A facile method for synthesis of 1,2-oxazoline derivative of N-acetylglucosamine promoted by potassium fluoride

Article abstract of DOI:10.1246/cl.2002.150

A potassium fluoride-promoted intramolecular cyclization reaction of 2-acetamido-2-deoxy-α-D-glucopyranosyl chloride took place smoothly, giving the corresponding 1,2-oxazoline derivative in good yield. Potassium fluoride behaves as a nucleophile for anomerization of the glycosyl chloride as well as an acid captor to scavenge the protonic acid liberated. This is an extremely practical method for preparation of sugar oxazoline derivatives with simple experimental procedures.

Full text of DOI:10.1246/cl.2002.150

150
Chemistry Letters 2002
A Facile Method for Synthesis of 1,2-Oxazoline Derivative of
N-Acetylglucosamine Promoted by Potassium Fluoride
Shin-ichiro Shoda,ꢀ Ryuko Izumi, Masako Suenaga, Kenji Saito, and Masaya Fujita
Department of Materials Chemistry, Graduate School of Engineering, Tohoku University, Aoba 07, Aoba-ku, Sendai 980-8579
(Received November 1 ,2001; CL-011093)
A potassium fluoride-promoted intramolecular cyclization
reaction of 2-acetamido-2-deoxy-ꢀ-D-glucopyranosyl chloride
took place smoothly, giving the corresponding 1,2-oxazoline
derivative in good yield. Potassium fluoride behaves as a
nucleophile for anomerization of the glycosyl chloride as well
as an acid captor to scavenge the protonic acid liberated. This is an
extremely practical method for preparation of sugar oxazoline
derivatives with simple experimental procedures.
glycosyl bromides to the corresponding ꢁ-glycosyl fluorides with
inversion of configuration.15 It has also been established that
alkali metal fluorides can act as acid captors and be utilized for
many synthetic organic reactions based on its characteristic
property of forming a strong hydrogen bond with various protic
organic compounds.16{19 We postulated that the utilization of a
metal fluoride enabled us to develop a new method for synthesis
of cyclic compounds because the metal fluoride would play two
roles at the same time, a nucleophile for activation of the
functional group X and a scavenger of protonic acid liberated
from the group YH, leading to a cyclic compound (Figure 1).
The 1,2-oxazoline derivatives of 2-acetamido-2-deoxy
sugars are the most useful key intermediates for preparation of
various 2-acetamido-2-deoxy glycosides. Since Micheel et al.
first reported the ‘‘oxazoline method’’ in 1958,1 this methodology
has extensively beenemployed instereoselective synthesis of 1,2-
trans-2-aminoglycosides.2 This method is also applicable to the
synthesis of natural or non-natural chitin derivatives and
hyperbranched polysaccharides.3;4 Recently, sugar oxazolines
having no protecting groups were found to be recognized by an
endo-N-acetylglucosamidase for the first time and utilized as
efficient glycosyl donors for enzymatic glycosylations.5{8
A well-developed method for the synthesis of sugar
oxazolines includes treatment of N-acetylated aminosugars with
hydrogen chloride in acetyl chloride followed by treatment of the
chloride formed with a silver salts and 2,4,6-collidine.9 Fully
acetylated aminosugars can be converted to the oxazolines by
using anhydrous ferric(III) chloride, tin(IV) chloride, or
trimethylsilyl triflate.10{12 An acid-catalyzed acetolysis of the
corresponding methyl glycoside has also been reported.13
Another promising approach is to start from an ꢀ-glycosyl
chloride derivative, one of the most easily available glycosyl
donor. The treatment of 2-acetamido-2-deoxy-glycosyl chlorides
with sodium bicarbonate in the presence of tetraalkylammonium
chloride affords the corresponding oxazoline derivatives.14 This
reaction consists of the following two processes: 1) the
anomerization of ꢀ-glycosyl chloride to ꢁ-anomer by a
nucleophilic attack of the chloride ion to the anomeric carbon
atom of the ꢀ-glycosyl chloride and 2) the intramolecular attack
of the carbonyl oxygen of the 2-acetamide group to the anomeric
center as a result of proton abstraction on the nitrogen by a base. It
is, therefore, necessary toutilize two kinds of reagents, quaternary
ammonium salt and sodium bicarbonate, for the reaction to occur.
However, the yields of these reactions are normally low. In
addition, these reactions require an ammonium compound which
is very difficult to be removed from the reaction mixture and
consequently much organic solvent is necessary to purify the
product by column chromatography. The usage of such organic
compounds should be minimized from the viewpoint of green
chemistry.
Figure 1. Fluoride ion-promoted formation of cyclic
compound via nucleophilic displacement of a leaving
group X and subsequent proton abstraction from the
functional group YH.
Here we report an extremely convenient procedure for
synthesis of the 1,2-oxazoline derivative of 2-acetamido-2-
deoxy-D-glucopyranose 2 starting from peracetylated 2-aceta-
mido-2-deoxy-D-glucopyranosyl chloride 1 promoted by potas-
sium fluoride.
Scheme 1.
All the reactions were carried out by using acetonitrile as
solvent (Table 1). The best result concerning the yield of 2 was
obtained when 1 was treated with four equivalent of potassium
fluoride under reflux for 15 hours (Run 1). Since the reaction
proceeds in a heterogeneous system, two or one equivalent of
It is well known that an alkali metal fluoride can convert ꢀ-
Copyright Ó 2002 The Chemical Society of Japan

Chemistry Letters 2002
151
toward the anomeric carbon atom to enhance the SN2type
reaction with the inversion of configuration. The second step
involves a participation of the carbonyl oxygen of the 2-
acetamido group from the ꢀ side of the pyranose ring. The
resulting cyclic intermediate suffers a proton abstraction on the
nitrogen by the action of another fluoride ion. This process may
proceed smoothly because the acidity of the proton is increased
through resonance.
potassium fluoride was not sufficient and the glycosyl chloride 1
was recovered (Runs 2and 3). The reaction did not proceed
completely when carried out at room temperature (Runs 4–6).
Sodium fluoride was not so effective compared with potassium
fluoride probably because its poor solubility toward acetonitrile
(Run 7). In case of using cesium fluoride, the reaction system
becomes basic due to its higher solubility toward acetonitrile,
affording the eliminated product of glycal derivative (Run 8).
According to the present method of using potassium fluoride,
it is not necessary to utilize the quaternary ammonium chloride
that is very difficult to be removed from the reaction mixture. This
fact makes the reaction procedure extremely simple; filtrating the
complex of potassium fluoride-hydrogen fluoride (KF-HF) and
KCl can easily isolate the product. The present method can be
applied to synthesis of various sugar oxazoline derivatives that
are important synthetic intermediates in glycotechnology.
Table 1. Potassium fluoride-promoted synthesis of 2a
run Metal fluoride Equiv. Temp/ꢁC Time/h Yield/%b
1
KF
4
8215
90
2KF
3
28215 3
2
KF
KF
1
4
8215
rt
trace
48
4
5
6
7
20
26
KF
KF
2rt
1
48 9
rt
2
48
The present research is partially supported by Nagase
Science and Technology Foundation.
NaF
CsF
4
4
8215
8215
55
38
8
aSolvent:acetonitrile. bDetermined by 1H NMR spectroscopy.
Dedicated to Professor Teruaki Mukaiyama on the occasion
of his 75 th birthday.
The typical experimental procedure is as follows: A
suspension of potassium fluoride (232 mg, 4.0 mmol) and 2-
acetamido-3,4,6-tri-O-acetyl-2-deoxy-ꢀ-D-glucopyranosyl
chloride (366 mg, 1.0 mmol) in acetonitrile (15 mL) was refluxed
under argon for 15 hours with vigorous stirring. After cooling the
mixtureto roomtemperature, solid materials (KF-HF þ KCl)was
removed by filtration and the filtrate was evaporated to dryness to
give a crude mixture of 2-methyl-(3,4,6-tri-O-acetyl-1,2-di-
deoxy-ꢀ-D-glucopyrano)-[2,1-d]-2-oxazoline 2 containing trace
amount of ꢁ-glycosyl fluoride. The resulting product was found to
be pure enough for glycosylation reactions, which was confirmed
by NMR spectroscopy.
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Figure 2. Proposed mechanism for formation of oxazoline ring
starting from 2-acetamido-2-deoxy-ꢀ-D-glucopyranosyl chlor-
ide derivative promoted by fluoride ions which behave as
nucleophile and acid captor.