Fe2(SO4)3·xH2O-catalyzed per-O-acetylation of sugars compatible with acid-labile protecting groups adopted in carbohydrate chemistry

Article abstract of DOI:10.1016/j.tet.2008.01.027

Fully acetylated saccharides are inexpensive and very useful starting materials for the synthesis of many naturally occurring glycosides, oligosaccharides, and glycoconjugates. Ferric sulfate hydrate (Fe₂(SO₄)₃·xH₂O) was found to be a valuable Lewis acid promoter in the per-O-acetylation reaction of saccharides with acetic anhydride in 100% of conversion rate and 88-99% yields. Interestingly, the procedure is perfectly compatible with the presence of a variety of acid-labile protecting groups, such as isopropylidene, benzylidene, trityl, and TBDMS groups. The reactions were simply performed by stirring the mixture of a sugar with a slight excessive acetic anhydride in the presence of 2.0 mol % of Fe₂(SO₄)₃·xH₂O at rt and the pure products were obtained by a simple dilution of the reaction mixture with dichloromethane and washings with aqueous Na₂CO₃.

Full text of DOI:10.1016/j.tet.2008.01.027

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2572e2575
www.elsevier.com/locate/tet
Fe2(SO4)3$xH2O-catalyzed per-O-acetylation of sugars compatible with
acid-labile protecting groups adopted in carbohydrate chemistry
*
Lei Shi, Guisheng Zhang , Feng Pan
School of Chemical and Environmental Sciences, Henan Key Laboratory for Environmental Pollution Control, Henan Normal University,
46 East Construction Road, Xinxiang, Henan 453007, PR China
Received 28 October 2007; received in revised form 21 December 2007; accepted 8 January 2008
Available online 11 January 2008
Abstract
Fully acetylated saccharides are inexpensive and very useful starting materials for the synthesis of many naturally occurring glycosides,
oligosaccharides, and glycoconjugates. Ferric sulfate hydrate (Fe2(SO4)3$xH2O) was found to be a valuable Lewis acid promoter in the per-
O-acetylation reaction of saccharides with acetic anhydride in 100% of conversion rate and 88e99% yields. Interestingly, the procedure is per-
fectly compatible with the presence of a variety of acid-labile protecting groups, such as isopropylidene, benzylidene, trityl, and TBDMS groups.
The reactions were simply performed by stirring the mixture of a sugar with a slight excessive acetic anhydride in the presence of 2.0 mol % of
Fe2(SO4)3$xH2O at rt and the pure products were obtained by a simple dilution of the reaction mixture with dichloromethane and washings with
aqueous Na2CO3.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Fe2(SO4)3$xH2O; Per-O-acetylation; Sugars
1. Introduction
triflate,9 indium(III) triflate,10 copper(II) triflate,11 bismuth(III)
triflate,12 lithium triflate,13 cerium(III) triflate,14 were found to
be effective as Lewis acid promoters in per-O-acetylation of
saccharides. However, many of these methods suffer from
some drawbacks. The amines and pyridine, which are used
as both solvent and a nucleophilic catalyst, present well known
toxicity, have unpleasant odors, and are not easy to remove.
Handling of large volumes of pyridine and other homogeneous
catalysts is troublesome and their recovery is also difficult.
Large scale acetylation involving sodium acetate requires spe-
cial modification of the apparatus to keep the reaction under
control.15 Iodine was shown to be a versatile promoter, the
work-up, however, is elaborate and iodine was not recovered.
Scandium and indium triflates are expensive catalysts. The
cost, availability, toxicity, and difficulty in handling can limit
the widespread application of other triflate derivatives.
Furthermore, many of these reactions are carried out under
reflux, the promoter is used in non-catalytic amounts or te-
dious work-up is required. Thus, introduction of new efficient
methodologies for per-O-acetylation reactions of sugars is still
in strong demand.
Per-O-acetylation is most commonly used for the protec-
tion of hydroxyl groups in carbohydrate chemistry. Fully acet-
ylated saccharides are inexpensive and very useful starting
materials for the synthesis of many naturally occurring glyco-
sides, oligosaccharides, and glycoconjugates. The structural
elucidation of such natural products is very often facilitated
by transformation to their per-O-acetates of their sugar moie-
ties. Thus, the per-O-acetylation of carbohydrates provides
a wide range of opportunities for exploitation of precious
renewable compounds.
Acetylation of saccharides is invariably carried out using
acetic anhydride in the presence of a base or acid catalyst
such as pyridine or other amines,1 sodium acetate,1 zinc chlo-
ride,2 ferric chloride,3 toluene sulfonic acid,4 montmorillon-
ite,5 iodine,6 and molecular sieves.7 Recently, several triflate
derivatives, such as scandium(III) triflate,8 trimethylsilyl
* Corresponding author. Tel./fax: þ86 373 3325250.
E-mail address: zgs6668@yahoo.com (G. Zhang).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.027

L. Shi et al. / Tetrahedron 64 (2008) 2572e2575
2573
Fe2(SO4)3 xH2O (2 mol%)
O
was also tested. In our process, Fe2(SO4)3$xH2O was easily re-
covered from the reaction mixture by filtration and subsequent
washing with chloromethane. The recovered catalysts were
used directly for the next reaction cycle. This recycle protocol
was repeated five times and the percentage of the catalyst
recovery was always more than 85%, while the yields of the
peracetylated glucoside were always more than 95%.
O
OAc(R)
OH(R)
(AcO)n
(HO)n
Ac2O, rt
100% of conversion
1-16b
1-16a
Scheme 1. Acetylation of sugars catalyzed by Fe2(SO4)3$xH2O.
In our efforts to develop clean methods for functional group
transformations, we found Fe2(SO4)3$xH2O was an efficient,
reusable, operationally simple, and environmentally benign
catalyst for tetrahydropyranylation of alcohols16 and prepara-
tion of acylals.17 Herein, we present our results on the utility
of Fe2(SO4)3$xH2O as an efficient and environmentally benign
catalyst for the per-O-acetylation of a variety of carbohydrates
using acetic anhydride (Scheme 1).
In
a
typical reaction procedure, Fe2(SO4)3$xH2O
(2.0 mol %) was added to a stirred suspension of D-glucose
(2a, 1 mmol) in acetic anhydride (1 mL) at rt and the reaction
was monitored using TLC. After 5 h, TLC (ethyl acetate/hex-
ane, 1:1, v/v) showed the presence of only the pentaacetate.
The reaction mixture was then diluted with dichloromethane,
filtered to recover the Fe2(SO4)3$xH2O. The combined filtra-
tions were washed with saturated sodium carbonate solution
and dried over anhydrous Na2SO4. The solvent was removed
to give clear colorless syrup which crystallized on drying un-
2. Results and discussion
We first examined the acetylation of methyl a-D-glucoside
(1a) with slight excessive acetic anhydride in the presence of
0.5, 1.0, 2.0, 5.0, and 10.0 mol % of Fe2(SO4)3$xH2O18 at rt.
The reactions were completed in 3 h in quantitative conversion
rateand 99% isolatedyieldwhen the catalystwas usedin amount
of 2.0e10.0 mol %, while it took longer time (approximately
5 h) when the catalyst was used in amount of 0.5 or 1.0 mol %.
Thus, in our method, the acetylation of saccharides was per-
formed in the presence of 2.0 mol % of Fe2(SO4)3$xH2O.
In view of green chemistry, efficient recovery and reuse of
the catalyst are highly preferred. The reusability of the catalyst
1
der high vacuum (98% yield, nearly quantitative). H NMR
spectrum of this product showed it to be a mixture of a-D-glu-
copyranose pentaacetate with 28% of the b-isomer. The solid
was pure peracetylated glucose (2b) in 2.5:1 a/b ratio deter-
1
mined by H NMR spectroscopy.
In order to extend the scope of this work, the described
methodology was examined on different carbohydrate sub-
strates (Table 1). The reactions were simply performed by stir-
ring the mixture of a sugar with a slight excessive acetic
anhydride in the presence of 2.0 mol % of Fe2(SO4)3$xH2O
Table 1
The peracetylation of saccharidic compounds promoted by Fe2(SO4)3$xH2O
Entry
1
Substrate
Product
OAc
Time (h)
3
Yield (%)
99
a/b
OH
O
O
HO
HO
AcO
AcO
1a
2a
1b
2b
d
HO
AcO
OMe
OMe
OH
OAc
O
O
2
5
98
2.5:1
3:1
HO
HO
AcO
OH
OAc
AcO
AcO
AcO
OH
OAc
HO
OH
OAc
O
O
3
4
3a
4a
3b
4b
16
5
90
90
OH
OAc
HO
OH
OAc
OAc
O
HO OH
O
AcO
1:1.3
HO
AcO
OH
OH
OAc
OAc
HO
AcO
O
O
HO
HO
AcO
5
6
5a
6a
5b
6b
5
99
91
1:1.5
6:1
HO
AcO
OH
OAc
O
O
AcO
AcO
OH
OAc
15
HO
OH
OAc
AcO
HO
OAc
O
OH
OH
O
OAc
O
O
7
8
7a
8a
7b
8b
11
7
97
89
1.5:1
O
OH
OH
O
OAc
OAc
AcO
HO
HO
AcO
OAc
OAc
O
OH
OH
OH
OAc
OH
OAc
O
AcO
AcO
O
O
HO
HO
1:3
O
O
HO
AcO
OAc
OH
OH
OAc
OH
OAc
O
O
OAc
OH
HO
HO
O
OAc
9
9a
9b
10
94
1:2.7
O
OH
AcO
AcO
HO
O
O
AcO
OAc
AcO
HO
OH
(continued on next page)

2574
L. Shi et al. / Tetrahedron 64 (2008) 2572e2575
Table 1 (continued)
Entry
Substrate
Product
O
Time (h)
Yield (%)
a/b
O
NH
NH
HO
AcO
AcO
AcO
10
11
10a
11a
10b
11b
7
89
d
N
O
N
O
O
O
OH
O
OAc
O
HO
H3C
OAc
H3C
NH
NH
HO
HO
7
88
d
N
O
O
N
O
O
O
O
OH
OAc
NH
NH
N
O
O
N
O
O
O
O
O
12
13
12a
13a
12b
13b
3
6
99
99
d
d
O
O
O
O
O
O
O
O
O
OH
AcO
O
O
OTr
OTr
O
O
HO
HO
AcO
AcO
14
15
16
14a
15a
16a
14b
15b
16b
30
3
89
90
97
d
d
d
AcO
HO
OMe
OMe
OTBDMS
O
OTBDMS
O
AcO
AcO
HO
HO
HO
AcO
OMe
OMe
O
O
Ph
Ph
O
O
O
O
2
AcO
HO
HO
AcO
OMe
OMe
at rt. As shown in Table 1, several monosaccharides (1ae6a),
disaccharides (7ae9a), nucleosides (10a and 11a), and sac-
charides with acid-labile protecting group (12ae16a) were
acetylated in excellent yields. It should be outlined the sim-
plicity of the proposed procedure, cheap commercially avail-
able reagents being used without resorting to particular
experimental precautions. The catalyst can be used without
any preliminary activation and recovered by simple filtration.
In all cases pure products were obtained by a simple dilution
with dichloromethane, filtration to recover the catalyst, and
washings with aqueous Na2CO3.
The ratio of a- and b-pyranose anomers for the per-O-acet-
ylation products (2be9b) in Table 1 was determined by
400 MHz 1H NMR spectral analysis. In the case of D-galactose
(3a), formation of furanose per-O-acetate was observed (ap-
proximately 9% yield). The peracetylation of substrates 3a,
6a, and 14a needed longer time due to their poor solubility.
It is noteworthy that an excellent yield was obtained for per-
O-acetylated cellobiose (8a), which gave only scarce results
in other acetylation procedures.6,14 Uridine (10a) and thymi-
dine (11a) were transformed, respectively, into 20,30,50-tri-
and 30,50-diacetylated products, and the subsequent simple
work-up provided these valuable intermediates for the nucleo-
side chemistry. NMR spectra confirm that no N-acetylated
pyrimidine base is present.
In carbohydrate chemistry, some acid-labile groups such as
isopropylidene, benzylidene, trityl, and TBDMS ether are of-
ten used to protect partial hydroxyl groups in saccharides,
and the rest hydroxyl groups are subsequently acetylated. In
order to check the efficiency of Fe2(SO4)3$xH2O in these
cases, we performed reactions of some substrates 12ae16a us-
ing our method. Interestingly, the acid-labile groups such as
isopropylidene, benzylidene, trityl, and TBDMS survived the
present conditions and the yields of acetylated products were
excellent. No formation of fully acetylated compounds was
observed. In contrast, in most examples of the above cited
acid Lewis promoted acetylations, the cleavage of acid-labile
acetal, trityl, and silyl ether functionalities has been reported.
3. Conclusion
In conclusion, we have developed a simple, clean, and effi-
cient method for the per-O-acetylation of saccharides. The
procedure was shown to be perfectly compatible with a variety

L. Shi et al. / Tetrahedron 64 (2008) 2572e2575
2575
of acid-labile protecting groups adopted in carbohydrate
Acknowledgements
chemistry. The Fe2(SO4)3$xH2O was found to be an efficient
and environmentally benign heterogeneous catalyst, used in
very low percentage, and can be recovered after reaction and
reused without significant loss of activity. In addition, a very
small amount of acetic anhydride (1 mmol of substrate with
1 mL of acetic anhydride) was used in the procedure compared
to other known methods (e.g., using cerium triflate: 1 mmol of
substrate with 5 mL of acetic anhydride14). The simplicity of
manipulation, inexpensive and reusable catalyst, excellent
yields, compatibility with a variety of acid-labile protecting
groups, a very small amount of acetic anhydride usage, and
environmentally benign characters make the present method
a very good way for per-O-acetylation of sugars.
This work was supported by ‘the National Natural Science
Foundation of China’ (20672031), ‘the Program for New Cen-
tury Excellent Talents in University of Henan Province (2006-
HACET-06)’, and ‘Innovation Scientists and Technicians
Troop Construction Projects of Henan Province’ to G.Z.
Supplementary data
Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2008.01.027.
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To a stirred suspension of D-glucose (1 mmol) in acetic an-
hydride (1 mL), was added Fe2(SO4)3$xH2O (2 mol %). The
mixture was stirred at rt and the reaction was monitored using
TLC. After 5 h, TLC (ethyl acetate/hexane, 1:1, v/v) showed
the presence of only the pentaacetate. The reaction mixture
was then diluted with dichloromethane, filtered to recover
the Fe2(SO4)3$xH2O, subsequently washed with dichlorome-
thane. The combined filtrations were washed with saturated
aqueous sodium carbonate solution and dried over anhydrous
Na2SO4. The solvent was removed to give a clear colorless
syrup which crystallized on drying under high vacuum (98%
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1
yield, nearly quantitative). H NMR spectrum of this product
showed it to be a mixture of a-D-glucopyranose pentaacetate
with approximate 28% of the b-isomer.
is calculated based on the formula: MFe ðSO Þ $xH O
¼
2
4
2
3
0:5 ꢀ ðWFe ðSO Þ $xH O ꢀ FeðIIIÞ%O55:8Þ.
2
4
2
3