Stereoselective O-glycosylation reactions employing diphenylphosphinate and propane-1,3-diyl phosphate as anomeric leaving groups

Article abstract of DOI:10.1039/a805206i

Glycosidation of tetra-O-benzyl-D-glucose using diphenylphosphinate as the leaving group afforded β-O-linked glycosides as the major products, whilst the use of propane-1,3-diyl phosphate as the leaving group resulted in the exclusive formation of β-O-lin

Full text of DOI:10.1039/a805206i

View Article Online / Journal Homepage / Table of Contents for this issue
Stereoselective O-glycosylation reactions employing diphenylphosphinate and
propane-1,3-diyl phosphate as anomeric leaving groups
Vankayalapati Hariprasad, Gurdial Singh*† and Isabelle Tranoy
Department of Chemistry, University of Sunderland, Sunderland, UK SR1 3SD
Glycosidation of tetra-O-benzyl-D-glucose using diphenyl-
phosphinate as the leaving group afforded b-O-linked
glycosides as the major products, whilst the use of propane-
1,3-diyl phosphate as the leaving group resulted in the
exclusive formation of b-O-linked glycoside.
The essential role that glycoconjugates play in a large number of
molecular processes is now well recognised. The impact of
these complex molecules in biological processes such as
neuronal development, fertilisation, proliferation of cells and
the organisation into specific tissues is truly remarkable.1
Furthermore in tumours there are changes in the carbohydrate
structures found at the cell surface and these appear to be
intimately involved with metastasis.2 Carbohydrates are also
important in inducing protective antibody response which is
Scheme 1 Reagents and conditions: i, N-methylimidazole, Ph2POCl
responsible for the protection of the organism during infection.3
As a direct consequence of these properties there has been a
reaction; furthermore, these processes had received scant
resurgence of interest in the chemistry of carbohydrates by both
attention in the literature and in addition we would have a
chemists and biologists and thus an enormous amount of
flexible method that would allow the synthesis of O-glyco-
pyranosides.
Treatment of tetra-O-benzyl-d-glucopyranose 1 with di-
phenylphosphinyl chloride and N-methylimidazole resulted in
the formation of the phosphinates 2‡ and 3 (ratio 10:1) in 95%
yield (Scheme 1), which could be separated by column
methodology has been developed for O-glycosylation.4 In
particular there have been a number of reports regarding
glycosyl donors that have a phosphorus atom in the leaving
group at the anomeric centre. Interest in this has arisen due to
the fact that phosphorus compounds can be readily modified by
several other atoms allowing the preparation of a range of
chromatography. However for ease we conducted all of our
leaving groups. The coupling reactions of glycosyl diphenyl
reactions with this anomeric mixture, which could be stored at
phosphates, glycosyl diphenylphosphinimidates and glycosyl
220 °C for 3–4 months without decomposition.10 Similar
phosphoramidates have received much attention;5 in all of these
treatment of 1 with the cyclic phosphoroyl chloride 4 resulted in
reports 1,2-trans-b-linked glycosides are formed with a stereo-
formation of the phosphates 5‡ and 6, which were inseparable
selectivity of ca. 3:1 in favour of the b-isomer. The employ-
by chromatography, in 65% yield, (ratio ca. 10:1).
ment of S-glycosyl phosphorodimidothioates has also been
We thus proceeded to study the reactions of the phosphinates
reported and affords 1,2-cis-glycosidic linkages,6 and the use of
2 and 3 and also of the cyclic phosphates 5 and 6 with a range
dimethylphosphinothioate as glycosyl donors has also been
of nucleophiles (Scheme 2, Table 1). In the case of the reaction
investigated.7
of n-butanol with pure 2 there was little difference in the
stereochemical outcome of the reaction to that found using the
In order to extend the scope of this methodology we decided
to investigate the possibility of using the diphenylphosphinyl
anomeric mixture. In general the chemical yield was excellent,
group for coupling of sugars with peptides/amino acids. Our
however the observed stereoselectivity in these cases was poor,
attraction to this approach was derived from the fact that its use
being in the order of 3:1 in favour of the desired b-isomer. The
had been elegantly demonstrated for the coupling and
stereochemistry of products was established by 1H and 13C
N-protection of amino acids.8 One of the major considerations
NMR analysis. The 13C NMR spectra were particularly useful
in adopting this approach was the principle that one should be
able to utilise the same coupling reagent for the synthesis of
oligosaccharides and peptides, although in the former case we
as the b-isomers 7 had chemical shifts above d 100 whilst the
a-isomers 8 had a resonance at ca. d 96,11 allowing assignment
of the newly formed stereocentre.
are forming a glycosidic bond rather than an amide bond;
In the case where we employed propane-1,3-diyl phosphate
however the leaving group is the same in both reactions. In
as the leaving group the stereoselectivity was improved, with
addition the employment of the diphenylphosphinate and
the b-isomer being the major compound in the case of oxygen
propane-1,3-diyl phosphate groups9 should result in the prepa-
nucleophiles. To our surprise the use of serine- and thereonine-
ration of O-glycosides with improved stability, enabling ready
derived nucleophiles resulted in the formation of 8 as the major
isolation and storage of these compounds. Additionally we
isomer; this may be as a result of a hydrogen bonding interaction
chose to study propane-1,3-diyl phosphate as the leaving group
with the N–H, resulting in delivery from the a-face of the
as this would provide a comparison of the effect of pKa on
leaving group ability. Furthermore the introduction of the cyclic
phosphate group would allow us to assess the influence of steric
requirements at the anomeric centre.
We chose to investigate the coupling at the anomeric centre
of tetra-O-benzyl-d-glucopyranose. Our attraction to this was
multi-faceted, with the major consideration being that there
would be no participation by the C-2 substituent in the coupling
Scheme 2 Reagents and conditions: i, nucleophile (1 equiv.), TMSOTf (1
equiv.), 278 °C, 25 min
Chem. Commun., 1998
2129

View Article Online
Table 1 Results of reaction of 2, 3, 5 and 6 with nucleophiles
dd, J 3.3, 11.9), 7.10–7.84 (m, 30H); dC(100.40 MHz, CDCl3) 68.08 (C-6),
72.10, 73.21, 74.64, 76.67, 79.14 (C-4), 79.20 (C-2), 81.13 (C-3), 84.28
(C-5), 92.79 (C-1), 127.41–128.24 (Ar-C), 130.31–132.40 (Ar-C),
137.57–138.40 (Ar-C); dP(161.70 MHz, CDCl3) 32.50. For 5: mp 101–103
°C; [a]D +65.7 (c 1.4, CHCl3); dH(270 MHz, CDCl3) 1.55–1.63 (1H, m, JPH
15.2), 2.14–2.28 (1H, m, JPH 15.2), 3.61–3.78 (4H, m), 3.89–3.99 (2H, m),
4.15–4.41 (4H, m), 4.44 (1H, d, J 11.87), 4.52 (1H, d, J 11.87), 4.56 (1H,
d, J 11.87), 4.63 (1H, d, J 11.21), 4.71 (1H, d, J 11.87), 4.80 (1H, d, J 10.56),
4.84 (1H, d, J 11.22), 4.94 (1H, d, J 11.22), 5.85 (1H, dd, J 10.56, 3.30),
7.13–7.37 (20H, m); dC(67.8 MHz, CDCl3) 25.84 (1C, d, J 7.01), 68.14,
68.65 (d, J 7.01), 68.86 (d, J 7.01), 75.51, 76.94, 79.03, 94.78,
127.60–128.09 (Ar-C), 137.50–138.47 (Ar-C); dP(109.25 MHz, CDCl3)
210.99; m/z (EI) 660.6 (M+) (Found: C, 67.4; H, 6.3; P, 4.7. C37H41O9P
requires C, 67.3; H, 6.3; P, 4.7%). For 6: (selected features) dH(270 MHz,
CDCl3) 5.24 (1H, app t, J 13.19, 7.26); dC(67.8 MHz, CDCl3) 98.44;
dP(109.25 MHz, CDCl3) 210.60. For 7 (Nu = OBu): mp 69–71 °C; [a]D
+16.5 (c 1.3, CHCl3); dH(270 MHz, CDCl3) 0.91 (3H, t, J 7.26), 1.35–1.71
(4H, m), 3.41–3.50 (2H, m), 3.52–3.69 (4H, m), 3.73 (1H, dd, J 10.55, 1.98),
3.97 (1H, dt, J 12.53, 5.93), 4.39 (1H, d, J 7.91, H-1), 4.51 (1H, d, J 11.21),
4.55 (1H, d, J 11.87), 4.61 (1H, d, J 12.54), 4.71 (1H, d, J 10.55), 4.76 (1H,
d, J 11.21), 4.80 (1H, d, J 10.56), 4.91 (1H, d, J 10.55), 4.93 (1H, d, J 10.56),
7.10–7.37 (20H, m); dC(67.8 MHz, CDCl3) 13.85, 19.29, 31.82, 67.88,
69.02, 69.78, 73.45, 74.85, 74.98, 75.66, 77.96, 82.29, 84.72, 103.60 (C-1),
127.58–128.37 (Ar-C), 138.23, 138.32, 138.61, 138.74 (Found M+,
596.3138. C38H44O6 requires 596.3138). For 7 (Nu = 13):12 [a]D +65.5 (c
3.3, CHCl3); dH(270 MHz, CDCl3) 1.99 (3H, s), 2.02 (3H, s), 2.08 (3H, s),
3.29 (3H, s), 3.41–3.55 (3H, m), 3.64–3.80 (2H, m), 3.84–3.97 (4H, m), 4.38
(1H, d, J 8.57), 4.46 (1H, d, J 11.87), 4.49 (1H, d, J 11.87), 4.56 (1H, d, J
11.87), 4.58 (1H, d, J 10.55), 4.64 (1H, d, J 11.21), 4.74 (1H, d, J 11.22),
4.81–4.85 (3H, m), 4.89 (1H, d, J 10.55), 4.91 (1H, d, J 11.21), 5.36 (1H,
app t, J 4.62), 7.03–7.27 (20H, m); dC(67.8 MHz, CDCl3) 20.68, 20.70,
29.59, 66.83, 68.43, 69.51, 70.24, 70.82, 73.15, 74.67, 74.82, 75.12, 75.47,
80.21, 81.27, 82.49, 84.71, 96.61 (C-1A), 102.93 (C-1), 127.52–128.51 (Ar-
C), 137.72, 138.06, 138.34, 138.50, 170.10, 170.29, 170.40.
Phosphinate/
phosphate
Nucleophile Yield (%)a
Ratio 7:8
2
BunOH
BunOH
MeOH
PriOH
9
10
11
12
13
BunOH
MeOH
PriOH
9
10
11
12
13
89
90
94
93
88
94
85
92
84
99
96
98
91
83
88
68
72
2:1
2:1
4:1
3.5:1
2.5:1
1:2
2:1
2:1
3:1
7 only
7:3
7:3
1:2
1:2
4:1
7 only
7 only
2 and 3
2 and 3
2 and 3
2 and 3
2 and 3
2 and 3
2 and 3
2 and 3
5 and 6
5 and 6
5 and 6
5 and 6
5 and 6
5 and 6
5 and 6
5 and 6
a All yields are for isolated products.
1 A. Varki, Glycobiology, 1993, 3, 97.
2 J. Kellerman, F. Lottspeich, A. Henschen and W. Muller-Esterl, Eur.
J. Biochem., 1986, 154, 471; S. Hakomori, Cancer Res., 1985, 45, 2405;
J. Montreuil, Adv. Carbohydr. Chem. Biochem., 1980, 37, 157.
3 N. Sharon, Trends Biochem. Sci., 1984, 9, 198.
4 G. J. Boons, Tetrahedron, 1996, 52, 1095; K. Toshima and K. Tatsuta,
Chem. Rev., 1993, 93, 1503; K. J. Hale and A. C. Richardson,
Carbohydrates, in The Chemistry of Natural Products, ed. K. H.
Thomson, Blackie, 1993, ch. 1, p. 1.
5 S. Hashimoto, T. Honda and S. Ikegami, Tetrahedron Lett., 1991, 32,
1653; S. Hashimoto, T. Honda and S. Ikegami, Heterocycles, 1990, 30,
775; S. Hashimoto, T. Honda and S. Ikegami, Chem. Pharm. Bull.,
1990, 38, 2323; S. Hashimoto, T. Honda and S. Ikegami, J. Chem. Soc.,
Chem. Commun., 1989, 685.
6 H. Harada, S. Hashimoto, T. Honda and S. Ikegami, Tetrahedron Lett.,
1992, 33, 3523; S. Hashimoto, T. Honda and S. Ikegami, Tetrahedron
Lett., 1990, 31, 4769.
7 T. Inazu and T. Yamanoi, Chem. Lett., 1990, 849; T. Inazu and T.
Yamanoi, Chem. Lett., 1989, 69; T. Inazu, H. Hosokawa and Y. Satoh,
Chem. Lett., 1985, 297.
8 R. Ramage, D. Hopton, M. J. Parrott, G. W. Kenner and G. A. Moore,
J. Chem. Soc., Perkin Trans. 1, 1984, 1357 and references cited
therein.
9 T. R. Fukuto and R. L. Metcalf, J. Med. Chem., 1965, 8, 759; F.
Ramirez, H. Tsuboi, H. Okazaki and R. F. Marecek, Tetrahedron Lett.,
1982, 23, 5375; R. N. Hunston, S. A. Jones, C. McGuigan, T. Richard,
J. Balzarini and E. De Clercq, J. Med. Chem., 1984, 27, 440; E. L. Eliel,
S. Chandraserkaran, L. E. Carpenter II and J. G. Verkade, J. Am. Chem.
Soc., 1986, 108, 6651.
glucose. We were gratified to observe that we had attained our
goal of excellent selectivity in the formation of 7 in the cases
where we employed sugar-derived nucleophiles. This is partic-
ularly encouraing as we have a 2-O-benzyl protecting group
which is non-participating in glycosylation reactions and would
be expected to result in the formation of the a-glycosides. As a
result of these findings one could, in principle, use O-benzyl
protected sugars as starting materials and by changing the
activating group of the glycosyl donor either desired stereo-
isomer can be obtained, thus alleviating the need for differ-
entially protected starting sugars.
We have thus established that tetra-O-benzyl-d-gluco-
pyranose can be converted into O-linked glycosides with high
stereoselectivity in the cases where we employed propane-
1,3-diyl phosphate as the leaving group, adding to the
methodology available for the synthesis of complex carbohy-
drates.
We thank Professor R. Ramage (Edinburgh University) for
helpful discussions and encouragement. We also thank the
EPSRC for access to the mass spectrometry service at the
University of Wales, Swansea (Director, Dr J. A. Ballantine).
10 A. Esswein and R. R. Schmidt, Liebigs Ann. Chem., 1988, 675.
11 K. Bock and C. Pedersen, Adv. Carbohydr. Chem. Biochem., 1983, 41,
27.
12 S. Houdier and P. J. A. Votte´ro, Tetrahedron Lett., 1993, 34, 3283; for
the a-isomer of this compound, see: P. G. Garegg, J.-L. Maloisel and S.
Oscarson, Synthesis, 1995, 409.
Notes and References
† E-mail: gurdial.singh@sunderland.ac.uk
‡ All compounds gave satisfactory spectral and microanalytical data.
Selected data for 2:10 [a]D +83.3 (c 4.3, CHCl3); dH(400 MHz, CDCl3)
3.62–3.77 (4H, m), 3.86–4.07 (2H, m), 4.36 (1H, d, J 11.87), 4.47 (1H, d,
J 10.50), 4.51 (1H, d, J 11.87), 4.60 (1H, d, J 11.22), 4.73 (1H, d, J 11.22),
4.80 (1H, d, J 10.56), 4.85 (1H, d, J 10.56), 4.96 (1H, d, J 11.21), 5.99 (1H,
Received in Liverpool, UK, 6th July 1998; 8/05206I
2130
Chem. Commun., 1998