An environmentally benign and practical synthesis of sugar orthoesters promoted by potassium fluoride

Article abstract of DOI:10.1016/j.tetlet.2004.09.175

An extremely practical method for synthesis of sugar orthoesters has been developed without using any organic amines or heavy metals as additives. Various sugar orthoesters were prepared in good yields by the reaction of an acylated glycosyl bromide and a

Full text of DOI:10.1016/j.tetlet.2004.09.175

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8847–8848
An environmentally benign and practical synthesis of sugar
orthoesters promoted by potassium fluoride
Shin-ichiro Shoda,* Masashi Moteki, Ryuko Izumi and Masato Noguchi
Department of Biomolecular Engineering, Graduate School of Engineering, Tohoku University, Aoba 6-6-07, Sendai 980-8579, Japan
Received 6 September 2004; revised 28 September 2004; accepted 30 September 2004
Available online 14October 2004
Abstract—An extremely practical method for synthesis of sugar orthoesters has been developed without using any organic amines or
heavy metals as additives. Various sugar orthoesters were prepared in good yields by the reaction of an acylated glycosyl bromide
and an alcohol in the presence of potassium fluoride.
Ó 2004 Elsevier Ltd. All rights reserved.
Sugar 1,2-orthoesters are one of the most useful inter-
mediates in the synthetic field of carbohydrate chemis-
try.1 The Ôorthoester methodÕ originally reported by
Kochetkov and co-workers2 has extensively been uti-
lized at a key stage of oligosaccharide synthesis of com-
plex structure because sugar 1,2-orthoesters can be
efficiently converted to the corresponding 1,2-trans-glyco-
sides by the action of protonic or Lewis acids such as
trimethylsilyl trifluoromethanesulfonate.3 The sugar
1,2-orthoester moieties are also very important for the
selective protection of a pyranose ring4 while the other
acetyl groups on 3, 4, and 6 positions are converted,
for example, to benzyl groups.5 Furthermore, the
hydrolysis of 1,2-orthoester leads to the formation of a
1-acetoxy pyranose or a 2-acetoxy pyranose, depending
on gluco or galacto type.6
an acyloxonium ion, and (3) attack of the hydroxyl
group of the alcohol to the acyloxonium ion as a result
of scavenge of a proton from the hydroxyl group by a
sterically hindered base. It is, therefore, necessary to uti-
lize two kinds of reagents, quaternary ammonium salt
and bulky amine compound, for the reaction to occur.
However, the removal of such amine compounds from
the reaction mixture is normally very difficult and conse-
quently much organic solvent is required in order to
purify the product by column chromatography. Carbo-
hydrate 1,2-orthoesters are also obtained by treating
1-hydroxy sugars with 1-chloro-2,N,N-trimethyl-propen-
ylamine followed by the addition of alcohols in the
presence of triethylamine.8 From the viewpoint of green
and sustainable chemistry, the usage of such organic
amine compounds should be minimized. This communi-
cation describes an extremely facile procedure for syn-
thesis of 1,2-orthoesters 4 starting from peracylated
glycopyranosyl bromides and alcohols promoted by
potassium fluoride9 without using any amine com-
pounds or heavy metal salts.
A well-known method for the preparation of sugar 1,2-
orthoesters involves the treatment of a per-acetylated
a-glycosyl bromide with an alcohol in the presence of
tetrabutylammonium bromide and sym-collidine (2,4,6-
trimethylpyridine)7 or silver triflate and 2,4-lutidine.3c
The former reaction consists of the following three pro-
cesses: (1) the anomerization of a-glycosyl bromide to b-
anomer by a nucleophilic attack of the bromide ion to
the anomeric carbon atom of the a-glycosyl bromide,
(2) the intramolecular attack of the carbonyl oxygen
of the 2-acetoxy group to the anomeric center affording
All the reactions were carried out at 50°C by using
acetonitrile as solvent (Table 1). The best result concern-
ing the yield of orthoester was obtained when the
glycosyl bromide was treated with 5 or 10equiv of
potassium fluoride for 24h (entries 3 and 4). Since the
reaction proceeds in a heterogeneous system, 2 or
1equiv of potassium fluoride was not sufficient and the
glycosyl bromide was recovered (entries 1 and 2). When
the reaction was carried out by using lithium fluoride,
sodium fluoride, and cesium fluoride, good result could
not be obtained. Sodium fluoride was not so effective
Keywords: Sugar orthoesters; Potassium fluoride; Glycosyl bromides.
*
Corresponding author. Tel.: +81 22 217 7230; fax: +81 22 217
7293; e-mail: shoda@poly.che.tohoku.ac.jp
0040-4039/$ - see front matter Ó 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.175

8848
S. Shoda et al. / Tetrahedron Letters 45 (2004) 8847–8848
Table 1. Synthesis of sugar orthoesters 4 by the KF-promoted reaction
of peracylated glycosyl bromides and alcoholsa
ROCO
OCOR
O
X-
O
O
Entry
R
Alcohol
Equiv of KF
Yield %b
+
ROCO
ROCO
ROCO
ROCO
1
Me
Me
EtOH
EtOH
EtOH
1.0
2.0
5.0
90
53
87
90c
OCOR
2
Br
O
3
4Me
Me
2
1
R
X = F or Br
EtOH
Me
Me
10.0
5
6
7
8
9
BnOH
i-PrOH
5.0
5.0
5.0
5.0
5.0
84
84
69
30
93
OCOR
OCOR
O
O
O
Me
Me
Cyclohexanol
t-BuOH
EtOH
R'OH
ROCO
ROCO
ROCO
ROCO
Ph
O
O
O
+
a The reaction was carried out at 50°C for 24h in the presence of
molecular sieves 3A(100wt% for 1).
4
3
R
˚
OR'
R
b Determined by 1H NMR spectroscopy.
c The diastereomer ratio (exo-isomer:endo-isomer) was determined to
be 5:1 by 1H NMR spectroscopy.
Figure 1. Proposed mechanism of the formation of 1,2-orthoester
derivative starting from peracylated glucopyranosyl bromide deriva-
tive promoted by fluoride ion which behaves as acid captor.
compared with potassium fluoride probably because its
poor solubility toward acetonitrile. In case of using
cesium fluoride, the reaction system becomes too basic
due to its higher solubility toward acetonitrile, afford-
ing the eliminated product of glycal derivative. The reac-
tion proceeds effectively when perbenzoylated glycosyl
bromide was utilized (entry 9). This method can
successfully be applied to other alcohols such as benzyl
alcohol, secondary alcohols, and a tertiary alcohol
(entries 5–8).
of galactose, mannose, and lactose that are important
synthetic intermediates in glycotechnology.
References and notes
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The typical experimental procedure is as follows: A mix-
ture of 2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl bro-
mide (200mg, 0.49mmol), ethyl alcohol (0.29mL,
4.9mmol), potassium fluoride (142mg, 2.45mmol), and
˚
molecular sieves 3A(200mg) in acetonitrile (2.4mL)
was vigorously stirred under argon at 50°C for
1day. The solid materials (KF–HF + KBr + MS3A)
were removed by filtration and the filtrate was evapo-
rated to dryness to give a crude product of 4. The
resulting product was found to be pure enough for
glycosylation reactions, which was confirmed by NMR
spectroscopy.
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It is assumed that the cyclization proceeds through a
carbenium ion intermediate 2 as a result of SN1 type
C–Br bond cleavage (Fig. 1).10 The second step involves
a participation of the carbonyl oxygen of the 2-acetyloxy
group from the a side of the pyranose ring. The resulting
cyclic acyloxonium ion intermediate suffers an attack on
the carbon atom by the hydroxyl group of the alcohol
activated by a fluoride ion. In this reaction, alkyl glyco-
sides could not be detected. The precise mechanism of
the selective orthoester formation has not been made
clear. According to the present method of using potas-
sium fluoride, it is not necessary to utilize the quaternary
ammonium salt that is very difficult to be removed from
the reaction mixture. This fact makes the reaction proce-
dure extremely simple; filtrating the complex of potas-
sium fluoride–hydrogen fluoride (KF–HF) and KBr
can easily isolate the product. The present method can
be applied to synthesis of various orthoester derivatives
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10. The reaction of 2,3,4,6-tetra-O-acetyl-b-glucopyranosyl
fluoride with ethanol in the presence of KF under the
same reaction conditions did not afford the corresponding
orthoester, indicating that the b-glucosyl fluoride does not
participate as an intermediate.