Direct Highly Regioselective Functionalization of Carbohydrates: A Three-Component Reaction Combining the Dissolving and Catalytic Efficiency of Ionic Liquids

Article abstract of DOI:10.1002/ejoc.201600536

An unprecedented regioselective functionalization of unprotected polyols has been realized with the use of an ionic liquid NHC precatalyst. The protocol is robust, scalable, and the products can be isolated in good to excellent yields without chromatography. Moreover, the methodology enables successful recycling of the catalyst.

Full text of DOI:10.1002/ejoc.201600536

DOI: 10.1002/ejoc.201600536
Communication
N-Heterocyclic Carbenes
Direct Highly Regioselective Functionalization of
Carbohydrates: A Three-Component Reaction Combining the
Dissolving and Catalytic Efficiency of Ionic Liquids
[a]
[a]
[a]
Anton Axelsson, Linda Ta, and Henrik Sundén*
Abstract: An unprecedented regioselective functionalization of products can be isolated in good to excellent yields without
unprotected polyols has been realized with the use of an ionic chromatography. Moreover, the methodology enables success-
liquid NHC precatalyst. The protocol is robust, scalable, and the ful recycling of the catalyst.
Introduction
Polyols such as carbohydrates and sugar alcohols are an impor-
tant class of complex, biologically relevant raw materials readily
available from biomass. Simple carbohydrates, such as mono-
and oligosaccharides are common structural motifs in drug dis-
[
1]
covery, whereas cellulose and other polysaccharides are of
[
2]
great interest for the development of new materials. However,
due to the intricate structure of these compounds, containing
both primary and secondary hydroxy groups, their modification
is nontrivial often involving laborious protecting-group strate-
[
3]
gies. Recently, regioselective functionalization of polyols by
[
4]
catalysis have emerged as such a method. For instance, modi-
fications of hydroxy groups in biologically relevant natural prod-
ucts and carbohydrates have been achieved by utilizing both
[
5]
[6]
Lewis acid catalysis and organocatalysis.
Within organocatalysis, catalysis with N-heterocyclic carb-
enes (NHCs) have received much attention due to the develop-
[
7]
ment of several distinct reaction patterns often including the
[
8]
[8f,8g,8i,8n]
acylation of simple alcohols and in some cases diols.
Recently, complex polyols such as adequately protected carbo-
hydrates have also been used in combination with various NHC
activation strategies. For example, Liu and co-workers have re-
ported the C-glucosidations on nitroglucans according to a
Scheme 1. Regioselective functionalization of carbohydrates.
Stetter reaction path (Scheme 1, A), and Wendeborn has re- tion to being used as NHC precursors in catalysis,[12] ILs are
ported the use of protected carbohydrates in the synthesis of being regarded as safe and recyclable reaction solvents with
[9]
2
-deoxylactones (Scheme 1, B).[10] Even though NHC-catalyzed good solvating properties.[13] For example, ILs, especially dialk-
reactions often involve functionalization of alcohols, reactivity ylimidazolium compounds, have been used for the dissolution
[
14]
and selectivity towards polyols containing both primary and of carbohydrates, such as cellulose.
secondary hydroxy groups have not been investigated.[11]
Recently, we reported the IL-mediated stereoselective syn-
A convenient way of generating NHCs is through the depro- thesis of oxotriphenylhexanoates, involving unsaturated alde-
[
12m]
tonation of dialkylimidazolium-based ionic liquids (ILs). In addi- hydes, chalcones and simple alcohols.
To further explore
the utility of ILs as NHC precursors, using both the catalytic and
solvating properties of ILs, it was envisioned that ILs could be
used in combination with complex polyols such as carbo-
hydrates. We speculated that the encumbered IL-derived acyl-
azolium compound (Scheme 1) could have a regio-discrimina-
ting effect on the incoming polyol nucleophile and thus lead
to a selective acylation.
[
a] Chemistry and Chemical Engineering, Chalmers University of Technology
Kemivägen 10, 41296, Göteborg, Sweden
E-mail: sundenh@chalmers.se
www.chalmers.se
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600536.
Eur. J. Org. Chem. 0000, 0–0
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Results and Discussion
Table 2. Scope of the hexopyranosides.[a]
Here, we report on the first regioselective NHC-catalyzed func-
tionalization of unprotected hexopyranosides using ILs as NHC
precatalysts. Initially, the unprotected pyranoside methyl α-D-
mannopyranoside was subjected to IL, chalcone, and cinnam-
aldehyde. Most surprisingly, the reaction proceeded with total
selectivity towards the primary hydroxy group, and the 6-OH-
substituted mannopyranoside was obtained in 72 % yield
(
Table 1, Entry 1) leaving the secondary hydroxy groups un-
touched (see Supporting Information). As a testament to the
tremendous selectivity towards primary over secondary alco-
hols, a solvent screen revealed that even 2-propanol could be
used as reaction solvent delivering 1 in 54 % yield (Table 1,
Entry 9). A survey of reaction conditions revealed that ILs could
successfully promote the formation of 1, whereas non-IL NHCs
were ineffective (see Supporting Information). The result can
be ascribed to the inherent ability of the ILs to dissolve the
hexopyranosides, thus enabling homogeneous phase reactions.
When comparing three different ILs, EMIMAc performed better
than EMIMCl and BMIMCl (Table 1, Entries 1, 2 and 3). A lower
loading of EMIMAc, even with prolonged reaction time, resulted
in a decreased yield (Table 1, Entry 4). The choice of base and
solvent also proved to be important. The sterically hindered
base DBU afforded the best yields delivering 1 in 83 % yield in
acetonitrile (Table 1, Entry 8) and 72 % in dichloromethane
(
Table 1, Entry 1). Based on these results several hexopyran-
osides were investigated to determine the scope of the reaction
(
Table 2).
In all cases total regioselectivity towards the primary alcohol
was observed with exclusive stereoselctive formation of the two
anti diasteromers in a 1:1 ratio. Both the α- and ꢀ-anomers of
the hexopyranosides were well tolerated, as accentuated in the
[
a] Standard reaction conditions. [b] Isolated yield of the two anti diastereoi-
somers, dr 1:1. [c] Gram-scale. [d] Dichloromethane as solvent.
case of the two methyl -glucopyranosides 3 and 5, where both
D
Table 1. Optimization of the NHC-catalyzed acylation of mannopyranoside.[a]
adducts were obtained in good yields. Also, a phenyl substitu-
ent in the anomeric position does not appear to affect the yield
or selectivity (7). Furthermore, the reaction of both methyl α-
D
-mannopyranoside (8) and methyl ꢀ- -galactopyranoside (10)
D
were successfully giving 9 and 11 in 81 % and 74 % yield, re-
spectively. To survey the scope with regard to the keto ester
unit, methyl glucopyranosides were treated with different chalc-
ones and α,ꢀ-unsaturated aldehydes (Table 3).
Base[b]
Yield [%][c]
The reactions proceeded in good yields and both electron-
donating and electron-withdrawing aromatic substituents on
the chalcone are well tolerated (Table 3, compounds 12–16),
which is illustrated by the swift synthesis of functionalized
carbohydrates bearing aromatic chloro (12; 75 % yield), bromo
Entry
Solvent
IL
1
2
3
4
5
6
7
8
9
dichloromethane
dichloromethane
dichloromethane
dichloromethane
dichloromethane
dichloromethane
dichloromethane
acetonitrile
DBU
DBU
DBU
DBU
tBuOK
EMIMAc
EMIMCl
BMIMCl
72
45
56
20
52
0
0
83
54
[
15]
[
d]
EMIMAc
EMIMAc
EMIMAc
EMIMAc
EMIMAc
EMIMAc
(13; 81 % yield) and methyl substituents (14; 72 % yield). It is
Et
Na
3
N
worth mentioning that methoxy derivative 15, isolated in 83 %
yield, can be obtained as a single diastereomer after recrystalli-
zation from THF. In addition, heteroaromatic substituents such
as furan and pyridine can be incorporated into the keto ester
backbone in 69 % and 87 % yield (17 and 18), respectively.
Having demonstrated that hexopyranosides can be modified
directly without the need for protecting groups, our attention
turned to acyclic sugar alcohol mannitol (21) (Scheme 2).
Mannitol, a biologically relevant sugar alcohol with several me-
2
CO
3
DBU
DBU
2-propanol
[
(
(
a] Standard conditions: solvent, base (0.5 equiv.), IL (2.5 equiv.), chalcone
1 equiv., 0.08 ), cinnamaldehyde (3 equiv.), methyl α- -mannopyranoside
3 equiv.), room temp., 24 h. [b] DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene;
EMIMAc = 1-ethyl-3-methylimidazolium acetate; EMIMCl = 1-ethyl-3-methyl-
imidazolium chloride; BMIMCl = 1-butyl-3-methylimidazolium chloride. [c]
M
D
1
Yield of the two anti diastereoisomers, dr 1:1, determined by H NMR spectro-
scopy against an internal standard. [d] 0.25 equiv., 72 h.
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Communication
Table 3. Reaction scope, chalcones and α,ꢀ-unsaturated aldehydes.[a]
workup method enables recycling of the IL, and 3 could be
afforded in 77 %, 79 % and 72 % yield in three consecutive runs,
with recycled IL. Moreover, gram quantities of hexopyranoside 3
were obtained in excellent 93 % yield using standard laboratory
equipment, demonstrating that these reactions are robust and
scalable (Table 2).
Scheme 2. NHC-catalyzed regioselective conversion of mannitol into 22.
To gain insight into the regioselectivity of the reaction, the
relative stability of the tetrahedral intermediate formed by an
attack by either the primary 6-OH or the secondary 4-OH group
in methyl α-D-glucopyranoside toward the acyl azolium com-
pound (Scheme 1) were investigated at the B3LYP/6-31G* level
of theory. Regarding the choice of reference, the relative react-
ivity of the secondary alcohols has been shown to vary within
[
18]
different pyranosides,
whereas Bols et al. reported that the
electron density, and by extension also the nucleophilicity, va-
ries according to 6-OH > 3-OH > 2-OH > 4-OH within the most
[
19]
common pyranoside scaffolds.
However, since the reaction
exhibits a general selectivity towards the 6-OH group, even in
the presence of a large excess of 2-propanol, we argued that
the results should be similar regardless of which of the second-
ary alcohols were chosen as a reference. In the end, the 4-OH
group was chosen since it has been reported to be kinetically
favored in DMAP-catalyzed acylations of other alkyl α-
D
-gluco-
[
20]
pyranosides in chloroform.
Investigation of all possible dia-
stereomers of the tetrahedral intermediates (see Supporting In-
formation) revealed that the most stable 6-OH intermediate
Scheme 3) was favored by 6 kJ mol– compared to the most
1
(
stable 4-OH intermediate (Scheme 3), which is consistent with
experimental observations. Further inspection revealed that the
solvation energy accounts for 4 kJ mol– of the total energy
1
difference. This can be rationalized by the fact that the 6-OH
intermediate can adopt a more compact conformation and
thereby minimize the contact between the hydrophobic re-
gions and the polar solvent (acetonitrile), while placing the po-
lar imidazolium and pyranoside moieties out towards the sol-
vent. Contrariwise, the 4-OH intermediate adopts an elongated
conformation to relieve steric encumbrance and is therefore
[
a] Standard reaction conditions. Yields refer to isolated yields of the two anti
stabilized to a lesser degree by solvation. The non-covalent in-
teraction (NCI) plots (Scheme 3) of these two intermediates sup-
diastereoisomers, dr 1:1.
port this notion, indicating similar interactions within the two
(derived from the reduction of mannose or intermediates except for some steric interactions within the
[
16]
dicinal uses
[
17]
fructose ). The reaction with mannitol proceeded in a highly keto ester backbone and between the sugar moiety and the
regioselective manner, and the monoacylated product 22 was second phenyl substituent in the 4-OH intermediate.
obtained in 1:1 dr and 70 % yield. Furthermore, it is important
to mention that the monofunctionalized carbohydrates are iso-
lated from the reaction mixtures without chromatography (ex-
Conclusions
traction and filtration) by using minimal amounts of solvents, Herein, we have reported a highly regioselective NHC-catalyzed
thereby reducing the environmental impact. In addition, the three-component reaction yielding monofunctionalized carbo-
Eur. J. Org. Chem. 0000, 0–0
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
was collected and dissolved in EtOAc (40 mL), and the mixture was
sonicated at ambient temperature for 45 min and then stirred over-
night. Heptane (60 mL) was added, and the mixture was stirred for
1
h and then filtered through a frit yielding 9 as a white solid
= 3421 (s, br.),
(
3
263.3 mg, 0.49 mmol, 81 %, 1:1 dr). IR (KBr): ν˜
max
087 (w), 3062 (w), 3028 (w), 1731 (vs), 1684 (vs), 1137 (s), 1064 (s,
–
1 1
br.), 981 (m), 744 (m), 703 (vs) cm . H NMR (400 MHz, [D ]DMSO):
6
δ = 7.71–7.62 (m, 4 H), 7.54 (m, 2 H), 7.43–7.09 (m, 24 H), 5.07–4.57
(m, 6 H), 4.42–4.37 (m, 2 H), 4.10–3.95 (m, 2 H), 3.82–3.69 (m, 2 H),
3.60–3.47 (m, 6 H), 3.43–3.39 (m, 2 H), 3.31–3.21 (m, 4 H), 3.12 (s, 3
H, diastereomer 1) 3.08 (s, 3 H, diastereomer 2), 2.80–2.54 (m, 6 H),
2
1
1
7
4
.32–2.21 (m, 2 H) ppm. 13C NMR (101 MHz, [D ]DMSO): δ = 198.5,
6
98.5, 171.4, 171.3, 142.7, 142.7, 142.4, 142.4, 136.6, 133.0, 128.6,
28.4, 128.3, 128.2, 128.2, 127.7, 126.7, 126.5, 100.9, 100.9, 70.8, 70.7,
0.6, 70.6, 70.0, 70.0, 66.9, 66.8, 63.9, 63.8, 53.9, 53.9, 47.2, 47.1, 46.4,
6.3,42.4, 42.3, 38.6, 38.5 ppm. HRMS (ESI): calcd. for C H O [M +
31 34 8
+
H] 535.2332; found 535.2343.
Acknowledgments
This work was supported by the Swedish Research Council (VR)
and Formas, Magnus Bergvalls stiftelse and Chalmers areas of
advance nanoscience and nanotechnology. We would also like
to express our gratitude to Professor Per-Ola Norrby for discus-
sions regarding the computational chemistry.
Scheme 3. NCI plots of the hemiacetal intermediate. Hydrogen atoms not
active in bonding interactions are omitted for clarity. Red isosurfaces repre-
sents strong stabilizing, green isosurfaces represent weakly stabilizing, and
blue isosurfaces represent destabilizing interactions.
Keywords: Ionic liquids · Organocatalysis · Carbohydrates ·
NHCs · Regioselectivity
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Received: April 29, 2016
Published Online: ■
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
N-Heterocyclic Carbenes
A. Axelsson, L. Ta, H. Sundén* ........ 1–6
Direct Highly Regioselective Func-
tionalization of Carbohydrates: A
Three-Component Reaction Com-
bining the Dissolving and Catalytic
Efficiency of Ionic Liquids
A sweet tooth for selectivity! Sugars liquid. The method enables gram-
and other carbohydrate derivatives are scale, regioselective production of
selectively functionalized by an ionic functionalized carbohydrates in high
liquid mediated three-component re- yields and tolerates a wide variety of
action, which utilizes both the catalytic coupling partners.
and solvating properties of the ionic
DOI: 10.1002/ejoc.201600536
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim