirred for 2 h at room temperature. Upon comple-
tion of the reaction (monitored by TLC), the reaction mixture
was concentrated under reduced pressure and the resulting
residue was subjected to flash chromatograph (petroleum
ether–EtOAc, 4:1) to afford the desired product 1j. Yield: 98%;
colorless oil. 1H NMR (400 MHz, CDCl3): δ = 7.52 (dd, J = 8.8,
5.2 Hz, 2 H), 7.04 (t, J = 8.7 Hz, 2 H), 5.18–5.24 (m, 3 H), 4.23–
4.29 (m, 2 H), 4.10 (dd, J = 12.8, 5.4 Hz, 1 H), 2.11 (s, 3 H), 2.08
(s, 3 H), 2.05 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 170.4,
169.5, 169.3, 164.4, 161.9, 136.3, 126.3, 116.1, 88.0, 80.1, 73.6,
71.3, 63.3, 20.7, 20.5. HRMS (ESI): m/z [M +H]+ calcd for
References and Notes
(1) Lian, G.; Zhan, X.; Yu, B. Carbohydr. Res. 2015, 403, 12.
(2) Hoeksema, H.; Bannister, B.; Birkenmeyer, R. D.; Kagan, F.;
Magerlein, B. J.; Mackellar, F. A.; Schroeder, W.; Slomp, G.; Herr,
R. R. J. Am. Chem. Soc. 1964, 86, 4223.
(3) Nicolau, K. C.; Randall, J. L.; Furst, G. T. J. Am. Chem. Soc. 1985,
107, 5556.
(4) Sugiyama, S.; Diakur, J. M. Org. Lett. 2000, 2, 2713.
(5) Tsegay, S.; Williams, R. J.; Williams, S. J. Carbohydr. Res. 2012,
357, 16.
(6) For Pd-catalyzed thioglycosylation, see: (a) Brachet, E.; Brion, J.-
D.; Messaoudi, S.; Alami, M. Adv. Synth. Catal. 2013, 355, 477.
(b) Brachet, E.; Brion, J.-D.; Alami, M.; Messaoudi, S. Adv. Synth.
Catal. 2013, 355, 2627. (c) Bruneau, A.; Roche, M.; Hamze, A.;
Brion, J.-D.; Alami, M.; Messaoudi, S. Chem. Eur. J. 2015, 21, 1.
(7) For Ni-catalyzed thioglycosylation, see: Brachet, E.; Brion, J.-D.;
Messaoudi, S.; Alami, M. A. Chem. Eur. J. 2013, 19, 15276.
(8) For Cu-catalyzed thioglycosylation, see: Yuan, X.; Kou, Y.; Yu, L.;
Zhang, Z.-X.; Xue, W. Org. Chem. Front. 2015, 2, 1604.
(9) Dasgupta, F.; Singh, P. P.; Srivastava, H. C. Carbohydr. Res. 1980,
80, 346.
C
17H20FO7S: 387.0914; found: 387.0917.
(20) InBr3-Catalyzed Reaction of Fully Acetylated Aldose with
Phenylselenol; Typical Procedure: To a solution of β-ribofura-
nose tetraacetate (0.1 mmol) and phenylselenol (0.12 mmol) in
CH2Cl2 (2 mL) was added InBr3 (0.01 mmol) and the reaction
mixture was stirred for 1.5 h at room temperature. Upon com-
pletion of the reaction (monitored by TLC), the reaction mixture
was concentrated under reduced pressure and the resultant
residue was rapidly eluted through a short column of silica gel
(ethyl acetate–petroleum ether, 30%) to give the desired product
2c. Yield: 97%; colorless oil. 1H NMR (400 MHz, CDCl3): δ = 7.64
(d, J = 6.4 Hz, 2 H), 7.38–7.27 (m, 3 H), 5.55 (d, J = 4.0 Hz, 1 H),
5.43–5.38 (m, 1 H), 5.26 (t, J = 5.2 Hz, 1 H), 4.32–4.23 (m, 2 H),
4.12–4.05 (m, 1 H), 2.08 (s, 6 H), 2.07 (s, 3 H). 13C NMR (100
MHz, CDCl3): δ = 170.5, 169.6, 169.4, 135.6, 129.2, 128.6, 83.2,
80.0, 75.5, 71.2, 63.2, 20.8, 20.6, 20.5. HRMS (ESI): m/z [M +H]+
calcd for C17H21O7Se: 417.0452; found: 417.0454.
(10) Contour, M.-O.; Defaye, J.; Little, M.; Wong, E. Carbohydr. Res.
1989, 193, 283.
(11) Das, S. K.; Roy, N. Carbohydr. Res. 1996, 296, 275.
(12) Tai, C.-A.; Kulkarni, S. S.; Hung, S.-C. J. Org. Chem. 2003, 68, 8719.
(13) Weng, S.-S.; Lin, Y.-D.; Chen, C.-T. Org. Lett. 2006, 8, 5633.
(14) Weng, S.-S. Tetrahedron Lett. 2009, 50, 6414.
(15) Mehta, S.; Pinto, B. M. J. Org. Chem. 1993, 58, 3269.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D