Efficient glycosylation using In(OTf)3 as a lewis acid: Activation of n-phenyltrifluoroacetimidate or thioglycosides with halogenated reagents or PhIO

Article abstract of DOI:10.1246/cl.140167

In(OTf) ₃ efficiently activated N-phenyltrifluoroacetimidate and In(OTf) ₃ in combination with various halogenated reagents or PhIO promoted glycosylation using thioglycoside in good yields. The combination with iodine interhalogens

Full text of DOI:10.1246/cl.140167

CL-140167
Received: February 28, 2014 | Accepted: March 26, 2014 | Web Released: June 5, 2014
Efficient Glycosylation Using In(OTf)3 as a Lewis Acid:
Activation of N-Phenyltrifluoroacetimidate or Thioglycosides
with Halogenated Reagents or PhIO
Regina M. Salmasan, Yoshiyuki Manabe, Yuriko Kitawaki, Tsung-Che Chang, and Koichi Fukase*
Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka 563-0043
(E-mail: koichi@chem.sci.osaka-u.ac.jp)
In(OTf)3 efficiently activated N-phenyltrifluoroacetimidate
and In(OTf)3 in combination with various halogenated reagents
or PhIO promoted glycosylation using thioglycoside in good
yields. The combination with iodine interhalogens (e.g., ICl or
IBr) effectively promoted α-sialylation.
Table 1. Glycosylation with N-phenyltrifluoroacetimidate
OBn
O
BnO
BnO
OH
O
Lewis acid
(1.5 equiv)
OBn
O
BnO
BnO
NPh
O
BnO
BnO
BnO
O
BnO
MS4A
solvent
0 °C
O
BnO
CF3
BnO
BnO
(1.5 equiv)
OMe
BnO
1
2
3
OMe
(1 equiv)
Entry Lewis acid
Solvent Time
Resulta
1
2
3
InF3
InCl3
TMSCl
InCl3 (1.5 equiv)
+ TMSCl (1.5 equiv)
InBr3
CH2Cl2 2 h
CH2Cl2 1.5 h
CH2Cl2 1.5 h
NR
Recently, indium(III) salts have attracted much attention as
Lewis acids for various organic reactions because of their mild
acidity, tolerance to moisture, and stability at high temperature
or over a prolonged reaction time.1 In(III) salts have been
applied to a number of carbohydrate reactions such as Ferrier-
type rearrangements and glycosylation reactions.2,3 In(III) salts
have been used as Lewis acid catalysts for glycosylation with
several glycosyl donors: InCl3 for glycosylation with glycosyl
bromides,3a InBr3 for glycosylation with sugar peracetates,3b
indium(III) trifluoromethanesulfonate (In(OTf)3), InCl3, and
InBr3 for glycosylation with glycosyl trichloroacetimidates,3c
and In(OTf)3 for C-glycosylation with glycal derivatives.3d
In the present study, we further investigate In(III)-promoted
glycosylation using thioglycoside and N-phenyltrifluoroacetimi-
date donors. The latter is effectively activated by In(OTf)3,
affording the corresponding glycoside in good yield. The
combination of In(OTf)3 with halogenation reagents or PhIO
efficiently promotes glycosylation with thioglycosides. Addi-
tionally, effective α-sialylation is achieved using In(OTf)3 with
iodine interhalogens as oxidants.
10% (α:β = 48:52)
29% (α:β = 62:38)
4
CH2Cl2 1.5 h
53% (α:β = 44:56)
5
6
7
8
9
CH2Cl2 1.5 h
CH2Cl2 10 min 68% (α:β = 28:72)
CH2Cl2 10 min 84% (α:β = 59:41)
71% (α:β = 50:50)
InI3
In(OTf)3
In(OTf)3
In(OTf)3
Et2O
EtCN
30 min 86% (α:β = 73:27)
30 min 60% (α:β = 15:85)
aEstimated by NMR.
Thioglycosides have been used in numerous synthetic works
because of their stability and ease of preparation. They are
commonly activated by NIS/TfOH7 or NBS/TfOH,8 although
our previous work used NBS in combination with several strong
acids (e.g., Bu4NOTf and Ph2IOTf) as activators.9 We have also
reported glycosylation with thioglycosides using PhIO in
combination with various acids.10 Other activation methods for
thioglycosides have also been reported.11
We initially examined glycosylation with O-benzylated
N-phenyltrifluoroacetimidate4 donor 1 and acceptor 2 in the
presence of In(III) salts in dichloromethane at 0 °C (Table 1).
InF3 did not activate the donor even after a prolonged reaction
time (Entry 1), whereas InCl3 resulted in a low yield with an
almost equal ratio of α- and β-isomers (Entry 2). The enhanced
Lewis acidity of InCl3 by the combined use of TMSCl2d,5
increased the reaction rate and yield compared to InCl3 or
TMSCl (Entries 3 and 4). Higher yields were obtained with InI3,
InBr3, and In(OTf)3 (Entries 5-7). Among these, the reactions
with InI3 and In(OTf)3 were completed within 10 min, with a
higher β-selectivity observed in the former, but a higher yield
in the latter. Larger amounts of In(III) salts were necessary to
activate N-phenyltrifluoroacetimidate compared to trichloroace-
timidates.3c The reactivities of the In(III) salts tested followed
the order In(OTf)3 = InI3 > InBr3 > InCl3 + TMSCl > InCl3 >
InF3.
The efficiency of glycosylation using In(III) with various
oxidants was then investigated. Because In(OTf)3 afforded the
best result among the In(III) salts, its efficiency in thioglycoside
activation was compared with TfOH and AgOTf in combination
with NBS, NIS, ICl, IBr, or PhIO as the oxidant (Table 2).12
In(OTf)3 was as good and in some cases even better as an
activator than TfOH or AgOTf. All the five tested oxidants
afforded the desired disaccharide in good yields (Entries 3, 6, 9,
12, and 15). The initial reaction rates estimated by TLC were
[ICl = IBr > NBS > NIS > PhIO]/In(OTf)3. However, the re-
action rates using ICl and IBr significantly differed during the
reaction, suggesting that the active chemical species changed
from ICl (or IBr) to PhSI or another species. Consequently, the
reaction temperature was raised from ¹80 to 0 °C to complete
the reaction.
To further investigate the efficiency of In(OTf)3 as an
activator, several armed and disarmed thioglycosides were
utilized (Table 3). NBS/In(OTf)3 and NIS/In(OTf)3 were
effective for glycosylation with both armed benzylated donor
4 and disarmed benzoylated donor 7 (Entries 1, 2, 6, 7, 11, and
12). Although ICl/In(OTf)3 was a good promoter for glyco-
sylation of both 4 and 7 with primary (1°) alcohol acceptor 2
Considering the reaction time and yield, glycosylation using
In(OTf)3 was further examined by employing other solvents
[e.g., diethyl ether (Et2O) and propionitrile (EtCN)] (Entries 8
and 9). Common solvent effects of ether and nitrile were
observed.6
956 | Chem. Lett. 2014, 43, 956–958 | doi:10.1246/cl.140167
© 2014 The Chemical Society of Japan

temperatures facilitate the formation of α-anomeric products.15
We recently reported stereoselective α-sialylation using a C5-
acetamido N-phenyltrifluoroacetimidate donor with TMSOTf.16
A high yield and stereoselectivity require strict temperature
control at ¹80 °C and the efficient removal of the reaction heat.
In this work, we develop practical α-sialylation using
commercially available sialyl thioglycoside 10 with a similar
low-temperature control (Scheme 1). Although sialylation using
sialyl thioglycosides with NIS-TfOH has been widely used to
synthesize various sialylated glycans, these conditions did not
promote the glycosylation of 10 with galactose acceptor 11 at
¹85 °C. Because the combination of halogenated reagents with
In(OTf)3 efficiently promoted the glycosylation with thioglyco-
side donors 4 and 7, we examined sialylation with NBS, NIS,
ICl, and IBr with In(OTf)3 in propionitrile at ¹85 °C. Although
NBS/In(OTf)3 and NIS/In(OTf)3 did not activate 10 at ¹85 °C,
ICl or IBr together with In(OTf)3 promoted sialylation at the
same temperature. ICl/AgOTf and IBr/AgOTf have been
reported to activate thioglycoside in sialylation.17 We observed
that both ICl/AgOTf and IBr/AgOTf showed lower reactivities
than the ICl/In(OTf)3 system. The reproducibility of the reaction
with IBr was low, likely because of the inherent instability
of IBr. Thus, ICl/In(OTf)3 was used as a promoter for the
α-sialylation of thioglycosides 10 and 15. In α(2,6)-sialylation,
disaccharide 12 was obtained in good yield with a high
selectivity. On the other hand, α(2,3)-sialylation with acceptor
13 resulted in 26% yield, albeit with perfect α-selectivity. The
low yield probably attributed to the steric hindrance in the 2°
alcohol acceptor. This promoter system was also applied to
prepare sialyl Tn antigen (STn antigen), a disaccharide often
expressed in tumors and a variety of cancers.18 Glycosylation
formed desired disaccharide 17 in good yield and selectivity
after the amounts of ICl and In(OTf)3 were optimized to prevent
cleavage of the isopropylidene group.
Table 2. Glycosylation with a thioglycoside donor using In(III) salts,
halogenated reagents, and PhIO
OBn
O
BnO
BnO
OH oxidant (1.5 equiv)
OBn
O
acid (1.5 equiv)
O
BnO
BnO
O
BnO
BnO
BnO
O
STol
BnO
MS4A
OMe CH2Cl2
BnO
BnO
BnO
(1.5 equiv)
BnO
4
2
3
OMe
(1.0 equiv)
Entry Oxidant Acid
Temp/°C
¹80
Time/min Resulta
1
2
3
4
5
6
7
8
9
NBS
NBS
NBS
NIS
NIS
NIS
ICl
TfOH
AgOTf ¹80 to 0
In(OTf)3 ¹80 to ¹40
TfOH
AgOTf ¹80 to 0
In(OTf)3 ¹80 to 0
TfOH
AgOTf ¹80 to 0
In(OTf)3 ¹80 to 0
10
10
10
10
10
10
30
10
10
30
10
10
10
30
10
quant (α:β = 7:93)
97% (α:β = 27:73)
98% (α:β = 16:84)
91% (α:β = 14:86)
96% (α:β = 26:74)
96% (α:β = 21:79)
45% (α:β = 54:46)
33% (α:β = 44:56)
92% (α:β = 42:58)
39% (α:β = 71:29)
98% (α:β = 19:81)
61% (α:β = 65:35)
93% (α:β = 25:75)
NR
¹80
¹80 to rt
ICl
ICl
10 IBr
TfOH
¹80 to rt
11 IBr
12 IBr
AgOTf ¹80 to 0
In(OTf)3 ¹80 to 0
13 PhIO
14 PhIO
15 PhIO
TfOH
AgOTf ¹80 to rt
In(OTf)3 ¹80 to 0
¹80 to ¹40
86% (α:β = 60:40)
aEstimated by NMR.
(Table 2: Entry 9, Table 3: Entry 8), the yields with secondary
(2°) alcohol acceptor 5 were lower than those with NBS/
In(OTf)3 and NIS/In(OTf)3 (Table 3: Entries 3 and 13).
IBr/In(OTf)3 afforded a good yield in the glycosylation of
benzoylated donor 7 with 2 (Table 3: Entry 9). When less
reactive acceptor 5 was used, the donors decomposed (Table 3:
Entries 4 and 14). The yields with PhIO/In(OTf)3 were
generally moderate (Table 3, Entries 5, 10, and 15).
Stereoselective α-sialylation has been intensively studied to
synthesize sialoglycans,13 which have diverse biological func-
tions in the blood, nerve, immune systems, etc.14 The electron-
withdrawing carboxylic acid at C1 and the lack of participating
groups at C3 are inherent difficulties in α-sialylation. A kinetic
solvent effect of nitrile for α-sialylation is well known, and low
In conclusion, In(III) salts promoted glycosylation with
N-phenyltrifluoroacetimidate. Among the salts tested, In(OTf)3
afforded the best results. In(OTf)3 together with various oxidants
efficiently activated thioglycosides to afford the corresponding
Table 3. In(OTf)3-mediated glycosylation of armed and disarmed thioglycosides
oxidant (1.5 equiv), In(OTf)3 (1.5 equiv)
donor (1.5 equiv)
acceptor (1.0 equiv)
products
MS4A, CH2Cl2
Entry
Donor
Acceptor
Product
Oxidant
Temp/°C
¹80 to ¹40
¹80 to 0
¹80 to rt
¹80 to rt
¹80 to rt
Time/min
Resulta
1
2
3
4
5
NBS
NIS
ICl
IBr
PhIO
10
10
30
30
10
79% (α:β = 41:59)
76% (α:β = 46:54)
64% (α:β = 54:46)
38% (α:β = 44:56)
65% (α:β = 61:39)
OBn
O
OBn
O
OBn
O
OBn
O
BnO
BnO
BnO
BnO
HO
BnO
STol
STol
STol
O
BnO
BnO
BnO
BnO
4
OMe
BnO
5
6
OMe
6
7
8
9
10
NBS
NIS
ICl
IBr
PhIO
¹80 to 0
¹80 to 0
¹80 to rt
¹80 to rt
¹80 to rt
10
30
10
60
30
quant
quant
87%
97%
89%
OBz
O
OH
O
OBz
O
BzO
BzO
BzO
BzO
BnO
BnO
O
O
BnO
BzO
BnO
OBz
BnO
OMe
7
BnO
2
8
OMe
11
12
13
14
15
NBS
NIS
ICl
IBr
PhIO
¹80 to rt
¹80 to rt
¹80 to rt
¹80 to rt
¹80 to rt
10
60
30
30
60
98%
98%
69%
21%
69%
OBz
O
OBn
O
OBz
O
OBn
O
BzO
BzO
HO
BnO
BzO
BzO
O
BnO
BzO
BnO
OBz
BnO
OMe
OMe
7
5
9
aEstimated by NMR.
Chem. Lett. 2014, 43, 956–958 | doi:10.1246/cl.140167
© 2014 The Chemical Society of Japan | 957

OH
OH
O
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BzO
OAc
OAc
CO2Me
BzO
AcO
OPr
11 (1.0 equiv)
ICl (2.9 equiv)
In(OTf)3 (2.0 equiv)
O
O
AcHN
HO
4
5
6
AcO
OAc
OAc
CO2Me
SPh
O
AcO
BzO
O
BzO
OPr
AcHN
MS5A, EtCN
3 h, -85 °C
12
AcO
10 (1.5 equiv)
70% (brsm: 84%, α:β = 92:8)
OBn
OBn
O
O
HO
CO2Me
OBn
OAc
OAc
OBn
AcO
OMe
BnO
O
7
8
9
O
O
13
(1.0 equiv)
AcHN
O
ICl (2.9 equiv), In(OTf)3 (2.0 equiv)
AcO
OBn
10 (1.5 equiv)
OMe
14
MS5A, EtCN
3 h, -85 °C
26% (brsm: quant, α only)
O
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O
O
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Tables 2 and 3, while solid ICl or IBr was used for the experiment in
Scheme 1.
OAc
OAc
CO2Me
AcHN
AcO
CO2tBu
O
O
O
O
N3
FmocHN
AcO
16
O
OAc
OAc
CO2Me
SPh
ICl (1.25 equiv)
In(OTf)3 (0.625 equiv)
O
AcO
AcHN
O
O
N3
MS4A, EtCN
3 h, -78 °C
AcO
15
FmocHN
CO2tBu
17
62% (brsm: 94%, α:β = 92:8)
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Scheme 1. ICl/In(OTf)3-promoted α-sialylation.
glycosides in similar or better yields and selectivities compared
to those with TfOH or AgOTf. Because In(OTf)3 was a
relatively harder acid than AgOTf, but had a soft character,
In(OTf)3 could efficiently activate thioglycosides when com-
bined with various oxidants, although In(OTf)3 was a mild
Lewis acid. In general, the combination of In(OTf)3 with NBS or
NIS was effective for various glycosylations of both reactive and
less reactive donors and acceptors. Additionally, the ICl/
In(OTf)3 system was effective for α-sialylation reactions. The
reactivity using ICl/In(OTf)3 is higher than that using other
activators such as NIS/TfOH, NIS/AgOTf, or IBr/AgOTf; only
ICl/In(OTf)3 system smoothly promotes the sialylation using
sialyl donor 10 at very low temperature to realize excellent
α-selectivity.19
This work was financially supported in part by a Grant-in-
Aid for Scientific Research on Innovative Areas “Organic
Synthesis Based on Reaction Integration: Development of New
Methods and Creation of New Substances” No. 21106008, by a
Grant-in-Aid for Scientific Research No. 23241074 and by a
Grant-in-Aid for JSPS Fellows No. 13F03329 from the Japan
Society for the Promotion of Science. We also thank Prof. Akio
Baba and Dr. Makoto Yasuda for their valuable advice about the
character of In salts.
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19 Supporting Information is available electronically on the CSJ-Journal
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958 | Chem. Lett. 2014, 43, 956–958 | doi:10.1246/cl.140167
© 2014 The Chemical Society of Japan