Trichloroacetimidates as Glycosyl Donors in Recyclable Ionic Liquids

Article abstract of DOI:10.1055/s-2003-42099

The trichloroacetimidates of different glycopyranoses were glycosylated in ionic liquids with different acceptors, affording the corresponding glycopyranosides in fair to excellent yields and allowing to recycle the solvent without additional Lewis acid.

Full text of DOI:10.1055/s-2003-42099

LETTER
2297
Trichloroacetimidates as Glycosyl Donors in Recyclable Ionic Liquids
a
b
a
a
T
L
richloroacetim
a
idates as
G
u
lycosyl
D
on
r
ac yclable Ionic Li
P
a
Dip. Di Chimica Organica e Industriale, via Venezian, 21, 20133 Milano, Italy
Fax +39(02)50314061; E-mail: laura.poletti@unimi.it
b
C.N.R., Istituto di Scienze e Tecnologie Molecolari, via Golgi, 19, 20133 Milano, Italy
Received 20 August 2003
The model reaction was performed using isopropanol as
an acceptor and trimethylsilyl triflate (TMSOTf) as a pro-
moter (Scheme 1). The differently protected trichloroace-
timidates (TCA) tested as donors ranged from disarmed to
armed sugars, belonging both to the D- and to the L-series,
in order to enlarge the scope of the methodology as widely
Abstract: The trichloroacetimidates of different glycopyranoses
were glycosylated in ionic liquids with different acceptors, afford-
ing the corresponding glycopyranosides in fair to excellent yields
and allowing to recycle the solvent without additional Lewis acid.
Key words: carbohydrates, ionic liquids, glycosylations, green
chemistry, stereoselectivity
7
as possible. These compounds were conventionally pre-
pared according to the procedures published in the litera-
ture.6
Room temperature ionic liquids (RTILs) have recently
emerged as a new class of solvents for a wide range of or- After
ganic reactions, due to their capability of dissolving many imidazolium hexafluorophosphate ([bmim]·[PF ]) and 1-
a
preliminary screening, 1-methyl-3-butyl-
8
6
9
organic substrates and to their appealing green proper- methyl-3-ethylimidazolium trifluoromethanesulfonate
1
ties. In particular, the high polarity of RTILs can provide ([emim]·[OTf]) were selected as solvents.
strong accelerating effects to reactions involving cationic
intermediates.
As shown in Table 1, the reaction afforded the desired iso-
propyl glycosides in fair to excellent yields. In the case of
2
It is commonly recognised that the glycosylation reaction donor 3 (entries 5–7) the stereochemistry of the product
3
is a very complex step in oligosaccharide synthesis. In strongly depended on the solvent and on the presence of
fact, it involves different charged intermediates whose re- the catalyst. When the reaction was carried out in
activity strongly depends on the protecting group pattern, [bmim]·[PF ] (entry 5), the expected a-product was pre-
6
the solvent and the catalyst. We reasoned that, due to the dominantly recovered in excellent yield. On the other
highly polar microenvironment provided by ionic liquids, hand, in [emim]·[OTf] the same donor smoothly reacted
performing this reaction in such media could significantly without addition of the Lewis acid, displaying an unex-
4
affect its course. Recently, Yadav et al. reported the use pected good b-selectivity even in the absence of a partici-
of ionic liquids for a Dy(OTf) mediated synthesis of 2,3- pating group at C-2 (entry 6). At the same time, the
3
usaturated glucopyranosides; The coupling of a glucopyr- addition of the Lewis acid (entry 7) resulted in a higher re-
anosyl diethyl phosphite donor with different alcohols, action rate and in a lower b-selectivity. Donors 4 and 6,
performed in an ionic liquid, was recently reported as also lacking in a participating group at C-2, displayed in
5
well.
[emim]·[OTf] the prevalent formation of b-glycosides, al-
lowing to speculate on the possible assistance of this sol-
On the other hand, the wide range of substrates used in the
synthesis of oligosaccharides strongly demands for high
versatility of the glycosyl donor. For this reason, we fo-
cussed on the trichloroacetimidate as a suitable activating
group to investigate glycosylation reaction in ionic liq-
1
0
vent in the reaction mechanism. The long reaction times
required in reactions 5, 6, and 8–11 were mainly due to the
scarce solubility of the substrates in the reaction media. In
particular, the comparison of entries 6 and 10 with entries
7 and 11 suggests that the presence of the catalyst drove
the reaction to products as soon as the substrates dis-
solved.
6
uids, due to its wide applicability and effectiveness. In
this communication we report our results on the coupling
between different trichloroacetimidate donors and alco-
hols.
One of the most attracting features of RTILs is the possi-
bility of their recycling. In fact, these low-melting salts
are immiscible with some organic solvents that can be
used for product recovery by extraction, while the ionic
liquid could be separated and re-used. For this reason, we
verified the effectiveness of iterating the same reaction in
a recycled solvent. Reaction 4 reported in Table 1 was
iPrOH
TMSOTf, r.t.
O
O
O
RO
OTCA
RO
ionic liquid
Scheme 1 Synthesis of the isopropyl glycosides
7
taken as a model. After the first cycle, the ionic liquid
was recovered by phase separation during the work up,
dried in vacuo and re-used in the same way (Table 2).
SYNLETT 2003, No. 15, pp 2297–2300
Advanced online publication: 22.10.2003
0
1
.1
2
.2
0
0
3
DOI: 10.1055/s-2003-42099; Art ID: G21103ST
©
Georg Thieme Verlag Stuttgart · New York

2
298
L. Poletti et al.
LETTER
Table 1 Reaction of Isopropanol with Different Trichloroacetimidates in Ionic Liquids A/B as Solvent7
b
Entry
Donor
Solventa
Yield (%)
a/b ratio
£2/98
5/95
Reaction time
OAc
O
1
2
3
4
5
16a
A
B
A
B
A
56
57
80
68
98
10 min
10 min
10 min
10 min
24 h
AcO
AcO
OTCA
OAc
1
OAc
O
AcO
AcO
26a
£2/98
£2/98
76/24
OTCA
OAc
2
OBn
O
36a
BnO
BnO
OTCA
OBn
6
7
3
3
B
B
85c
20/80
45/55
48 h
quant.
20 min
Ph
O
O
46b
8
9
O
B
B
45
37
37/63
98/2
1 h
4 h
OTCA
AcO
N3
OAc
OAc
O
56a
AcO
AcO
OTCA
OTCA
1
0
1
O
66c
B
B
quant.c
quant.
16/84
18/82
24 h
4 h
OBn
OAc
OAc
1
6
a
b
c
A: [bmim]·[PF ], B: [emim]·[OTf].
Ratio determined by NMR.
Reaction carried out without addition of the Lewis acid.
6
Table 2 Recycling of the Solvent
Noteworthy, in the subsequent cycles the reaction afford-
ed the product without addition of any acidic promoter,
thus proving the capability of the ionic liquid to retain the
catalytic properties of the Lewis acids. This is in line with
other examples reported in the literature.4 Moreover, in
the subsequent cycles the yield of the reaction was not
significantly affected.
Entry Cycle
number
Extraction solvent Yield (%)
Reaction time
,11
1
2
3
4
5
6
1
2
1
2
3
4
Toluene
67
63
68
78
82
82
10 min
10 min
10 min
2 h
Toluene
Chloroform
Chloroform
Chloroform
Chloroform
O
OTCA
RO
2,6
O
TMSOTf, r.t.
ionic liquid
O
O
2.5 h
4 h
+
RO
O
11–16
OMe
HO
7–10 OMe
Scheme 2 Synthesis of the disaccharides
Synlett 2003, No. 15, 2297–2300 © Thieme Stuttgart · New York

LETTER
Trichloroacetimidates as Glycosyl Donors in Recyclable Ionic Liquids
2299
Table 3 Synthesis of Disaccharides 9–12 from Donors 2 and 612
Entry
Donor Acceptor
Solventa
Product
Yield a/b
Reaction
time
b
(
%)
ratio
OH
OAc OAc
O
AcO
AcO
O
O
1
2
7
A
AcO
1114
54
£2/98
10 min
AcO
OMe
OAc
AcO
O
AcO
AcO
OMe
2
3
2
7
B
B
11
12
74
58
£2/98
£2/98
30 min
30 min
OH
OAc OAc
O
O
BnO
BnO
86a
O
2
AcO
BnO
OMe
OAc
BnO
O
BnO
BnO
OMe
OMe
OBn
O
OAc
OAc
BnO
4
5
6
2
2
6
6
913
1014
7
B
B
B
B
O
BnO
O
13
14
15
16
63
67
98
72
£2/98
£2/98
28/72
25/75
1 h
HO
BnO
AcO
AcO
O
BnO
OMe
OMe
OAc
OBn
OAc
O
OAc
OAc
O
OMe
BnO
BnO
O
2 h
HO
BnO
O
BnO
OAc
OAc
O
O
OAc
OBn
2 h
O
AcO
AcO
OAc
AcO
OMe
O
O
OBn
7
8
1 h 30 min
O
BnO
OAc
OAc
BnO
BnO
OMe
a
A: [bmim]·[PF ]; B: [emim]·[OTf].
Determined by NMR.
6
b
To test the formation of the saccharidic linkage, donors 2 some cases, avoiding the use of the Lewis acid catalyst.
and 6 were chosen to perform the glycosylation reaction Moreover, the ionic liquid could be recycled without loss
1
2
6a 13
14
with glycosyl acceptors 7, 8,
9
and 10, affording of the Lewis acid catalytic properties. These reaction con-
1
5
disaccharides 11–16
in good yields (Scheme 2, ditions are compatible with different protecting groups
and strongly influence the selectivity of the reaction. This
1
6
Table 3).
opens new perspective for the application of ionic liquid
A particular feature in these reactions was that the less re-
active acetylated acceptors afforded better yields than the
benzylated ones and again fucosyl donor 6 afforded main-
ly the b-linked disaccharides (entries 6, 7).
in sugar chemistry, especially from an industrial point of
view. Work is in progress to broaden the scope of the
methodology.
In summary, we have demonstrated that trichloroacetimi-
date glycosyl donors can be efficiently employed in
glycosylation in ionic liquids. The coupling reactions pro-
Acknowledgment
We gratefully acknowledge CNR (National Research Council) and
ceed under mild conditions, at room temperature and, in MIUR (Ministero dell’Istruzione, dell’Università e della Ricerca).
Synlett 2003, No. 15, 2297–2300 © Thieme Stuttgart · New York

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L. Poletti et al.
LETTER
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16) In a typical procedure the acceptor (60 mg, 1 equiv) and
trimethylsilyl triflate (0.01 equiv) were dissolved in the ionic
liquid (0.5 mL). The donor (1.5 equiv) was added as a solid
and the reaction was stirred at r.t. until completion. After
extraction with chloroform the crude was purified by flash
chromatography.
(
7) In a typical procedure the donor (100 mg, 1 equiv) and
isopropanol (20 equiv) were dissolved in the ionic liquid (0.5
mL) and trimethylsilyl triflate (0.01 equiv) was added. The
reaction was stirred at r.t. The work-up was performed by
extracting the ionic liquid in chloroform or toluene (see
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purified by flash chromatography.
Synlett 2003, No. 15, 2297–2300 © Thieme Stuttgart · New York