Selective formation of α-glycosyl phosphate from N-acetylneuraminic acid glycosyl chloride [2]

Full text of DOI:10.1007/s11172-005-0284-6

Russian Chemical Bulletin, International Edition, Vol. 54, No. 2, pp. 481—482, February, 2005
481
Selective formation of αꢀglycosyl phosphate from
Nꢀacetylneuraminic acid glycosyl chloride
ꢀ
A. M. Shpirt, L. O. Kononov, V. I. Torgov, and V. N. Shibaev
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5328. Eꢀmail: kononov@ioc.ac.ru
Recently, we have shown1 that readily available βꢀglyꢀ
cosyl chloride 1 derived from Nꢀacetylneuraminic acid
(Neu5Ac), which has been previously regarded as a
nonreactive glycosyl donor, reacts efficiently with salts of
dibenzylphosphoric acid in the absence of glycosylation
promoters giving glycosyl dibenzyl phosphate 2 with the
βꢀanomeric configuration in a high yield (Scheme 1). The
stereoselective formation of βꢀphosphate 2, i.e., the overꢀ
all retention of the configuration of the anomeric center
upon nucleophilic substitution of the Cl atom in glycosyl
chloride 1, may be due to anomerization of the αꢀphosꢀ
phate formed initially, as the βꢀisomers of Neu5Ac are
known to be thermodynamically more stable.2 Note that
in the syntheses of other glycosyl phosphates using
dibenzyl phosphate salts, it is often possible to isolate the
kinetically controlled reaction product with the inverted
configuration of the anomeric center.3
We found that the reaction of tetrabutylammonium
dihydrogen phosphate as the phosphate nucleophile with
glycosyl chloride 1 allows the preparation of Neu5Ac
αꢀglycosyl phosphate (αꢀ3) isolated as the major reaction
product (see Scheme 1). Previously,4 the related Neu5Ac
phenyl phosphate with the αꢀconfiguration was isolated
as the minor product upon the reaction of glycosyl phosꢀ
phite 6 with PhOP(O)(OH)2 at –40 °C (α : β ≈ 1 : 6).
The reaction of glycosyl chloride 1 with [Bu4N]H2PO4
(4.5 equiv.) in MеCN (20 °C, 3.5—4 h) gave a mixture of
glycosyl phosphates αꢀ3, βꢀ3 and 4 and glycal 5 5 (see
Scheme 1). Using reversedꢀphase chromatography (Mega
Bond Elut C18 cartridge (Varian), gradient elution with
H2O–MeCN (0→20% MeCN, deionized water)), we were
able to isolate pure glycosyl phosphates αꢀ3 (yield 27%)
and βꢀ3 (yield 12%), and a mixture of phosphodiester 4
anomers (yield 13%), which was apparently formed in the
Scheme 1
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 470—472, February, 2005.
1066ꢀ5285/05/5402ꢀ0481 © 2005 Springer Science+Business Media, Inc.

482
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 2, February, 2005
Shpirt et al.
reaction of glycosyl chloride 1 with phosphoric monoꢀ
esters 3.
calculated for C19H25NO15P: 538.1), and a peak for the
dimer (found: m/z 1382.1 [M2 – Bu4N]; calculated for
C56H94N3O32P2: 1382.53) containing two Neu5Ac resiꢀ
dues per tetrabutylammonium cation. Meanwhile, the
mass spectrum of phosphoric diester 4 exhibits only the
molecular ion peak (found: m/z 1043.2 [M – Bu4N];
calculated for C40H56N2O28P: 1043.28).
The stereoselective synthesis of Nꢀacetylneuraminic
acid phosphate with the αꢀconfiguration first proposed in
this study is attractive as regards experimental simplicity
and availability of the reactants. The moderate yield is
compensated for by the small number of steps, because
there is no need to remove protective groups from the
phosphoric acid residue.
The structure of phosphates 3 and 4 follows from
1H NMR, 13C NMR and 31Р NMR spectroscopy (Bruker
ACꢀ200, CDCl3) and mass spectrometry (Finnigan LCQ,
electrospray ionization (ESI), MeCN, detection of negaꢀ
tive ions). All the signals in the NMR spectra of phosꢀ
phates 3 and 4 are broadened compared to the signals in
the spectra of glycosyl phosphate 2 with the protected
phosphoric acid residue,1 which may be related to exꢀ
change processes or to aggregation of the solute molꢀ
ecules.
The assignment of anomeric configurations of glycoꢀ
syl phosphates αꢀ3 and βꢀ3 is based on a lowerꢀfield posiꢀ
1
tion of the Heq(3) signal in the H NMR spectrum of the
This work was financially supported by the Russian
Foundation for Basic Research (Projects No. 02ꢀ03ꢀ32271
and No. 04ꢀ03ꢀ32854) and by the Foundation of the Rusꢀ
sian Federation President (Program for the Support of
Leading Scientific Schools of the Russian Federation,
grant NShꢀ1557.2003.3).
αꢀanomer (δ 3.00) with respect to that for the βꢀanomer
(δ 2.68; cf. Ref. 6: δ 2.73 for the product of debenzylation
of compound 2).
The signals in the 31Р NMR spectra of anomeric glyꢀ
cosyl phosphates 3 are clearly discernible: δ ≈ –5.0 for αꢀ3
and –3.9 for βꢀ3. Note that, although each particular
spectrum contains only one signal for the respective
anomers, the spectra of different samples of glycosyl phosꢀ
phates 3 are somewhat different (for example, for αꢀ3,
δ –4.9, –5.0 and –5.2). This "scatter" in the position of
signals may imply the presence of different ionic forms of
phosphate 3.
References
1. A. M. Shpirt, L. O. Kononov, V. I. Torgov, V. N. Shibaev,
Izv. AN. Ser. khim., 2004, 684 [Russ. Chem. Bull., Int. Ed.,
2004, 53, 717].
2. G.ꢀJ. Boons and A. V. Demchenko, Chem. Rev., 2000,
100, 4539.
3. V. N. Shibaev and L. L. Danilov, in Glycopeptides and Related
Compounds, Eds D. G. Large and C. D. Warren, Marcel
Dekker, New York, 1997, 427.
4. T. J. Martin and R. R. Schmidt, Tetrahedron Lett., 1993,
34, 1765.
The 1H NMR spectrum of phosphoric diester 4 exhibꢀ
its two singlets of equal intensity (δ 3.78 and 3.82
(CO2Me)), which suggests the presence of two types of
Nꢀacetylneuraminic acid residues in the molecule. The
31Р NMR spectrum exhibits a set of signals expected of
phosphoric diesters containing two Neu5Ac residues
with unusual highꢀfield chemical shifts (δ –10.1, –12.7
and –13.1).
5. K. Okamoto, T. Kondo, and T. Goto, Bull. Chem. Soc. Jpn,
1987, 60, 631.
6. M. M. Sim, H. Kondo and C.ꢀH. Wong, J. Am. Chem. Soc.,
1993, 115, 2260.
The mass spectra of glycosyl phosphates α,βꢀ3 contain
the expected molecular ion peak (found: m/z 569.9
[M – Bu4N]; calculated for C20H29NO16P: 570.1), its
fragments (found: m/z 538.1 [M – Bu4N – OMe – H];
Received December 10, 2004