Green glycosylation promoted by reusable biomass carbonaceous solid acid: An easy access to β-stereoselective terpene galactosides

Article abstract of DOI:10.1039/c0gc00883d

An efficient green protocol has been developed for the atom economic glycosylation of unprotected, unactivated glycosyl donors and glycosylation of glycosyl trichloroacetimidates with the aid of reusable eco-friendly biomass carbonaceous solid acid as catalyst. The Royal Society of Chemistry.

Full text of DOI:10.1039/c0gc00883d

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Green glycosylation promoted by reusable biomass carbonaceous solid acid:
an easy access to b-stereoselective terpene galactosides†
Bala Kishan Gorityala, Jimei Ma, Kalyan Kumar Pasunooti, Shuting Cai and Xue-Wei Liu*
Received 4th December 2010, Accepted 4th January 2011
DOI: 10.1039/c0gc00883d
An efficient green protocol has been developed for the
atom economic glycosylation of unprotected, unactivated
glycosyl donors and glycosylation of glycosyl trichloroace-
timidates with the aid of reusable eco-friendly biomass
carbonaceous solid acid as catalyst.
such as (a) no work-up procedures, (b) easy separation and (c)
easy recovery and reusability.
To date several silica- and alumina-supported solid acid
catalysts have been developed and employed in glycosylation.17
For example Toshima and coworkers performed glycosylation
by using a sulfated zirconia and montmorillonite K-10 as
activators.18 Corma et al. reported the Fischer glycosylation
by using zeolites.19 Unfortunately, many of the reported solid
acids did not control the stereoselectivity at the anomeric centre,
and hence provided glycosides as anomeric mixture. More
importantly, most of solid acids are mechanically unstable in
various solvents, therefore practically they are not recyclable.
In order to address the above-mentioned practical difficulties
and in our continuous effort to explore new glycosylation
protocols,20 herein we wish to report glycosylation of vari-
ous unprotected, unactivated monosaccharides and glycosyl
trichloroacetimidates promoted by sulfonated biomass car-
bonaceous material, which is inexpensive, moisture stable and
environmentally benign with high catalytic performance. The
most striking feature of this catalyst is its remarkable reusable
capacity and, when employed with activated sugars, it delivered
desired O-glycosides with exclusive anomeric selectivity. The
sulfonated carbonaceous solid acid material was synthesized
according to the given literature procedure.21 It consists of
flexible polycyclic carbon sheets, which bear phenolic hydroxyl
(–OH), carboxylic acid (–COOH) and sulfonic acid (–SO3H)
groups. Elemental analysis of the solid acid revealed its sulfur
content, which was found to be 1.13%. Since all sulfur atoms
in the carbon material were in the form of SO3H groups, the
density of SO3H groups in solid acid was thus estimated to be
0.35 mmol g-1. The solid acid was further characterized by X-ray
diffraction (XRD).
Glycosylation provides an unique platform to synthesize an
array of carbohydrate-derived novel therapeutic agents.1 It has
gained much attention and witnessed a vast development ever
since the historical discovery of Koenigs-Knorr method and
its amended versions.2 Over the past few decades, there has
been significant amount of advancement in glycosyl donors
and acceptors.3 It is essential to chose appropriate donor and
employ suitable promoter to attain regio- and stereoselective
glycoside synthesis. The most common promoters include
strong and highly moisture sensitive Lewis acids, such as
BF3·Et2O,4 TBSOTf,5 Tf2O,6 ZnBr,7 LiClO4,8 LiOTf,9 AgOTf10
and TMSOTf.11 These promoters need dry reaction conditions,
low temperatures and required in stoichiometric amounts.
Moreover, they mostly furnish glycosides as a/b anomers.
When using mineral and Lewis acid catalysts, the final glycoside
isolation requires aqueous work-up and neutralization steps,
which subsequently results in the disposal of massive amounts
of hazardous waste. Most of the times, cost of the pollutants is
significantly greater than the cost of the product. The principles
of “Green Chemistry” emphasize the usage of environmentally
benign catalysts/chemicals in order to have minimal dete-
riorating effects on the environment.12 As an alternative to
homogenous catalysis, nowadays environmentally sustainable
nontoxic solid acid catalysts with strong acidic sites have become
more prominent in organic transformations. Several solid acid
catalysts have been reported in the literature, such as high silica
zeolites,13 ion exchange resins14 and mesoporous materials.15
Solid acid catalysts have several advantages16 over liquid acids
To begin with, we tried to test the catalytic efficiency of
the solid acid by performing glycosylation on unprotected
and unactivated sugars. Glycosylation of unprotected alcohols22
remains particularly challenging due to self-condensation, ring
chain tautomerism and in situ anomerization.23 From a greener
prospective, glycosylation of unprotected sugars is atom eco-
nomic since it avoids unwieldy protection-deprotection steps
thus leading to high atom economy and improved E-factor.24
Moreover direct synthesis of O-glycosides from O-unprotected
donors accounts for (a) enhancing the reactivity, (b) controlling
21 Nanyang Link, Division of Chemistry and Biological Chemistry,
School of Physical & Mathematical Sciences, Nanyang Technological
University, Singapore, 637371. E-mail: xuewei@ntu.edu.sg;
Fax: +65-6791 1901; Tel: +65 6316 8901
† Electronic supplementary information (ESI) available: Detailed
experimental procedures and characterization data. See DOI:
10.1039/c0gc00883d
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Table 1 Catalytic efficiency of solid acid compared against various
Pleased by this result, we began to probe the breadth of this
catalytic application on various unprotected and unactivated
monosaccharides. The scope of the neat glycosylation on various
sugar moieties such as D-galactose, D-mannose, D-fucose, D-
xylose, D-ribose, 2-deoxy-D-ribose, N-acetyl glucosamine was
investigated. We chose allyl alcohol as aglycone because of the
fact that allyl glycosides find substantial applications in the
synthesis of oligosaccharides, for example (a) reducing sugars
were attained via the deprotection of anomeric O-allyl moiety at
any length of the saccharide chain by using various reagents,25
(b) reducing sugars could be coupled with proteins to obtain cor-
responding glycoconjugates,26 (c) with the assistance of a spacer-
arm, anomeric O-allyl group could be availed to synthesize
glycoconjugates,27 and (d) asymmetric functionalization of O-
allyl moiety paves a new way to synthesize enantiomerically pure
compounds, thereby contributing to the asymmetric organic
synthesis.28 Under the standard experimental conditions, all
the monosaccharides furnished corresponding allyl glycosides
in good to excellent yields (72–96%, Table 2, entries 5–11). As
predicted, mannose gave allyl glycoside as pure a-diastereomer
(Table 2, entry 8) and it is worthy of note that fucose and 2-deoxy-
D-ribose afforded the corresponding allyl glycosides with good
selectivities (Table 2, entries 6 and 11 respectively). Meanwhile,
galactose, xylose and ribose afforded respective allyl glycosides
in good to excellent yields with moderate to good selectivities
(Table 2, entries 5, 9 and 10 respectively). It is important
to note that all the glycosylation reactions are distinguished
with the exclusive formation of thermodynamically more stable
pyranosides than the corresponding kinetically favored fura-
nosides. Having synthesized various synthetically useful allyl
glycosides, we extended the scope of the catalytic activity by
synthesizing long chain glycosides. From a synthetic point of
view, there has been enormous interest in alkylpolyglycosides
(APG),29 which are a part of carbohydrate-derived surfactants.
APGs are known to play significant role in food and cosmetic
industries, as they are preferred candidates to serve as non-
ionic surfactants for cosmetics and as food emulsifiers.30 These
factors encouraged us to synthesize n-butyl glycopyranoside and
n-octyl glycopyranoside through direct glycosylation. Both the
APGs were isolated in good yields with acceptable anomeric
selectivities (Table 2, entries 1 and 2).
Then we embarked on checking the recyclability of the solid
acid catalyst, which is the most crucial factor that reckons its
practical utility while employing in glycosylation reactions. After
recovering the carbonaceous solid acid via a simple filtration
and removing the volatile solvents under vacuum, the catalyst
was reused without further activation in catalyzing the reaction
between unprotected mannose and allyl alcohol. To our delight,
glycosylation proceeded smoothly even after 7 runs without any
extension of reaction time or marked loss in yield (Fig. 1). In
each experiment, allyl mannoside has maintained a-anomeric
selectivity.
Finally, we scrutinized the catalytic efficacy of the solid acid
by glycosylating glycosyl trichloroacetimide with various ter-
penoid alcohols to synthesize biologically active carbohydrate-
containing terpenoids and steroids. Nowadays, diversity ori-
ented synthesis (DOS) for synthesizing oxygen-rich small
molecules with definite stereochemistry has gained much
attention.31 Terpenes possess a significant amount of biological
Lewis acidsa
Catalyst load- Temp./ Time/ Yield a/b
Entry Catalyst
ing (mol%)
◦C
h
(%)b
ratioc
1
2
3
4
5
6
7
8
Solid acid
Solid acid
Solid acid
ZnCl2
1
1
5
5
5
5
5
5
5
5
5
25
80
80
80
80
80
80
80
80
80
80
24
14
8
26
82
84
42
71
24
—
49
—
41
45
73 : 27
73 : 27
73 : 27
65 : 35
63 : 37
69 : 31
—
73 : 27
—
70 : 30
68 : 32
24
24
24
24
24
24
24
24
BF3·OEt2
FeCl3
AgOTf
Sc(OTf)2
InCl3
AuCl3
Yb(OTf)3
9
10
11
a The reaction was conducted with 1 eq. of D-glucose and 10 eq. of allylic
alcohol. b Isolated yields. c Determined by 1H NMR.
the a/b selectivity and (c) making the process modifica-
tions with more ease by reducing the number of synthetic
steps.
A systematic study of glycosylation was undertaken by per-
forming neat glycosylation between D-glucose and allyl alcohol
to test the catalytic activity and performance. Glycosylation was
sluggish when the reaction was carried out at room temperature
with 1 mol% of the catalytic loading and resulted in desired allyl
glycoside (a/b = 73 : 27) in 26% yield.
However, when the temperature has been raised to 80 ◦C,
we were intrigued by the formation of the glycoside in 82%
yield (Table 1, entry 2). We have tried different temperatures
such as 40 ◦C and 60 ◦C. Best yields were obtained when
the temperature was maintained at 80 ◦C. A detailed probe
into the optimization showed that the reaction time required
for complete conversion of monosaccharide to corresponding
glycoside is inversely proportional to the amount of solid acid
loaded and temperature (Table 1, entries 1–3). However, it was
found that increasing the catalytic loading to 10 mol% could
not make an impact on reaction time and yield. A series of
experiments were conducted to compare the efficiency of solid
acid catalyst against commonly used Lewis acid catalysts. Under
the same conditions (5 mol% Lewis acid catalyst and at 80 ◦C),
the model glycosylation of glucose with allyl alcohol was carried
out. The results are summarized in Table 1. It was observed
that all the Lewis acids could not successfully converted the
monosaccharide into glycoside even after prolonged reaction
times except BF3·OEt2 which gave allyl glycoside (a/b =
63 : 37) in acceptable yield (71%). To our surprise AgOTf and
InCl3 proved to be inefficient candidates to carry out the
glycosylation transformation (Table 1, entries 7 and 9). However,
Lanthanide triflates such as Sc(OTf)2 and Yb(OTf)3 are able
to furnish the allyl glycoside in moderate yields. This study
clearly shows the preeminent catalytic efficiency of biomass
solid acid over Lewis acids in terms of yields, reaction time and
stereoselectivity when exerted with unprotected and unactivated
sugars.
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Table 2 Neat glycosylation of unprotected and unactivated glycosyl
donor with acceptorsa
Yield a/b
Entry Glycosyl donor
1
Acceptor
Time/h (%)b ratioc
8
8
8
8
8
62
68
55
70
72
44 : 56
56 : 44
71 : 29
68 : 32
60 : 40
2
3
4
5
Fig. 1 Catalytic performance of recovered solid acid.
trichloroacetimidate and◦citronellol in the presence of 5 mol%
solid acid catalyst at 80 C in toluene for 4 h afforded desired
citronellol galactoside in excellent yield (82%) with exclusive
b-anomeric selectivity (Table 3, entry 5). Encouraged by this
result, we tried to construct glycosyl bond between various
terpenes and galactose. endo-Fenchol, borneol and menthol
gave the corresponding galactosyl derivates in excellent yields
with absolute stereo selectivity (Table 3, entries 1, 2 and 3).
Pregnenolone, a steroid harmone involved in the steroidogenesis
of progesterone, also successfully transformed in to steroidal
b-galactoside (Table 3, entry 4). To broaden the substrate
scope and to show the catalytic utility we have synthesized
protected serine galactoside and bulky moieties containing
galactosides such as adamentane and ferrocene (Table 3, entries
6–8). To corroborate the solid acid’s practical reusability as a
glycosylation promoter, recycled catalyst was employed in the
above set of experiments.
In conclusion, we have demonstrated the remarkable catalytic
efficiency of environmentally sustainable biomass carbonaceous
solid acid as glycosylating promoter. Various unprotected and
unactivated glycosyl donors, which are usually prone to self-
condensation and in situ anomerization while performing the
glycosylation, were successfully glycosylated to afford corre-
sponding glycosides. This catalyst could also be employed for
the glycosylation of glycosyl trichloroacetimides. Some of the
salient features of the catalyst are: (a) derived from naturally
existing D-glucose hence quite economical to synthesize, (b)
air and moisture stable therefore easy to handle, (c) reaction
procedure is operationally simple which precludes the stringent
and inert conditions; use of molecular sieves can be avoided, (d)
easy recovery of the catalyst upon completion of the reaction
through simple filtration there by avoiding hectic aqueous work
ups and neutralization steps, (e) high reusable capacity; catalyst
is reusable up to 7 times while persisting the high catalytic
activity, (f) affords galactosides with exclusive b anomeric
selectivity when used with glycosyl trichloroacetimides. With
these advantages inhand, we strongly believe solid acid promoter
could become an alternative to other glycosylating promoters.
Its synthetic assets coupled with green principles could benefit
the glyco-chemists in their regular laboratory usage. The employ-
ment of heterogeneous solid acid catalyst in other glycochemical
transformation is currently underway in our laboratory.
6
7
8
8
8
8
82
75
94
90 : 10
50 : 50
100 : 0
9
8
90
70 : 30
10
11
8
8
96
80
75 : 25
85 : 15
a The reaction was conducted with 1 eq. of glycosyl donor and 10 eq. of
glycosyl acceptor. b Isolated yields. c Determined by 1H NMR.
activity32 and reports on synthesis of exclusive b-selective terpene
and steroidal galactose analogues are rare. Synthesis of terpene
glycosides generally relies on enzymatic methods.33
Due to their potential candidature as antimicrobial, anti-
fungal, antiparasitic, antitoxigenic and anticancer agents, we
envisaged to synthesize b-terpene and steroidal galactosides with
the aid of solid acid catalyst. Glycosylation between glycosyl
We gratefully acknowledge Nanyang Technological Univer-
sity (RG50/08) and the Ministry of Education, Singapore (MOE
2009-T2-1-030) for the funding support of this research.
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Table 3 Glycosylation of glycosyl trichloroacetimidates with various alcoholsa
Entry
1
Aglycone
Product
Time/h
4
Yield (%)b
88
2
4
2
82
94
3c
4c
8
76
5c
6c
4
6
82
92
7c
6
8
94
85
8c,d
a The reaction was conducted with 1 eq. of glycosyl donor and 1.5 eq. of acceptor in toluene at 80 ◦C. b Isolated yields. c Recovered catalyst was used.
d Dichloromethane was used as solvent.
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