Straightforward glycosylation of alcohols and amino acids mediated by ionic liquid

Article abstract of DOI:10.1016/j.carres.2012.03.004

Green glycosylation of functionalized alcohols and α-amino acids, using an ionic liquid as a recyclable solvent, was performed in one step directly from the unprotected monosaccharide under scandium triflate or ferric chloride catalysis. Pure α- and β-glycosides could be obtained after specific enzymatic hydrolysis.

Full text of DOI:10.1016/j.carres.2012.03.004

Carbohydrate Research 352 (2012) 202–205
Contents lists available at SciVerse ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Note
Straightforward glycosylation of alcohols and amino acids mediated
by ionic liquid
⇑
Olivier Monasson, Gwenaëlle Sizun-Thomé, Nadège Lubin-Germain, Jacques Uziel, Jacques Augé
University of Cergy-Pontoise, Laboratoire de Synthèse Organique Sélective et Chimie bioOrganique, Neuville-sur-Oise, F-95031 Cergy-Pontoise, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Green glycosylation of functionalized alcohols and
solvent, was performed in one step directly from the unprotected monosaccharide under scandium tri-
a
-amino acids, using an ionic liquid as a recyclable
Received 29 December 2011
Received in revised form 2 March 2012
Accepted 5 March 2012
flate or ferric chloride catalysis. Pure
hydrolysis.
a
- and b-glycosides could be obtained after specific enzymatic
Available online 10 March 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
O-glycosylation
Glycosides
Glycopeptides
Amino acids
Ionic liquids
Green chemistry
Carbohydrates play a fundamental role in many aspects of
chemistry and biology. Therefore, the chemistry of glycosides and
glycoconjugates has gained much attention for many years. In spite
of continuous progress in O-glycosylation methodologies since the
historical Koenigs–Knorr reaction, the chemical methods suffer
from tedious protection/deprotection steps. Besides, an appropri-
ate activating group must be introduced at the anomeric position,
which induces supplementary waste. Such a reaction sequence for
O-glycosylation leads to a poor atom economy and to a high
E-factor. Indeed, these reaction metrics can now be easily calcu-
lated for a complete sequence and such a calculation is extremely
instructive to figure out the greenness of a process.1 Even enzy-
matic methods using glycosyltransferases require the introduction
of an auxiliary such as an expensive sugar nucleotide. Moreover
the nucleoside diphosphates generated during the reaction are
potent glycosyltransferase inhibitors.2 New enzymatic methods
using glycosidases are emerging, such as the glycosynthase3 or
the transglycosidase4 approach, but these methods are very
specific and require activated sugars, such as fluoro or nitrophenyl
glycosides, respectively.
of glycosides if a large excess of aglycone is used.7 An alternative
strategy was investigated with the use of ionic liquids to
decrease the activity of water in glycosidase-catalyzed transgly-
cosylations.8,9
We and others have recently shown that it was possible to use
unprotected and non-activated monosaccharides in the O-glyco-
sylation of alcohols in order to produce alkylpyranosides in the
presence of an ionic liquid.10–12 The reaction which goes through
an oxocarbenium cation needs acidic conditions, either protonic
or Lewis acid conditions. We must be aware that these conditions
may lead to a secondary reaction, such as the dehydration of
carbohydrates affording 5-hydroxymethylfurfural (5-HMF). Such
a transformation in ionic liquid is now considered as a good oppor-
O
CHO
HO
Me
N
N
Bu
Cl
5-HMF14
OH
O
H3PW12O40
120°C
HO
HO
When starting from unprotected carbohydrates, enzymatic
reactions using glycosidases are driven more easily toward the
hydrolysis than toward the formation of glycosides, since the
natural medium of enzymes is water.5,6 The thermodynamic en-
zyme-catalyzed equilibrium can be driven toward the formation
OH
Me
OH
ROH
OH
O
N
N
Bu
HO
HO
OR
OH
OTf
Sc(OTf)3
80 °C
⇑
Corresponding author. Tel.: +33 1 34257051; fax: +33 1 34257071.
E-mail address: jacques.auge@u-cergy.fr (J. Augé).
Scheme 1. Dehydration versus glycosylation.
0008-6215/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.carres.2012.03.004

O. Monasson et al. / Carbohydrate Research 352 (2012) 202–205
203
Table 1
Glycosylation of octanol
fact, Fischer-type glycosylation of methanol in the presence of
FeCl3 gave methyl glucofuranosides from glucose and methyl
galactofuranosides from galactose.16 Later on, Plusquellec and co-
workers have shown that the direct O-glycosylation of reducing
sugars in the presence of 3 equiv of FeCl3 afforded furanosides in
Carbohydrate
Catalyst
(mol %)
Conditions Isolated
yield
a/b
Glucose
Sc(OTf)3 (5)
FeCl3 (5)
80 °C
24 h
80 °C
3 h
110 °C
24 h
110 °C
2 h 30 min
74
67
60
34
75/
25
55/
45
79/
21
100/
0
good to excellent yields in THF.17 In contrast,
a-pyranosides were
produced from N-acetylglucosamine in THF17 and from peracety-
lated glycosamines in dichloromethane.18 In both cases FeCl3 was
used in substoichiometric amounts. We found that a catalytic
amount of FeCl3 is sufficient to promote the glucosylation of
octanol in butylmethylimidazolium triflate ([BMIM][OTf]). The gly-
cosylation reaction is faster under FeCl3 than under Sc(OTf)3 catal-
ysis, but yields and selectivities are similar (Table 1). Curiously, the
glycosylation of octanol with N-acetylglucosamine requires
Glucose
N-Acetylglucosamine
N-Acetylglucosamine
Sc(OTf)3 (5)
FeCl3 (100)
OH
O
OH
1 equiv of FeCl3, affording pure
a derivative. Note that such total
O
a
HO
HO
HO
a
selectivity was previously observed in FeCl3-promoted glycosida-
HO
OR
tion of N-acetylglucosamine17 and glycosamine peracetates.18
In order to prepare glycoconjugates (Scheme 2) we planned to
investigate glycosylation of alcohols bearing halogen and nitrogen
functionality as a linker. Halogenoalcohols could be easily glycos-
ylated in butylmethylimidazolium triflate under Sc(OTf)3 catalysis
(Table 2). The yield is quantitative when using 3-chloropropanol.12
Curiously 2-chloro and 2-bromoethanol gave only moderate yields,
even if the reaction time is extended to 24 h. Poor yields were ob-
served when preparing 1 and 2 with 2-chloroethanol19 and 2-bro-
moethanol,20 respectively, using the same alcohol as the solvent.
With 2-azidoethanol or N-acylethanolamine, we did not succeed
in obtaining the corresponding glycosides. The replacement of
the amide by a carbamate function, allowed us to prepare free sug-
ars carrying a linker prone to be coupled with any derivative bear-
ing carboxylic acid function (Table 2).
OH
OH
OH
5
R = CH2CH2NHFmoc
1
2
3
R = CH2CH2Cl
R = CH2CH2Br
R = CH2CH2CH2Cl
NHCbz
R =
6
CO2CH3
NHFmoc
R =
7
4
R = CH2CH2NHCO2Et
CO2CH2CH=CH2
Scheme 2. Reagents and conditions: (a) ROH, 5 equiv, Sc(OTf)3 or FeCl3 0.05 equiv,
[BMIM][OTf], 80 °C
tunity to easily produce biofuels or bioproducts from biomass.13–15
Since we never observed the formation of 5-HMF when using buty-
lmethylimidazolium triflate as the ionic liquid, we decided to apply
our methodology (Scheme 1) to the straightforward O-glycosyla-
tion of functionalized alcohols including serine derivatives in order
to propose convenient methodologies in the coupling of sugars
with peptides.
The first studies were carried out with lanthanide or scandium
triflate as the catalyst.12 Indeed, since FeCl3 is a more accessible
catalyst than Sc(OTf)3, it was interesting to test it. As a matter of
Finally, serine protected by ester and carbamate groups, except
t-butyloxycarbamate, could be glycosylated, affording a mixture of
a
- and b serine derivatives (Table 3).
By enzymatic hydrolysis, and b derivatives could be obtained
as pure anomers. As an example (Scheme 3) the mixture of and
b-glucosylserines (6) was purified by enzymatic hydrolysis using
or b-glucosidase from Saccharomyces cerevisiae in a phosphate buf-
fer (pH 7.1) to afford quantitatively either b or glucosylserine.
a
a
a
a
Table 2
Glucosylation of functionalized alcohols as linkers in [BMIM][OTf]
Aglycone
Conditions
Product (isolated
yield, %)
a/b
Cl
Sc(OTf)3, 5%, 80 °C, 3 h
1 (52)
55/45
HO
Br
Sc(OTf)3, 5%, 80 °C, 3 h
Sc(OTf)3, 5%, 80 °C, 24 h
Sc(OTf)3, 5%, 80 °C, 24 h
2 (41)
3 (100)
4 (41)
55/45
71/29
54/46
HO
HO
Cl
NHCO2Et
HO
HO
NHFmoc
Sc(OTf)3, 5%, 80 °C, 24 h
5 (53)
54/46
Table 3
Glucosylation of serine derivatives in [BMIM][OTf]
Aglycone
Conditions
Product (isolated
yields, %)
a/b
Sc(OTf)3, 5%, 80 °C, 24 h
FeCl3 5%, 80 °C, 5 h
6 (62)
6 (62)
54/46
50/50
NHCbz
CO2Me
NHFmoc
CO2Allyl
HO
HO
Sc(OTf)3, 5%, 80 °C, 20 h
7 (71)
55/45

204
O. Monasson et al. / Carbohydrate Research 352 (2012) 202–205
OH
O
CO2Me
NHCbz
O
HO
HO
α-glucosidase
β-glucosidase
OH
O
OH
OH
HO
HO
CO2Me
NHCbz
O
OH
O
HO
HO
6
CO2Me
NHCbz
HO
50/50 mixture of α and β anomers
O
Scheme 3. Enzymatic separation of
a and b glycosylserine derivatives.
[BMIM][OTf] was largely used as a glycosylation promoter,
Glycosylserine as a 50/50 mixture of
added and the mixture stirred at 50 °C for 24 h. The solvent was
evaporated giving quantitatively either pure b or pure glycosyl-
serine. The crude reaction was then filtered through a silica gel
pad and eluted with MeOH/AcOEt.
a and b anomers was then
especially with thiophenyl and trichloroacetamidate glycoside do-
nors.21 We found that it is also a good promoter for unactivated
sugars, but we must underline that the purity of this ionic liquid
is a key factor. The commercially available ionic liquids are pre-
pared from methylimidazole. We have discovered that methylim-
a
idazole as
a remaining impurity in one commercial sample
1.4. 2-Bromoethyl-
D-glucopyranoside (2)
prevented glycosylation reactions. We strongly recommend to
check the absence of methylimidazole in [BMIM][OTf] samples
by NMR spectroscopy.
a
-Isomer: 1H NMR (400 MHz, CD3OD) d 4.84 (d, 1H, J1,2 3.9 Hz,
H-1), 3.98 (dt, 1H, J 11.5, 6.4 Hz, CHHCH2Br), 3.85 (dt, 1H, J 11.5,
5.9 Hz, CHHCH2Br), 3.77–3.81 (m, 1H, H-6b), 3.64–3.68 (m, 3H,
H-3, H-6a and H-5), 3.59 (dd, 2H, J 6.4, 5.9 Hz, CH2CH2Br), 3.39
(dd, 1H, J1,2 3.9 Hz, J2,3 9.7 Hz, H-2), 3.29 (m, 1H, H-4). 13C NMR
(100 MHz, CD3OD) d 100.5 (C-1), 74.9 (C-5), 74.0 (C-3), 73.5 (C-
2), 71.7 (C-4), 69.7 (OCH2CH2Br), 62.6 (C-6), 31.2 (OCH2CH2Br).
b-Isomer: 1H NMR (400 MHz, CD3OD):d 4.31 (d, 1H, J1,2 7.8 Hz,
H-1), 4.10 (ddd, 1H, J 11.2, 7.1, 6.2 Hz, CHHCH2Br), 3.90 (ddd, 1H,
J 11.2, 6.6, 6.5 Hz, CHHCH2Br), 3.85 (dd, 1H, J6a,6b 11.9 Hz, J6,5
1.6 Hz, H-6b), 3.61–3.68 (m, 1H, H-6a), 3.54 (m, 2H, CH2CH2Br),
3.33 (m, 1H, H-3), 3.24–3.27 (m, 2H, H-4 and H-5), 3.17 (dd, 1H,
J2,3 9.2 Hz, J1,2 7.8 Hz, H-2). 13C NMR (100 MHz, CD3OD) d 104.5
(C-1), 78.0 (C-5), 77.9 (C-3), 75.0 (C-2), 71.5 (C-4), 70.9
(OCH2CH2Br), 62.7 (C-6), 30.9 (OCH2CH2Br). HRMS: Calcd for
C8H15BrO6: 286.0052. Found: 286.0057.
In summary, 1-butyl-3-methylimidazolium trifluoromethane-
sulfonate was evidenced as an alternative medium for promoting
the glycosylation of alcohols and amino acids from unprotected
and unactivated carbohydrates. The notable feature of the proce-
dure lies on the reusability of the ionic liquid which makes it an
eco-friendly chemical process for the synthesis of glycopyrano-
sides of synthetic importance.
1. Experimental
1.1. General
1H and 13C NMR spectra were recorded on a Brucker Avance 250
DPX and a JEOL ECX-400 spectrometer. High resolution mass spec-
tra were obtained with a Q-TOF Waters apparatus equipped with
an ESI ion source.
Room temperature ionic liquids were purchased from Solvionic
and all other chemicals from Acros or Aldrich. Column chromatog-
raphies were performed on Silica Gel 60 (0.06–0.04 mm, Mache-
rey-Nagel). Reactions were monitored by TLC on silica gel 60
UV254 (Macherey-Nagel) with detection by charring with 10% sul-
furic acid in ethanol. Solvents were removed under reduced pres-
sure at temperature <50 °C.
1.5. 2-[(N-(Ethyloxycarbonyl)amino]ethyl-D-glucopyranoside
(4)
1H NMR (400 MHz, CD3OD) d 4.83 (d, 0.54H, J1 3.7 Hz H-1
a
),
4.30 (d, 0.46H, J1b,2 7.6 Hz, H-1b), 4.06–4.17 (m, 2H, CH2CH3), 3.78–
4.00 (H-6, CH2CHHN), 3.57–3.76 (m, H-2 H-5b, H-6 and
, CH2CH2N),
a
,2
a,
CH2CH2 N), 3.20–3.55 (m, H-8, H-2b, H-4, H-3 H-5
a
1.24–1.29 (t, 3H J 7.1 Hz, CH3). 13C NMR (100 MHz, CD3OD) d
173.0, 159.2 (CO), 104.4, 100.2 (C-1), 77.9 (C-3) 75.0 (C-2), 73.7,
73.4 (C-5), 71.6, 71.5 (C-4), 70.0, 68.3 (CH2), 62.6 (C-6), 61.7, 61.5
(CH2), 41.8, 41.5 (CH2), 14.9, 14.4 (CH3). HRMS: Calcd for
1.2. General procedure for glycosylation reaction
A
suspension of carbohydrate (0.5 mmol) and Lewis acid
C11H21NO8Na: 318.1317. Found: 318.1290.
(0.05 equiv) in alcohol (5 equiv) with ionic liquid (0.5 mL) was son-
icated for 5 min and then heated at 80 °C for 20 h. The crude reac-
tion was then filtered through a silica gel pad eluted with ethyl
acetate to afford the desired glycoside as an anomeric mixture.
The ionic liquid was recovered by adding a solution of 15% MeOH
in ethyl acetate. Identification of the glycopyranosides was done by
NMR. For known compounds (1)19 and (3)12 spectroscopic data
were identical to those previously reported in the literature. Only
the parent tetraacetate of compound 2 was previously isolated.20,22
1.6. 2-[N-(Fluoren-9-ylmethoxycarbonyl)amino]ethyl-D-
glucopyranoside (5)
1H NMR (400 MHz, CD3OD) d 7.29–7.77 (m, 8H, Fmoc-Ar), 4.78
(d, 0.54H, J1a,2 3.6 Hz, H-1 ), 4.33 (d, 2H, J 7.3 Hz, Fmoc–CH2), 4.25
a
(d, 0.46H, J1b,2 7.8 Hz, H-1b), 4.18 (t, 1H, J 7.3 Hz, Fmoc–CH), 3.76–
3.86 (m, 2H, H-6b and CHHCH2N), 3.54–3.68 (m, 3H, H-5, H-6a and
CHHCH2N), 3.32–3.50 (m, 2H, H-2a and CH2CHHN), 3.23–3.29 (m,
a
/b ratios were determined from 1H NMR spectra after addition of
3H, H-3 H-4 and CH2CHHN), 3.19 (dd, 0.46H, J 9.0, 7.8 Hz, H-2b).
13C NMR (100 MHz, CD3OD) d 158.9 (CO), 145.2, 142.5, 128.7,
128.1, 126.1, 120.8 (Fmoc-Ar), 104.4, 100.1 (C-1), 77.8 (C-3) 75.0
(C-5), 73.7 (C-2), 71.6 (C-4), 68.2 (OCH2CH2N), 67.7 (Fmoc–CH2),
62.5 (C-6), 48.3 (Fmoc–CH), 41.9 (OCH2CH2N). HRMS: Calcd for
CD3OD in NMR samples.
1.3. General procedure for enzymatic hydrolysis
Either
a or b-glucosidase from Saccharomyces cerevisiae was
C23H27NO7Na: 468.1634. Found: 468.1640.
added to 1 mL of a NaH2PO4/Na2HPO4 buffer (500 mM, pH 7.1).

O. Monasson et al. / Carbohydrate Research 352 (2012) 202–205
205
1.7. N-(Benzyloxycarbonyl)-3-O-(
a
/b-
D-glucopyranosyl)-
L-serine
(C-1b), 101.1 (C-1
a), 78.0 (C-4a), 75.0 (C-2b), 74.0 (C-3), 73.3 (C-
methyl ester (6)
5), 71.5 (C-2a), 70.4 (C-4b), 69.0 (Ser-CH2), 68.2 (Fmoc–CH2),
67.1 (CH2CH@CH2), 62.4 (C-6), 56.1 (Ser-CH), 48.2 (Fmoc–CH).
HRMS: Calcd for C27H32NO10: 530.2026. Found: 530.2017.
b-Isomer: 1H NMR (400 MHz, CD3OD) d 7.28–7.37 (m, 5H, Ph),
5.11 (s, 2H, CH2Ph), 4.47 (m, 1H, Ser-CH), 4.35 (dd, 1H, J 10.1,
4.1 Hz, Ser-CHH), 4.24 (d, 1H, J1,2 7.8 Hz, H-1), 3.83 (dd, 1H, J6a,6b
11.7 Hz, J6,5 1.6 Hz, H-6b), 3.75 (dd, 1H, J 10.1, 5.0 Hz, Ser-CHH),
3.73 (s, 3H, CH3), 3.60–3.68 (m, 1H, H-6a), 3.23–3.27 (m, 3H, H-3
H-4 and H-5), 3.15 (dd, 1H, J2,3 8.9 Hz, J1,2 7.8 Hz, H-2).13C NMR
(100 MHz, CD3OD) d 172.4, 158.8 (CO), 138.1, 129.5, 129.0, 128.9
(Ph), 104.6 (C-1), 78.1 (C-4), 77.8 (C-3), 75.0 (C-2), 71.4 (C-5),
70.5 (Ser-CH2), 67.8 (CH2Ph), 62.6 (C-6), 55.8 (Ser-CH), 52.9 (CH3).
Acknowledgment
The French Agence Nationale pour la Recherche (CP2D-GLYC-
ENLI Project) is gratefully acknowledged for funding.
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1H NMR (400 MHz, CD3OD, 50 °C): d 7.76–7.77 (m, 8H, Fmoc-
Ar), 5.90 (m, 1H, CH2–CH@CHH), 5.32 (dd, 1H, Jtrans 16.7 Hz, Jgem
1.4 Hz, CH2–CH@CHH), 5.19 (dd, 1H, Jcis 10.5 Hz, Jgem 1.4 Hz,
CH2–CH@CHH), 4.80 (m, 1H, H-1a), 4.63 (d, 2H, JCH2–CH@CH2
5.0 Hz, CH2–CH@CH2), 4.51 (t, 1H, J 5.0 Hz, Ser-CH), 4.29-4.48 (m,
3H, H-1b and Fmoc–CH2), 4.20 (t, 1H, J 6.8 Hz, Fmoc–CH), 3.93 (t,
2H, J 5 Hz, Ser-CHH), 3.71–3.90 (m, 2H, H-6), 3.55–3.70 (m, 2H,
H-5 and H-3), 3.27–3.40 (m, 2H, H-4 and H-2a), 3.18 (t, 1H,
J1,2 = J2,3 7.8 Hz, H-2b). 13C NMR (100 MHz, CD3OD): d 171.5 (CO es-
ter), 158.6 (CO Fmoc), 145.1, 142.5, 133.1, 128.8, 128.1, 126.2,
123.3, 120.9, 120.1 (Fmoc-Ar), 133.1, 118.9 (CH2CH@CH2), 104.4
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