Selectin ligands: 2,3,4-tri-O-acetyl-6-O-(2-naphthyl)methyl (NAP) α-D- galactopyranosyl imidate as a novel glycosyl donor for the efficient total synthesis of branched mucin core 2-structure containing the NeuAcα2,3(SO3Na-6)Galβ1,3GalNAcα seque

Article abstract of DOI:10.1039/a908511d

The stereo- and regioselective total synthesis of branched mucin core 2- structure 2, which contains the NeuAcα2,3(SO₃Na-6)Galβ1,3GalNAcα sequence, is accomplished through the use of the key glycosyl donor 19.

Full text of DOI:10.1039/a908511d

Selectin ligands: 2,3,4-tri-O-acetyl-6-O-(2-naphthyl)methyl (NAP)
-galactopyranosyl imidate as a novel glycosyl donor for the efficient total
a-
D
synthesis of branched mucin core 2-structure containing the
NeuAca2,3(SO3Na-6)Galb1,3GalNAca sequence
Wensheng Liao, Robert D. Locke and Khushi L. Matta*
Molecular & Cellular Biophysics, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA.
E-mail: klmatta@yahoo.com
Received (in Corvallis, OR, USA) 21st October 1999, Accepted 10th January 2000
The stereo- and regioselective total synthesis of branched
mucin core 2-structure 2, which contains the NeuAca-
2,3(SO3Na-6)Galb1,3GalNAca sequence, is accomplished
through the use of the key glycosyl donor 19.
glycosyl donor. Recently Spencer et al.4 reported selective
cleavage of the NAP group by hydrogenolysis (10% Pd/C,
ethanol) even in the presence of benzyl groups. However, when
we applied this method to the synthesis of oligosaccharides, our
pilot experiments showed that the hydrogenation reactions went
very slowly and the benzyl groups were also partially cleaved
(Scheme 1). Meanwhile, in our lab we have found that DDQ can
smoothly remove the NAP group and other usual protecting
groups (such as Ac, pivaloyl, TBS, phthalimido, Bn and
benzylidene) can still survive.5 The donor 19 was prepared as
shown in Scheme 2. On alkylation with 2-(bromomethyl)na-
phthalene, the readily accessible 14 provided 15 in quantitative
yield. Deacetonation followed by acetylation furnished com-
pound 17 (a+b 2+3). Selective removal of the anomeric O-
acetyl group from 17 gave, in 87% yield, 18 which on treatment
with CCl3CN–DBU (210 °C) afforded a 90% yield of
trichloroacetimidate 19 as the pure a-anomer.
Our recent study has shown that a core 2-branched sequence can
enhance L- and P-selectin binding, e.g. our synthetic compound
GalNAcb1,4(Fuca1,3)GlcNAcb1,6(NeuAca2,3Galb1,3)Gal-
NAcaOMe 1 was found to be 5- to 6-fold better at inhibiting L-
and P-selectins than sialyl Lewisx-OMe.1 It is now well
established that natural selectin ligands, such as CD34,
MadCAM-1, PSGL-1 and GlyCAM-1, are mucin type glyco-
proteins.1 Both PSGL-1 and GlyCAM-1 contain the Neu-
Ac2,3Galb1,3GalNAca sequence. In GlyCAM-1 it has been
demonstrated that, in addition to sialylation and fucosylation,
sulfation of the saccharide chains is important for high affinity
binding to L-selectin.2 Based upon this, we became interested in
the synthesis of sulfated analogs of our previously reported 1 as
Glycosidation of alcohol 3 with imidate 19 was performed
under Schmidt’s ‘inverse procedure’.6 The b-linked disaccha-
ride 20 was obtained in 74% yield, which was then O-
deacetylated to furnish triol 21. The sialylation of 21 with the
sialic acid donor 4 under NIS–TfOH catalysis at 230 °C gave
the trisaccharide 22 in 78% yield. Compound 22 was then
1
acetylated to give 23. The H NMR spectrum of 23 displayed
characteristic signals at d 5.07 (dd, 1H, J1A,2A 8.0, J2A,3A 10.4 Hz,
H-2A), 4.96 (d, 1H, J3A,4A 2.8 Hz, H-4A), 5.27 (dd, 1H, J6B,7B 2.8,
J
7B,8B 9.6 Hz, H-7B) and 2.59 (dd, 1H, Jgem 12.8, J3Beq,4B 4.9 Hz,
H-3Be) which confirmed an a(2 ? 3) glycosidic linkage.
Removal of the 4,6-benzylidene group in 23 (50% HOAc,
55 °C) afforded the trisaccharide diol 24 (90%).
Although preparation of the key GalNAc Lex glycosyl donor
29 has been reported,1 a simplified procedure based on
employing diol 6 as an acceptor was developed (Scheme 3).
Thus, regioselective condensation of phenylthio donor 5 and
diol 6 under NIS–TfOH conditions (265 °C) afforded the
b(1 ? 4) linked disaccharide 25 in 73% yield. Selectfluor–
potential ligands. Moreover, the sequences (SO3Na-6)Galb-
1,3GalNAca and especially NeuAca2,3(SO3Na-6)Galb1,3Gal-
NAca have been found to be part of O-linked glycoproteins.3
Thus, we turned our attention to the synthesis of our target
molecule 2, which contains the NeuAca2,3(SO3Na-6)Galb-
1,3GalNAca sequence, as a potential ligand.
BF3·Et2O promoted7 a-
-fucosylation of 25 with donor 7 in
L
CH3CN (0 °C) gave trisaccharide 27 in 75% yield. Hydro-
genolysis of 27, followed by acetylation and then acetolysis
Scheme 1 Reagents and conditions: i, 10% Pd/C, HOAc–MeOH, 16 h;
ii, DDQ (2.5 equiv. for 8, 5 equiv. for 11), CH2Cl2–H2O (15+2), 3 h,
quant.
Our present approach is based upon the use of imidate 19
bearing a 6-O-(2-naphthyl)methyl (NAP) group as a valuable
DOI: 10.1039/a908511d
Chem. Commun., 2000, 369–370
This journal is © The Royal Society of Chemistry 2000
369

Scheme 4 Reagents and conditions: i, 29 (1.5 equiv.), NIS–TfOH, CH2Cl2,
4 Å molecular sieves, 260 °C, 2 h, 70%; ii, DDQ (2.5 equiv.), CH2Cl2–
H2O, 3 h, quant.; iii, SO3·pyridine complex (5 equiv.), DMF, 0 °C, 3 h, 95%;
iv, LiI (40 equiv.), pyridine, 110 °C, overnight, 90%; v, hydrazine hydrate–
MeOH (1+4), 80 °C, 6 h; vi, MeOH–CH2Cl2 (1+1), Ac2O, 0 °C, 1 h; Na+
resin.
Glycosylation of 29 with diol 24 (NIS–TfOH, 260 °C) gave
the expected hexasaccharide 30 in 70% yield (Scheme 4).
Removal of the NAP group in the b-galactopyranosyl residue
by DDQ in CH2Cl2–H2O afforded 31, which was further treated
with 5 equiv. of sulfur trioxide–pyridine complex in DMF at
0 °C to give the sulfated compound 32. Finally, 32 was
converted to the target compound 2 in three successive steps: (i)
LiI–pyridine at 110 °C (methyl ester to free acid); (ii) 4+1
MeOH–hydrazine hydrate at 80 °C (removal of the phthalimido
and acetyl groups); (iii) 5+5+3 MeOH–CH2Cl2–Ac2O (N-
acetylation). The structure of 2 was confirmed by 1H, 13C NMR
and FAB mass spectroscopy.†
Scheme 2 Reagents and conditions: i, 2-(bromomethyl)naphthalene, KOH,
18-crown-6, THF, 2 h; ii, 80% AcOH, 75 °C, 95%; iii, pyridine–Ac2O,
DMAP; iv, hydrazine acetate, DMF, 2 h, 87%; v, CCl3CN–DBU, CH2Cl2,
210 °C, 90%; vi, 19 (1.5 equiv.), TESOTf, 4 Å molecular sieves, CH2Cl2,
room temp., 73%; vii, MeOH–Et3N–H2O, 4 °C; viii, 4 (2.0 equiv.), NIS–
TfOH, 3 Å molecular sieves, CH3CN–CH2Cl2, 230 °C, 3 h, 78%; ix, 50%
AcOH, 55 °C, 4 h, 90%.
We thank the National Cancer Institute for financial support
(Grant No. CA 63218) of this work.
Notes and references
† Selected data for 2: m/z (FAB) 1441.4 (M); [a]2D0 +3.1 (c 0.16, H2O);
dH(D2O, 400 MHz) 5.12 (d, 1H, J 3.6, H-1BB), 4.99 (d, 1H, J 3.6, H-1), 4.56
(d, 1H, J 8.4, H-1B), 4.55 (d, 1H, J 8.4, H-1Ú), 4.46 (d, 1H, J 8.0, H-1A), 4.09
(dd, 1H, J 3.3, 9.9, H-3A), 2.76 (dd, 1H, J 4.8, 12.2, H-3ÚBe), 2.07, 2.04, 2.00
and 1.97 (each s, 12H, 4 3 NHAc), 1.80 (t, J 12.0, H-3ÚBa), 1.28 (d, 3H, J
7.2, CMe); dC(D2O, 100.6 MHz) 105.21 (C-1B), 102.30 (C-1Ú), 101.81 (C-
1A), 101.00 (C-2ÚB), 99.56 (C-1BB), 97.13 (C-1), 76.60 (C-3A), 71.47 (C-6),
70.36 (CH2Ph), 68.73 (C-6A), 63.65 (C-6Ú), 62.52 (C-6B), 61.15 (C-9ÚB),
40.73 (C-3ÚB), 23.46, 23.31, 23.15, 23.06 (4 3 NHAc), 16.46 (C-6BB).
1 R. K. Jain, C. F. Piskorz, B.-G. Huang, R. D. Locke, H.-L. Han, A.
Koenig, A. Varki and K. L. Matta, Glycobiology, 1998, 8, 707.
2 Y. Imai, L. A. Lasky and S. D. Rosen, Nature, 1993, 361, 555.
3 C. Capon, C. L. Laboisse, J. M. Wieruszeski, J. J. Maoret, C. Augeron
and B. Fournet, J. Biol. Chem., 1992, 267, 19248; D. L. Chance and T.
P. Mawhinney, Carbohydr. Res., 1996, 295, 157.
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Gaunt, C. E. Boschetti, J. Yu and J. B. Spencer, Tetrahedron Lett., 1999,
40, 1803.
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Matta, Tetrahedron Lett., 2000, 41, 169.
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Scheme 3 Reagents and conditions: i, 5 (1.2 equiv.), NIS–TfOH, CH2Cl2,
4 Å molecular sieves, 265 °C; ii, pyridine–Ac2O, DMAP; iii, 7 (3.0 equiv.),
Selectfluor, BF3·Et2O, 3 Å molecular sieves, CH3CN, 0 °C, 75%; iv, 10%
Pd/C, HOAc–MeOH; v, Ac2O–HOAc–H2SO4, 70%; vi, PhSH, BF3·Et2O,
CH2Cl2, 73%.
with Ac2O–HOAc–H2SO4 provided the fully acetylated tri-
saccharide 28. Treatment of 28 with PhSH–BF3·Et2O furnished
GalNAc Lex glycosyl donor 29 in 73% yield.
Communication a908511d
370
Chem. Commun., 2000, 369–370