Facile Cu(OTf)2-Catalyzed Preparation of Per-O-acetylated Hexopyranoses with Stoichiometric Acetic Anhydride and Sequential One-Pot Anomeric Substitution to Thioglycosides under Solvent-Free Conditions

Article abstract of DOI:10.1021/jo030073b

Solvent-free per-O-acetylation of hexoses with a stoichiometric amount of acetic anhydride employing 0.03 mol % Cu(OTf)₂ proceeded in high yields (90-99%) at room temperature to give exclusively pyranosyl products as an anomeric mixture, the α/

Full text of DOI:10.1021/jo030073b

e.g., tetra-n-butylammonium bromide-sodium hydrox-
ide;11 (3) heterogeneous catalysts, such as anionic sur-
factants,12 Montmorillonite K10,13 Nafion-H,14 H-â zeo-
lite,15 and zirconyl sulfophenyl phosphonate;16 and (4)
enzyme catalysts, e.g., lipases.17 Boric acid in conjunction
with a catalytic amount of H2SO4 leads to the corre-
sponding furanosyl peresters.18 Very recently, use of a
dicyanamide-based ionic liquid19 both as a solvent and a
basic catalyst has been reported for per-O-acetylation.
A variety of other catalysts in combination with excess
acetic anhydride and solvents have been employed in the
O-acetylation of non-carbohydrate alcohols, including
Bu3P,20 CoCl2,21 TaCl5,22 TMSOTf,23 iminophosphorane
bases with enol esters,24 distannoxane catalysis,25 and
metal trifluoromethanesulfonates [M(OTf)n] such as Sc-
F a cile Cu (OTf)2-Ca ta lyzed P r ep a r a tion of
P er -O-a cetyla ted Hexop yr a n oses w ith
Stoich iom etr ic Acetic An h yd r id e a n d
Sequ en tia l On e-P ot An om er ic Su bstitu tion
to Th ioglycosid es u n d er Solven t-F r ee
Con d ition s
Cheng-An Tai,† Suvarn S. Kulkarni,‡ and
Shang-Cheng Hung*,‡
Institute of Chemistry, Academia Sinica, Taipei 115,
Taiwan, and Department of Chemistry, National Chung
Cheng University, Chiayi 621, Taiwan
schung@chem.sinica.edu.tw
Received February 25, 2003
26
(OTf)3 and its complex with trifluoromethanesulfona-
mide,27 In(OTf)3,28 VO(OTf)2,29 Bi(OTf)3,30 and Cu(OTf)2.31
In contrast, the potential of these versatile, water-stable,
and reusable M(OTf)n catalysts has been exploited scarcely
in carbohydrates.29 We have recently demonstrated that
Sc(OTf)3 is an efficient catalyst in per-O-acetylation and
Abstr a ct: Solvent-free per-O-acetylation of hexoses with a
stoichiometric amount of acetic anhydride employing 0.03
mol % Cu(OTf)2 proceeded in high yields (90-99%) at room
temperature to give exclusively pyranosyl products as an
anomeric mixture, the R/â ratio of which was dependent on
the temperature and amount of catalyst used. Sequential
anomeric substitution with p-thiocresol in the presence of
BF3‚etherate gave the thioglycosides, isolated exclusively or
predominantly as one anomer in 66-75% yields.
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Per-O-acetylated hexopyranoses and their derived
thioglycosides are valuable building blocks for the syn-
thesis of biologically potent oligosaccharides, glyco-
conjugates, as well as natural products.1 Per-O-acetyla-
tion is one of the most frequently used reaction in
carbohydrates primarily for initial protection of sugars
and also to aid spectral characterization and identifica-
tion of target molecules. This is generally performed
using acetic anhydride as the reagent and a variety of
catalysts. Pyridine, which serves a dual purpose as a
solvent and as a catalyst, is most widely employed despite
its known toxicity and unpleasant odor.2 Further addition
of pyridine derivatives, for example, 4-(N,N-dimethyl-
amino)pyridine and 4-(1-pyrrolidino)pyridine, as a co-
catalyst speeds up this transformation.3 Some common
methods involving sodium acetate-4 and iodine-promoted5
per-O-acetylation of sugars have been investigated. How-
ever, excess acetic anhydride as a solvent causes tedious
workup in the neutralization process. Other catalysts
that have been shown to be effective for this purpose
include (1) classical acids, for example, H2SO4,6 HClO4,7
ZnCl2,8 FeCl3,9 and TMSCl;10 (2) phase-transfer catalysts,
† National Chung Cheng University.
‡ Academia Sinica.
(1) (a) Garegg, P. J . Adv. Carbohydr. Chem. Biochem. 1997, 52, 179.
(b) Zhang, Z.; Ollmann, I. R.; Ye, X.-S.; Wischnat, R.; Baasov, T.; Wong,
C.-H. J . Am. Chem. Soc. 1999, 121, 734. (c) Ye, X.-S.; Wong, C.-H. J .
Org. Chem. 2000, 65, 2410.
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12196.
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Engl. 1978, 17, 569.
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2, 211.
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Li, T.-W.; Chao, S.-D.; Liu, C.-C.; Li, Y.-C.; Chang, I.-H.; Lin, J .-S.;
Liu, C.-J .; Chou, Y.-C. Org. Lett. 2001, 3, 3729.
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10.1021/jo030073b CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/09/2003
J . Org. Chem. 2003, 68, 8719-8722
8719

TABLE 1. Cu (OTf)2-Ca ta lyzed Solven t-F r ee
P er -O-a cetyla tion of D-Glu cose w ith a Stoich iom etr ic
Am ou n t of Acetic An h yd r id e
total consumption of the starting material, as outlined
in entry 4. This turned out to be the minimum concentra-
tion required for optimum catalytic activity, and the
reaction did not go to completion when a slightly less
amount (0.025 mol %) of catalyst was used (entry 5). In
all instances, a small amount of D-glucofuranosyl pen-
taacetate34 was also obtained as detected by the 1H NMR
spectra of the crude products. However, formation of this
isomer could be suppressed by conducting the addition
of Cu(OTf)2 at 0 °C (entry 6), and the product 2 was
isolated in 98% yield exclusively in the pyranosyl form
as an anomeric mixture. This study also revealed an
interesting phenomenon that the R/â ratios are affected
by the amount of catalyst and temperature.
entry
x
T (°C)
t (h)
R/â
yield (%)
1
2
3
4
5
6
0.5
0.1
0.05
0.03
0.025
0.03
rt
rt
rt
rt
rt
0 f rt
5
5
5
6
24
8
4.4/1
3.6/1
2.9/1
2.3/1
95
95
96
96
a
1.9/1
98
Per-O-acetylation of other important D- and L-hexoses
under this set of optimized conditions is illustrated in
Table 2. In entry 1, D-mannose 3 readily provided the
corresponding pyranosyl pentaacetate 435 almost quan-
titatively, whereas D-galactose 5 slowly afforded the
product 633 in very good yield (entry 2). The reaction time
of the later transformation could, however, be shortened
by a slight increase in the catalyst concentration (0.05
mol %, entry 3). In the L-series, since commercially
available L-rhamnose 7 contains one water molecule, 5
equiv of acetic anhydride is required to complete the
reaction. As indicated in entry 4, the corresponding
tetraacetate 836 was obtained in excellent yield and in
much shorter time. Similar results were observed in the
case of L-fucose 9 (entry 5), and the expected compound
1037 was isolated in 91% yield.
a
The reaction was not completed.
acetolysis of sugars under neat conditions.32 It proceeds
in excellent yields and requires a 0.5 mol % catalytic
amount. In continuation with this, we wish to report a
better catalyst, Cu(OTf)2, for solvent-free preparation of
per-O-acetylated hexopyranoses with a stoichiometric
amount of acetic anhydride and their applications to the
synthesis of thioglycosides via sequential one-pot ano-
meric substitution.
The results of per-O-acetylation of D-glucose 1 are
summarized in Table 1. To determine the minimum
amount of catalyst required, use of 0.5 mol % Cu(OTf)2
furnished D-glucopyranosyl pentaacetate 233 in 95% yield
(entry 1). A 5-fold (entry 2) and 10-fold (entry 3) decrease
in the catalytic concentration displayed similar results.
Lowering the catalyst quantity still further (0.03 mol %)
showed no significant variation in the outcome of the
reaction, except that an additional 1 h was required for
With such success in the stoichiometric neat per-O-
acetylation of hexoses to the pyranosyl products, we
turned our attention to the thioglycosides, which are
conventionally prepared by a nucleophilic addition of
TABLE 2. Cu (OTf)2-Ca ta lyzed Solven t-F r ee P er -O-a cetyla tion of Hexoses
a
0.05 mol % Cu(OTf)2 was used.
8720 J . Org. Chem., Vol. 68, No. 22, 2003

TABLE 3. On e-P ot P er -O-su bstitu tion of Hexoses to th e
Cor r esp on d in g Th ioglycosid es
yield. Similarly, D-galactose 5 (entry 3) and L-fucose 9
(entry 5) led to exclusive formation of the corresponding
â-thioglycosides 1338 and 1538 in 71% and 66% yields,
respectively. Under these conditions, D-mannose 3 (entry
2) furnished the R-glycoside 121b as the only product
whereas L-rhamnose 7 (entry 4) generated an anomeric
mixture 14, with predominance of the R-isomer in similar
high yield. Since the anomeric protons of 14R (J ) 1.5
Hz) and 14â (J ) 1 Hz) displayed similar coupling
constants, the identification was done by observation of
nuclear Overhauser enhancement between H1 and H5
protons in 14â (see the Supporting Information). The
anomeric selectivity is a direct consequence of the
neighboring group participation. It should be noted that
all the reactions are carried out on a preparative scale
(3 g) and are equally compatible for large-scale prepara-
tions.
In summary, Cu(OTf)2 is an extremely efficient catalyst
for per-O-acetylation of hexoses. Our method requires a
truly catalytic amount of the least expensive available
M(OTf)n that is water-stable and hence reusable. Fur-
thermore, the per-O-acetylation reactions are conducted
under solvent-free conditions using a stoichiometric
amount of acetic anhydride that allows an efficient one-
pot sequential per-O-acetylation-anomeric substitution
of hexoses to thioglycosides. The reaction conditions are
mild, convenient, and nonhazardous. We believe that this
method to prepare the common building blocks should
find a wide application in saccharide synthesis.
Exp er im en ta l Section
Gen er a l Meth od s. Solvents were purified and dried from a
safe purification system.39 Flash column chromatography40 was
carried out with silica gel 60 (230-400 mesh, E. Merck). TLC
was performed on precoated glass plates of silica gel 60 F254
(0.25 mm, E. Merck); detection was executed by spraying with
a solution of Ce(NH4)2(NO3)6 (0.5 g), (NH4)6Mo7O24 (24 g), and
H2SO4 (28 mL) in water (500 mL) and subsequent heating on a
hot plate. Melting points were determined with a capillary
apparatus and are uncorrected. Optical rotations were measured
at 589 nm (Na) at ∼29 °C. 1H and 13C NMR spectra were
recorded with 400 and 500 MHz instruments. Chemical shifts
are in ppm from Me4Si, generated from the CHCl3 lock signal
at δ 7.24. Mass spectra were obtained in the EI and FAB modes.
IR spectra were taken on an FT-IR spectrometer using NaCl
plates. Elemental analyses were determined with a Perkin-
Elmer 2400CHN instrument.
thiols on the respective anomeric acetates in the presence
of a Lewis acid catalyst such as BF3‚OEt2. In contrast to
the conventional per-O-acetylation, wherein an excessive
amount of Ac2O is used and neutralization followed by
elaborate tedious workup and purification is a priori to
the second step, our method employing stoichiometric
amount of Ac2O offers a chance to carry out the sequen-
tial per-O-acetylation-anomeric substitution of hexoses
in one pot under solvent-free conditions.
Thus, per-O-acetylation of hexoses was conducted as
before and monitored by TLC. After total consumption
of the starting material, p-thiocresol, and BF3‚OEt2 (2
equiv each) were added sequentially to the reaction
solution at room temperature without additional solvent,
and the mixture was left stirring for 2 days. Table 3
describes the yields and R/â ratios of the hexose-derived
thioglycosides. In entry 1, the reaction of D-glucose 1
afforded the â-thioglycoside 1138 as a sole product in 73%
Gen er a l P r oced u r e for P er -O-a cetyla tion of Hexoses. To
a
mixture of hexose (3 g scale) and stoichiometric acetic
anhydride (Tables 1 and 2) was added freshly dried Cu(OTf)2
(0.03 mol % of hexose) at 0 °C under nitrogen. The ice bath was
removed, and the mixture was kept stirring at room temperature
for 2.5-25 h (Tables 1 and 2). Methanol (same mole amount as
hexose) was slowly added to quench the reaction, and the
mixture was stirred for another 0.5 h followed by evaporation
under reduced pressure. Ethyl acetate (20 mL/g of hexose) was
added to dissolve the residue, and the mixture was consecutively
washed with saturated NaHCO3(aq), water, and brine. The
organic layer was dried over anhydrous MgSO4, the mixture was
filtered through paper, and the filtrate was concentrated in
vacuo. The crude product was purified by either recrystallization
in ethanol or flash column chromatography to afford the expected
compound in excellent yield (Tables 1 and 2).
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J . Org. Chem, Vol. 68, No. 22, 2003 8721

Gen er a l P r oced u r e for On e-P ot P er -O-a cetyla tion -
Su bstitu tion of Hexoses. Per-O-acetylation of hexose was
carried out as described above. When reaction was completed
according to TLC, without addition of methanol, p-thiocresol (2
equiv) and BF3‚etherate (2 equiv) were sequentially added to
the reaction solution, and the mixture was allowed to stir for 2
p -Met h ylp h en yl 6-d eoxy-2,3,4-t r i-O-a cet yl-1-t h io-â-L-
m a n n op yr a n osid e 14â: [R]29 +35 (c 1.0, CHCl3); mp 90-91
D
°C; IR (CHCl3) 2982, 2936, 2866, 1749, 1493, 1371, 1249, 1222,
1
1090, 1052 cm-1; H NMR (500 MHz, CDCl3) δ 7.40 (d, J ) 8.2
Hz, 2H, Ar-H), 7.12 (d, J ) 8.2 Hz, 2H, Ar-H), 5.63 (dd, J )
3.5, 1.0 Hz, 1H, H-2), 5.10 (t, J ) 9.9 Hz, 1H, H-4), 4.98 (dd, J
) 9.9, 3.5 Hz, 1H, H-3), 4.82 (d, J ) 1.0 Hz, 1H, H-1), 3.51 (dq,
J ) 9.9, 6.2 Hz, 1H, H-5), 2.33 (s, 3H, Ar-CH3), 2.20 (s, 3H,
Ac), 2.03 (s, 3H, Ac), 1.97 (s, 3H, Ac), 1.30 (d, J ) 6.2 Hz, 3H,
H-6); 13C NMR (100 MHz, CDCl3) δ 170.3 (C), 170.2 (C), 169.8
(C), 138.4 (C), 132.7 (CH), 129.9 (CH), 129.5 (C), 85.8 (CH), 74.9
(CH), 71.8 (CH), 71.0 (CH), 70.2 (CH), 21.1 (CH3), 20.8 (CH3),
20.6 (CH3), 20.6 (CH3), 17.7 (CH3); HRMS (FAB, MH+) calcd for
d. The reaction was quenched by addition of saturated NaHCO3(aq)
,
and the mixture was extracted with ethyl acetate three times.
The combined organic layers were washed with brine, dried over
anhydrous MgSO4, filtered, and concentrated in vacuo. Purifica-
tion of the residue through either flash column chromatography
or recrystallization in ethanol gave the desired thioglycoside in
good yield (Table 3).
p -Met h ylp h en yl 6-d eoxy-2,3,4-t r i-O-a cet yl-1-t h io-r-L-
C19H25O7S 397.1321, found 397.1324. Anal. Calcd for C19H24
O7S: C, 57.56; H, 6.10. Found: C, 57.96; H, 6.30.
-
m a n n op yr a n osid e 14r: [R]29 -123 (c 1.0, CHCl3); mp 111-
D
112 °C; IR (CHCl3) 2936, 1749, 1371, 1223, 1106, 1054 cm-1; 1H
NMR (500 MHz, CDCl3) δ 7.35 (d, J ) 8.2 Hz, 2H, Ar-H), 7.11
(d, J ) 8.2 Hz, 2H, Ar-H), 5.48 (dd, J ) 3.3, 1.5 Hz, 1H, H-2),
5.32 (d, J ) 1.5 Hz, 1H, H-1), 5.29 (dd, J ) 9.9, 3.3 Hz, 1H,
H-3), 5.12 (t, J ) 9.9 Hz, 1H, H-4), 4.35 (dq, J ) 9.9, 6.2 Hz, 1H,
H-5), 2.32 (s, 3H, Ar-CH3), 2.12 (s, 3H, Ac), 2.07 (s, 3H, Ac),
2.00 (s, 3H, Ac), 1.23 (d, J ) 6.2 Hz, 3H, H-6); 13C NMR (125
MHz, CDCl3) δ 170.0 (C), 169.9 (C), 138.2 (C), 132.4 (CH), 129.9
(CH), 129.3 (C), 86.0 (CH), 71.2 (CH), 71.1 (CH), 69.3 (CH), 67.6
(CH), 21.1 (CH3), 20.8 (CH3), 20.8 (CH3), 20.6 (CH3), 17.3 (CH3);
HRMS (FAB, MH+) calcd for C19H25O7S 397.1321, found 397.1332.
Anal. Calcd for C19H24O7S: C, 57.56; H, 6.10. Found: C, 57.59;
H, 6.11.
Ack n ow led gm en t. This work was supported by the
National Science Council of Taiwan R.O.C. (NSC 91-
2113-M-001-004 and NSC 91-2323-B-001-006).
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
all the per-O-acetates (2, 4, 6, 8, and 10) and thioglycosides
(11-15) and 13C NMR and 2D NMR spectra for compounds
14R and 14â. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O030073B
8722 J . Org. Chem., Vol. 68, No. 22, 2003