A facile synthesis of N-acetylneuraminic acid glycal

Article abstract of DOI:10.1055/s-2006-950354

Treatment of the readily available peracetylated N-acetylneuraminic acid glycosyl chloride [methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-2-chloro-2,3,5- trideoxy-β-D-glycero-D-galactononulopyranosonate)] with anhydrous Na ₂HPO₄ in refluxing MeCN quantitatively affords the peracetylated N-acetylneuraminic acid glycal [methyl 5-acetamido-4,7,8,9-tetra- O-acetyl-3,5-dideoxy-2,6-anhydro-D-glycero-D-galacto-non-2-enonate], which can be isolated from the reaction mixture by simple filtration and subsequent evaporation of the solvent. No glycal formation was detected at room temperature even after prolonged treatment with Na₂HPO₄. The method proposed is experimentally simple and allows ready preparation of substantial amounts of the title compound, which is an important intermediate in sialic acid chemistry. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950354

SHORT PAPER
4113
A Facile Synthesis of N-Acetylneuraminic Acid Glycal
cal ezhda Yu. Kulikova,a,b Anna M. Shpirt, Leonid O. Kononov*a
a
N
a
-Acetylneuramin
a
ic
A
cid
G
ly
d
N. D. Zelinsky Institute of Organic Chemistry of the Russian Academy of Sciences, Leninsky prospect, 47, 119991 Moscow,
Russian Federation
Fax +7(495)1355328; E-mail: kononov@ioc.ac.ru
The Higher Chemical College of the Russian Academy of Sciences, Miyuskaya pl. 9, 125047 Moscow, Russian Federation
b
Received 16 June 2006; revised 11 September 2006
The paper is dedicated to the memory of Professor Nikolay K. Kochetkov and his outstanding contribution to carbohydrate chemistry.
OAc
OAc
OAc
Abstract: Treatment of the readily available peracetylated N-
acetylneuraminic acid glycosyl chloride [methyl 5-acetamido-
OAc
O
Cl
O
2
CO Me
AcO
AcO
CO2Me
4
,7,8,9-tetra-O-acetyl-2-chloro-2,3,5-trideoxy-b-D-glycero-D-ga-
AcNH
AcNH
AcO
lactononulopyranosonate)] with anhydrous Na HPO in refluxing
AcO
2
4
1
2
MeCN quantitatively affords the peracetylated N-acetylneuraminic
acid glycal [methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-
dideoxy-2,6-anhydro-D-glycero-D-galacto-non-2-enonate], which
can be isolated from the reaction mixture by simple filtration and
subsequent evaporation of the solvent. No glycal formation was de-
tected at room temperature even after prolonged treatment with
Na HPO . The method proposed is experimentally simple and al-
OAc
OAc
OAc
O
OAc
O
OAc
CO2Me
SR
AcO
AcO
CO2Me
AcNH
AcNH
AcO
AcO
3
4a: R = β-Ph
b: R = α-Me
2
4
4
lows ready preparation of substantial amounts of the title com-
pound, which is an important intermediate in sialic acid chemistry.
Figure 1 Neu5Ac derivatives
Key words: carbohydrates, halides, eliminations, alkenes, phos-
phates
1
0
ing workup procedure. An alternative approach for the
synthesis of glycal 1 is based on the trimethylsilyl tri-
fluoromethanesulfonate (TMSOTf)-catalyzed elimination
reaction from the peracetylated Neu5Ac methyl ester 3 in
Sialic acid containing oligosaccharides play many impor-
tant roles in biological processes. For this reason, tremen-
dous efforts have been made in order to develop efficient
methods for their synthesis. The most reliable approaches
1
5
MeCN. The use of ‘fresh’ TMSOTf was reported to be
essential in order to reduce formation of the undesired 4,5-
oxazoline. This reaction was studied in detail and shown
to be highly ‘sensitive to changes in solvent and tempera-
ture’.5d A recently described transformation of Neu5Ac
thioglycosides 4a,b to Neu5Ac glycal 1 under oxidative
2
5
c
for the construction of sialyl glycosidic bond make use of
N-acetylneuraminic acid (Neu5Ac) derivatives with an
auxiliary stereocontrolling group at the C-3 atom of sialic
2
acid. The key intermediate for the preparation of these 3-
6
a
conditions (MCPBA, Py, CH Cl ) or by treatment with
2
2
substituted derivatives is the Neu5Ac glycal 1. This com-
pound has also found application in the synthesis of inhib-
itors of influenza virus sialidase, two of which were
commercialized recently as anti-influenza drugs (Relenza
and Tamiflu). Not surprisingly, several methods for the
preparation of this important intermediate were developed
DMTST and DBU6b albeit efficient require additional
steps for the preparation of the starting thioglycoside.
These limitations of the known methods call for search for
new approaches for the preparation of Neu5Ac 1, which
would be experimentally simple, robust and efficient.
3
4
–6
During the development of the synthesis of Neu5Ac glyc-
osyl phosphates by reaction of Neu5Ac glycosyl chloride
with various phosphate nucleophiles, we discovered
that treatment of Neu5Ac glycosyl chloride 2 with anhy-
drous Na HPO in refluxing MeCN for three hours quan-
titatively affords the peracetylated Neu5Ac glycal 1
Scheme 1). The pure product can be isolated from the re-
action mixture by simple filtration and subsequent evapo-
ration of the solvent. No chromatography or
crystallization is required thus making this approach po-
tentially applicable to large-scale preparation of 1. It is
important to note that no glycal formation was detected at
room temperature even after prolonged treatment with
Na HPO . The latter observation may allow the use of
Na HPO as an acid scavenger in the reactions of Neu5Ac
glycosyl chloride 2 (other bases are known to cause its
elimination, leading to the formation of glycal 1).
(Figure 1). Unfortunately, each has its own disadvan-
tages.
8
2
The most widely used synthesis of Neu5Ac glycal 1 in-
volves treatment of Neu5Ac glycosyl chloride 2, which
can be prepared quantitatively from peracetylated
Neu5Ac 3, with a base (initially Et N was used, later
DBU was suggested ) at room temperature. Although
this method is fairly straightforward on low-to-medium
scale (81% yield after chromatography and crystalliza-
tion), it can lead to disappointing results on a large scale
7
8
a
2
4
9
4a
3
(
4
b
(
20–50 g) due to partial hydrolysis of the methyl ester and
concomitant de-O-acetylation of acetylated glycal 1 dur-
2
4
SYNTHESIS 2006, No. 24, pp 4113–4114
x
x.
x
x
.
2
0
0
6
2 4
Advanced online publication: 02.11.2006
DOI: 10.1055/s-2006-950354; Art ID: P07506SS
Georg Thieme Verlag Stuttgart · New York
©

4
114
N. Yu. Kulikova et al.
SHORT PAPER
4
b
20
OAc
OAc
OAc
product was identical to that described in the literature; [a]D
6b 20
OAc
O
Cl
a
+56.6 (c = 1.3, CHCl ) {Lit. [a]D +56.0 (c = 1.3, CHCl )}.
3 3
O
AcO
AcNH
AcO
AcNH
CO2Me
13
CO2Me
C NMR: d = 20.6, 20.7, [C(O)CH ], 22.9 [NHC(O)CH ], 46.2 (C-
5), 52.5 (CH ), 61.9 (C-9), 67.5 (C-4), 68.1 (C-7), 70.9 (C-8), 76.5
(C-6), 108.0 (C-3), 145.0 (C-2), 161.5 (C-1), 170.1, 170.3 (2 C),
3
3
AcO
AcO
3
2
1
1
70.6, 170.8 (C=O).
Scheme 1 Reagents and conditions: (a) Na HPO , MeCN, reflux, 3
2
4
h, 95%.
Acknowledgment
The proposed method for the synthesis of Neu5Ac glycal
This work was financially supported by the Russian Foundation for
1
is experimentally simple and allows ready preparation Basic Research (Project No. 04-03-32854).
of substantial amounts of the title compound, which is an
important intermediate in sialic acid chemistry.
References
(
1) (a) Schauer, R. Biochemistry of Sialic Acid Diversity, In
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The reactions were performed with the use of commercial reagents
(
Aldrich and Fluka) and distilled solvents purified according to
standard procedures. MeCN was distilled over CaH under argon
2
Glycoconjugates, Vol. 3; Ernst, B.; Hart, G. W.; Sinaÿ, P.,
Eds.; Wiley-VCH: Weinheim, 2000, 227. (b) Angata, T.;
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prior to use. TLC was carried out on plates with silica gel 60 on alu-
minum foil (Merck). Spots of compounds were visualized with a so-
lution of 85% H PO in 96% EtOH (1:10) with subsequent heating
3
4
(2) Boons, G.-J.; Demchenko, A. V. Chem. Rev. 2000, 100,
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13
(
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4539.
tions in CDCl were recorded on a Bruker AC-200 instrument
3
(
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1
(
200.13, and 50.32, MHz, respectively). The H chemical shifts are
1
3
referred to the signal of the residual CHCl (d = 7.27), and the
C
3
of the 13C NMR, to the signal of CDCl (d = 77.0). All reactions
3
were carried out with the use of glycosyl chloride 2, which was
(
4) (a) Meindl, P.; Tuppy, H. Monatsh. Chem. 1969, 100, 1295.
freshly prepared from the fully acetylated neuraminic acid methyl
(
b) Okamoto, K.; Kondo, T.; Goto, T. Bull. Chem. Soc. Jpn.
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8
a
ester 3 according to a modified procedure and dried for 3 h under
vacuum (oil pump). The yield of glycal 1 was calculated with re-
spect to the amount of 3 taken.
1
(
1
Tetrahedron Lett. 1988, 29, 3643. (c) Ercegovic, T.;
Magnusson, G. J. Chem. Soc., Chem. Commun. 1994, 831.
Methyl 5-Acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-2,6-an-
hydro-D-glycero-D-galactonon-2-enonate (1)
(
d) Kok, G. B.; Mackey, B. L.; von Itzstein, M. Carbohydr.
Glycosyl chloride 2 [prepared from 3 (103.6 mg, 0.194 mmol)] was
dissolved in MeCN (4 mL), then Na HPO (33 mg, 0.23 mmol) was
Res. 1996, 289, 67.
2
4
(
6) (a) Kononov, L. O.; Komarova, B. S.; Nifantiev, N. E. Russ.
Chem. Bull. 2002, 51, 698. (b) Ikeda, K.; Konishi, K.; Sano,
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added and the suspension refluxed. The course of the reaction was
monitored by TLC [R 1 = 0.48, R 2 = 0.50 (EtOAc)]. After 3 h, the
f
f
mixture was cooled to the r.t., filtered through a Celite pad and the
volatiles were evaporated. The residue was dried under vacuum (oil
pump) to give crude glycal 1 (87.1 mg), which was pure according
to NMR spectroscopy. The product was subjected to silica gel col-
umn chromatography (gradient from EtOAc–hexanes, 1:1 to
(
(
1
EtOAc) to give glycal 1 (87.1 mg, 95%). The H spectrum of the
(
9) Marra, A.; Sinay, P. Carbohydr. Res. 1989, 190, 317.
(
10) Kononov, L. O., unpublished results.
Synthesis 2006, No. 24, 4113–4114 © Thieme Stuttgart · New York