A green and regioselective acetylation of thioglycoside with ethyl acetate

Article abstract of DOI:10.1016/j.tetlet.2010.10.135

Treatment of saccharidic polyols in ethyl acetate with catalytic sulfuric acid leads to the corresponding primary monoacetate derivatives in good yields. The transesterification was realized by simple stirring without rigorous exclusion of moisture or oxy

Full text of DOI:10.1016/j.tetlet.2010.10.135

Tetrahedron Letters 51 (2010) 6928–6931
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Tetrahedron Letters
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A green and regioselective acetylation of thioglycoside with ethyl acetate
⇑
Pi-Hui Liang , Yin-Jen Lu, Ting-Hsuan Tang
School of Pharmacy, College of Medicine, National Taiwan University, No. 1, Jen-Ai Road, Section 1, Taipei 100, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
Treatment of saccharidic polyols in ethyl acetate with catalytic sulfuric acid leads to the corresponding
primary monoacetate derivatives in good yields. The transesterification was realized by simple stirring
without rigorous exclusion of moisture or oxygen. Our protocol is applicable to the regioselective mono-
acetylation of amino sugars having different substituents at the 2-positions.
Received 23 September 2010
Revised 25 October 2010
Accepted 27 October 2010
Available online 31 October 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Regioselective acetylation
Thioglycosides
Ethyl acetate
Oligosaccharide synthesis is challenging and relies heavily on
protecting group manipulations. An efficient, convenient, and reg-
ioselective strategy for reaction of the hydroxyl groups would be
very useful, particularly if that minimizes the use and generation
of hazardous substances.1 Among the various methods developed
for selective acetylation of carbohydrate hydroxyl group,2 acetic
anhydride has been used as a versatile acetylating agent in the
presence of bases,3 molecular sieves,4 and metal complexes.5 Alter-
natively, acetyl chloride was used with a relatively bulky base, for
example, 2,4,6-collidine, for selective acetylation of the primary
alcohols of carbohydrates at low temperature.6 Even though the
aforementioned methods are effective, the regioselective acetyla-
tion must be conducted in strict conditions, for example, reaction
temperature and reaction time, to avoid over-acetylation. In addi-
tion, removal of acetic acid by-product may also cause problem
due to its high boiling point.
dure for the selective acetylation of the primary hydroxyl groups of
various carbohydrates by using EtOAc in the presence of a catalyst
of sulfuric acid.
Thioglycoside 1 was chosen for our initial study as it is rela-
tively stable, easy to prepare, and widely used as a building block
in oligosaccharide synthesis.12 Several common acids including
HCl (aq 37%), H2SO4 (aq 96%), HBr (aq 48%), and TMSOTf were
examined as the reaction catalyst (Table 1). Regioselective acetyla-
tion of the 6-OH group was best conducted by the catalysis of
H2SO4 (Table 1, entry 3). Thus, nearly complete conversion of 1
was accomplished at 40 °C within 8 h to afford 2 in 72% isolated
yield. Under such conditions, no hydrolysis of compound 1 was
Table 1
Selective acetylation of 1-thiotoluene-D-glucopyranoside in different conditions
To circumvent these problems, other acetylating agents and
transesterification with esters have been investigated.7 Ethyl ace-
tate (EtOAc) is a favorable solvent and diluent because of its low
cost, low toxicity, and agreeable odor. The permissible exposure
limits (PEL) for EtOAc is 400 ppm, much higher than 5 ppm for ace-
tic anhydride.8 Selective acetylation of polyols using EtOAc with
NaH,9 neutral alumina,10 or distannoxane11 has also been achieved.
However, excess NaH must be quenched with aqueous ethanol,
such process is potentially dangerous on large scale. On the other
hand, it is costly to use a large amount of Al2O3 (100-fold weight
of the starting alcohol), which had to be removed by filtration.
Use of distanoxane compound is disfavored because it is toxic
and commercially unavailable. Herein, we describe a simple proce-
OAc
OH
O
O
catalyst
solvent
HO
HO
HO
HO
STol
S
CH3
HO
HO
2
1
= STol
Entry
Reagents
Catalyst (mol %)
Temp
Time
Yielda (%)
1
2
3
4
5
6
7
8
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc/H2O = 10/1
Vinyl acetate
BzOEt/CH3CN
—
Reflux
60 °C
40 °C
40 °C
40 °C
Reflux
Reflux
80 °C
4 d
4 d
8 h
1 d
8 h
2 d
1 d
2 d
0
45
72
72
71
HCl (20)
H2SO4 (5)
HBr (10)
TMSOTf (5)
H2SO4 (20)
H2SO4 (10)
H2SO4 (10)
b
—
18b
a
⇑
Corresponding author. Tel.: +886 23123456x88385.
E-mail address: phliang@ntu.edu.tw (P.-H. Liang).
Isolated yield of 2.
Complicated mixture.
b
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.135

P.-H. Liang et al. / Tetrahedron Letters 51 (2010) 6928–6931
6929
observed. HBr and TMSOTf also effected this transformation, but
acetylation in the presence of concentrated HCl required prolonged
time for complete conversion and resulted in lower yield (45%) of
product. Other acids, including acetic acid, acetyl chloride,
BF3ÁOEt2, HNO3, TMSCl, TsOH, LiClO4, and Amberlite IR-120 were
less active or produced an intractable mixture.
Unlike the previously reported transesterification method that
requires anhydrous condition,7 our current acetylation method
could tolerate substantial amount of water. For example, acetyla-
tion of 1 in a mixed solvent of EtOAc/H2O (v/v, 10:1) was effected
by the catalysis of H2SO4 (10 mol %) to give a 56% yield of product
(Table 1, entry 6). Consistent with the effect of acetic anhydride,
when EtOAc is used as a solvent, eventual moisture can be elimi-
nated by the solvent itself. The result demonstrates the generality
of this method using the commercially available EtOAc without
further purification.
Other esters were also tested. Enol ester is a popular acylating
agent because the leaving group of enolate readily undergoes tauto-
merization to ketone (or aldehyde), and thus drives the acylation
irreversibly.13 However, vinyl acetate was unstable under the acidic
conditions, and the reaction gave a complicated mixture (Table 1,
entry 7). Ethyl benzoate (BzOEt) was also tested for benzoylation.
Due to immiscibility of BzOEt with compound 1, acetonitrile was
added as a co-solvent (Table 1, entry 8). Instead of the desired
Table 2
Sulfuric acid-catalyzed selective acetylation of different carbohydrates in EtOAc
Entry
Carbohydrate substrate
Temp (time)
Productsa (yields, %)
6-O-Ac
2,6-di-O-Ac
3,6-di-O-Ac
4,6-di-O-Ac
OH
O
1
1
2
40 °C (8 h)
40 °C (8 h)c
72
71
0b
16
14
8b
HO
HO
STol
HO
1
1.8b
9.3b
OH
O
HO
HO
2.2b
2.3b
1.9
3
3
rt (12 h)
83
HO
STol
4
5
3
40 °C (3 h)
40 °C (8 h)
72
75
6.3b
1.9b
6.3b
8.6
5.4
OH
OH
OH
13b
O
4
STol
HO
HO
OH
O
6
5
40 °C (20 h)
72 (70)d
4.9b (5)d
9.7b (10)d
14 (15)d
HO
HO
O
7
8
5
60 °C (16 h)
65
86
6.5b
—
11b
—
15
12
OH
O
OH
6
7
8
rt (8 h)
STol
STol
STol
BnO
BnO
OH
O
9
10
11
12
rt (42 h)
rt (12 h)
rt (12 h)
rt (10 h)
88
90
95
93
—
—
—
—
5.6
4.7
HO
HO
AcHN
OH
O
1.9
3.8
HO
HO
TrocHN
OH
1.1b
2.1b
4.0b
4.8b
O
9
HO
HO
STol
N3
OH
O
HO
HO
10
N3
STol
a
b
c
The isolated yields of pure products.
The di-O-acetates could not be separated, but their ratios were determined by 1H and 2D-COSY NMR spectral analysis.
TMSOTf (5 mol %) as the catalyst.
d
Ratio was determined by crude mixture of products by 1H and 2D-COSY NMR spectral analysis.

6930
P.-H. Liang et al. / Tetrahedron Letters 51 (2010) 6928–6931
benzoylation product, the acetylated compound 2 was obtained in
18% yield, presumably derived by acetonitrile as a source of acetyl
group.
charides to increase solubility of general carbohydrates for selective
acetylation.16 TMS-protected monosaccharides might be potential
to use in our conditions.
A variety of other saccharidic polyols were subjected to these
reaction conditions. In the standard protocol, H2SO4 (5–10 mol %
of sugar was used) in EtOAc (0.03–0.2 M, Table 2) was added to
the carbohydrate substrates with stirring at rt, and the mixture
could be warmed to 40–60 °C in appropriate cases.14 Commercial
ACS grade EtOAc was used without purification and the acetylation
method needed not to be conducted in inert atmosphere. Although
glycosides (e.g., glucoside 1 and galactoside 4) were only slightly
soluble in EtOAc, the reaction still proceeded well to form a
homogenous solution at the end of reaction. The reaction mixture
was neutralized with saturated NaHCO3, followed by separation,
extraction, and distillation of organic solvent. Most of the primary
acetate products were obtained by recrystallization, except for the
Our reaction protocol is also applied to the regioselective acet-
ylation of various amino sugars, which occur abundantly in natural
oligosaccharides with different amino protecting groups. Thus, D-
glucosamines derivatives 7À10 containing N-acetyl (Ac), N-trichlo-
roethoxycarbonyl (Troc), and azido groups were prepared,17,18 and
subjected to acetylation in EtOAc by the catalysis of H2SO4. To our
delight, the regioselective monoacetylated products were fur-
nished at rt in respectable yields (Table 2, 88–95%, entries 9–12).
According to a previous Letter,19 acetylation of saccharidic poly-
ols may occur at the secondary hydroxyl groups prior to the pri-
mary hydroxyl group. In such reaction, counter-ion generated by
acetate with two OH groups formed a cyclic transition state.20
The primary OH group directed the deprotonation toward the sec-
ondary OH groups at positions 3 and 4, thus facilitating the acety-
lation at secondary OH groups. In order to discern if the 6-acetyl
compound is obtained by a direct acetylation or derived from the
intramolecular transfer of the acetyl groups from the preformed
acetates of the secondary hydroxyls, the reaction progress was
monitored at ꢀ40% conversion of 5 at 4 h. An aliquot of the reac-
tion mixture was quenched by saturated NaHCO3. According to
the 2D-NMR analysis, the mixture was found to contain four
monoacetylation products, that is, 2-, 3-, 4-, and 6-O-Ac derivatives
in a ratio of 11:16:18:54. When the reaction was carried out in a
longer time (totally 20 h as that shown in entry 6 of Table 2), the
mixture consisted of 2,6-, 3,6-, and 4,6-diacetyl products and the
6-O-Ac monoacetyl product in a ratio of 5:10:15:70. No 2-, 3-,
and 4-monoacetyl compounds remained. This result indicated that
the 2-, 3-, and 4-monoacetyl compounds might undergo intramo-
lecular acetyl group migration to give the 6-O-Ac product in a ther-
modynamically favored process, or undergo the second acetylation
subsequently to give the 2,6-, 3,6-, and 4,6-O-Ac compounds.
To demonstrate the utility of our protocol, saccharides 11 and
12 having 6-O-Ac group were subjected to the acid-catalyzed ben-
zylation with benzyl trichloroacetimidate21,22 (Scheme 1) to give
high yields of 13 and 14, in which compound 14 is an important
intermediate for the synthesis of heparin analogs.23 In the previ-
ously reported methods, four-step procedures are required to pre-
pare 13 and 14. For example, (1) protection of the 6-OH with a
bulky group, such as triphenylmethyl (trityl) or t-butyldiphenylsi-
lyl (TBDPS),24 (2) benzylation of secondary hydroxyl groups, (3) re-
moval of trityl or TBDPS groups, and (4) acetylation of 6-OH.
Another four-step procedure includes (1) benzylidene formation
of 4,6-dihydroxyls, (2) perbenzylation of secondary hydroxyl
groups, (3) selective reduction to reveal free 6-OH group,25 and
(4) acetylation of 6-OH. The overall yield of four steps is usually
product of
9 which was purified by silica gel column
chromatography.
Themotherliquorcontainingdiacetateproductswas furthersub-
jected to column chromatography and characterized by 1H and
2D-COSY NMR spectra. The pure 3,6-di-O-acetates derivatives of
glucopyranoside 1 and galactosides 4 and 5 were isolated, in addi-
tion to the mixture of inseparable 2,6- and 4,6-di-O-acetates,
whereas the 4,6-di-O-acetates of 3 was isolated in addition to the
inseparable 2,6- and 3,6-di-O-acetates. In the glycoside series
(Table 2), the desired 6-acetylated derivatives were obtained as
the major products with the yields ranging from 70% to 95%. Regard-
less of the use of H2SO4 or TMSOTf as promoters, the acetylation gave
similar yields of isomers (Table 2, entries 1 and 2). Allyl galactoside
(Table 2, entry 6) gave similar results to thiogalactoside (Table 2, en-
try 5), indicating the applicability of this method for other alkyl
substituents at C-1 position. In the case of mannoside 3 (Table 2, en-
tries 3 and 4), three regioisomers of diacetates distributed equally,
but the 2,6-di-O-acetate isomers were the minor products in the glu-
co- and galacto-pyranoside series (Table 2, entries 1, 2, 5–7) irre-
spective to the stereochemistry at the anomeric position. This
result indicates the feasibility in the regioselective formation of pol-
yol diacetates, which would be useful for the synthesis of complex
carbohydrates, for example, 3,6-di-O-Ac thioglucoside as the syn-
thetic precursor of saponins.15 Using higher quantity of catalyst
did not increase the yield or reduce the reaction time significantly,
but caused inferior selectivity in acetylation. The reaction evaluated
temperature could reduce reaction time at the expense of selectivity
(Table 2, compared entries 3 and 4, as well as entries 6 and 7). Gen-
eralcarbohydrates(e.g., D-glucose)werealsosubjectedtothesimilar
conditions, but the reaction was difficult to proceed due to the solu-
bility problem (data not shown). Very recently, Gervay-Hague and
co-workers reported a method by using TMS-protected monosac-
NH
O
OAc
OH
OAc
O
OBn
BnO
CCl3
O
STol
STol
HO
4 Α M.S., TfOH, CH2Cl2, rt
HO
11
OAc
BnO
13 (83%)
NH
O
OAc
CCl3
O
HO
HO
O
BnO
BnO
4 A, M. S.,TfOH, CH2Cl2, rt
N3
N3
STol
STol
14 (88%)
12
Scheme 1. Benzylation of partially acetylated saccharides 11 and 12 by benzyl trichloroacetoimidate in mildly acidic conditions.

P.-H. Liang et al. / Tetrahedron Letters 51 (2010) 6928–6931
6931
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pears to be superior to the previous four-step procedures in terms
of easier operation and higher overall yields.
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In conclusion, a green, efficient, and economical protocol for the
selective acetylation of carbohydrates has been devised by using
EtOAc in the presence of a catalytic amount of sulfuric acid. After
simple workup and recrystallization, 6-O-acetyl glycosides were
obtained in high yields (70–95%). These 6-O-acetyl glycosides are
useful precursors for the synthesis of complex oligosaccharides.
As demonstrated in this study, the acid-catalyzed benzylation of
11 and 12 concluded an expeditious, synthesis of p-tolyl-6-O-ace-
tate-per-O-benzyl thioglycosides 13 and 14,23 which are utilized to
prepare biologically important substrates.
14. To a solution of 100 mg of glycopyranosides in EtOAc (10 mL) was added a
catalytic amount of concentrated H2SO4 (aq 96%) at rt. The reaction was
warmed to the desired temperature (Table 2). Upon complete acetylation, the
mixture was neutralized with saturated NaHCO3 solution (10 mL). The organic
layer was separated, and the water layer was washed with EtOAc (5 mL Â 2).
The combined organic layers were dried over MgSO4, filtered, and then
concentrated. Except for the reaction of 9 (entry 9, Table 2), the residue was
recrystallized from EtOAc/Et2O (glucopyranoside, entry 1, Table 2) or EtOAc/n-
hexane (other glycosides) to give 6-O-acetyl-glycopyranosides. Separation of
di-O-acetyl glycopyranosides in and from the reaction of 9 was performed by
flash chromatography of mother liquor with elution of EtOAc/n-hexane.
15. Song, G.; Yang, S.; Zhang, W.; Cao, Y.; Wang, P.; Ding, N.; Zhang, Z.; Guo, Y.; Li,
Y. J. Med. Chem. 2009, 52, 7368.
16. Witschi, M. A.; Gervay-Hague, J. Org. Lett. 2010, 13, 4312.
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T. Tetrahedron Lett. 1985, 26, 909; For N3: (b) Alper, P. B.; Hung, S.-C.; Wong, C.-
H. Tetrahedron Lett. 1996, 37, 6029.
18. Chao, C.-S.; Chen, M.-C.; Lin, S.-C.; Mong, K.-K. Carbohydr. Res. 2008, 343, 957.
19. Kurahashi, T.; Mizutani, T.; Yoshida, J. J. Chem. Soc., Perkin Trans. 1 1999, 465.
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Acknowledgments
We thank Professor J.-M. Fang of National Taiwan University for
advice in manuscript preparation, and the National Science Council
of Taiwan (NSC 98-2320-B-002-017-MY3) for financial support.
Supplementary data
Supplementary data (experimental section, spectroscopic data,
and copies of 1H, 2D-COSY, and 13C NMR spectra) associated with
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2010.10.135.
References and notes
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added 4 Å molecular sieves,
a freshly prepared solution of benzyl
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amount of TfOH (0.04 mol). The mixture was stirred at rt for 1 day and then
diluted with saturated NaHCO3 (10 mL). The organic layer was separated, and
the water layer was washed with EtOAc (5 mL Â 2). The combined organic
layers were dried over MgSO4, filtered, and then concentrated. The residue was
subjected to flash chromatography with elution of EtOAc/n-hexane to furnish
the benzylation products 13 and 14 in 83% and 88% yields, respectively.
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