Synthesis of 3-O-sialyl and 6-O-sulfo derivatives of dimeric N-acetyl lactosamine as specific acceptors for α-L-fucosyltransferases

Article abstract of DOI:10.1039/a605439k

The stereoselective syntheses of 3-O-sialyl and 6-O-sulfo dimeric lactosamine derivatives 1-4 are accomplished through the use of key glycosyl donors 13 and 15.

Full text of DOI:10.1039/a605439k

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Synthesis of 3-O-sialyl and 6-O-sulfo derivatives of dimeric N-acetyl
lactosamine as specific acceptors for a-l -fucosyltransferases
Rakesh K. Jain,† Bao-Guo Huang, E. V. Chandrasekaran and Khushi L. Matta*
Department of Gynecologic Oncology, Rosewell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA
The stereoselective syntheses of 3-O-sialyl and 6-O-sulfo
dimeric lactosamine derivatives 1–4 are accomplished
through the use of key glycosyl donors 13 and 15.
by acetylation with pyridine–acetic anhydride and deacetona-
tion provided the acceptor 16 in 66% yield. The 1H NMR
spectrum gave characteristic signals at d 5.70 (dd, H-3), 2.10
and 1.09 (2 3 OAc) and 1.27 and 1.23 (2 3 CMe3).
Condensation of the donor 15 with 16 under NIS–triflic acid
In continuation of our efforts towards the synthesis of
biologically important oligosaccharides, we have developed an
elegant synthesis of 3-O- and 6-O-substituted dimeric lacto-
samine derivatives. 1–41 (Fig. 1), which were prepared from the
key intermediates 5–13 (Fig. 2) by stereoselective transforma-
tion, as described in Schemes 1–3. Our approach is based upon
the observation that an O-acetyl group can be selectively
removed in the presence of a 6-O-pivaloyl substituent to give
6-O-pivaloyl b-d-galactopyranosyl linked compounds. Glyco-
sylation of 5 with 9 under Mukaiyama’s conditions (SnCl2–
AgOTf)2 followed by acetylation with pyridine–acetic anhy-
dride afforded the b(1?3) linked disaccharide 14 in 8% yield
1
conditions at 230 °C gave 17 in 76% yield. The H NMR
spectrum of 17 displayed characteristic signals at d 5.71–5.59 (2
3 dd and d, H-3, H-3B and H-4B), 5.46 (d, J = 8.3 Hz, H-1B),
5.24 (d, J = 8.5 Hz, H-1), 5.09 (dd, H-2AAA), 4.97 (dd, H-2A), 4.53
(d, J = 7.9 Hz, H-1AAA), 4.43 (d, J = 7.6 Hz, H-1A), 2.10–1.49
(cluster of singlets, 6 3 OAc) and 1.25, 1.23 and 1.94 (4 3
CMe3) which confirmed a b(1?3) conformation of the newly
incorporated glycosidic linkage. De-O-acetylation of 17 in
MeOH–CH2Cl2 (1:1, v/v) with MeOH–MeONa (pH 10) at 0 °C
provided the acceptor 18 in 95% yield. The 1H NMR spectrum
gave characteristic signals at d 5.58–5.69 (2 3 dd, H-3B and
H-3), 5.34 (d, H-1B, J = 8.2 Hz), 5.24 (d, H-1, J = 8.4 Hz), 4.82
(dd, H-2A), 4.73 (d, J = 7.8 Hz, H-1AAA), 4.35 (d, J = 7.7 Hz,
H-1A), 1.84, 1.75 and 1.49 (each s, 3 3 OAc) and 1.25, 1.23,
1.22 and 0.97 (each s, 4 3 CMe3) confirming the assigned
structure.
1
and the b(1?4) linked disaccharide 15 in 48% yield. The H
NMR spectrum of 15 displayed characteristic signals for H-3,
H-1 (d 5.71–5.67), H-1A (d 4.50, d, J = 8.0 Hz), 4 3 OAc (d
2.08, 2.04, 1.93 and 0.86) and 2 3 CMe3 (d 1.25 and 1.17).
Isopropylidenation of 11, using Catelani’s procedure,3 followed
OPiv
O
OPiv
O
AcO
AcO
OH
O
OH
OH
O
OH
O
HO
O
HO
RO
AcO
SPh
O
O
OBn
NHAc
NPhth
OAc
O
i, ii
O
HO
HO
14
5 + 9
NHAc
OH
OH
OPiv
O
OPiv
O
AcO
AcO
1 R = SO3Na, 2 R = NeuAc
O
SPh
OR1
O
OR1
AcO
OH
O
OH
O
HO
O
HO
R2O
NPhth
OAc
O
15
OMe
NHAc
3 R1 = SO3Na, R2 = H; 4 R1 = SO3Na, R2 = NeuAc
O
O
HO
HO
OPiv
O
OPiv
O
HO
HO
NHAc
OH
OH
iii, ii, iv
11
O
OBn
AcO
NPhth
OAc
Fig. 1 Target molecules sialyl and sulfated dimeric lactosamine 1–4
16
15
v
OPiv
O
OBn
O
17
HO
HO
HO
HO
vi
R
R
NPhth
5 R = SPh
6 R = OBn
NPhth
7 R = OMe
8 R = SPh
OPiv
OPiv
O
OPiv
O
OPiv
O
HO
O
HO
HO
O
O
OBn
O
AcO
AcO
OAc
OAc
NPhth
NPhth
OAc
18
OH
OPiv
O
AcO
AcO
SPh
1
vii, viii, ix
AcO
AcHN
CO2Me
O
F
18
OAc
OAc
9
10
v, x, ix
2
OPiv
OPiv
OPiv
OBn
O
AcO
HO
HO
Scheme 1 Reactions and conditions: i, 5 (1.0 equiv.), 9 (1.5 equiv.), AgOTf
(1.20 equiv.), 4 Å molecular sieves, CH2Cl2–toluene (5:1, v/v), 215 °C to
room temp., 5 h; ii, pyridine–Ac2O (2:1, v/v); iii, 0.15% CSA, DMP, 24 h,
MeOH–H2O (10:1, v/v), 100 °C, 6 h; iv, 70% aq. AcOH, 70 °C, 2 h; v, 15
(1.05 equiv.), or 10 (3.0 equiv.), NIS (3.0 equiv.)–triflic acid, 230 °C, 2 h;
vi, MeOH–CH2Cl2 (1:1, v/v), MeONa (pH 10), 2 h; vii, SO3–pyridine
complex in pyridine (6.0 equiv.), 5 °C, 16 h; viii, MeOH–hydrazine hydrate
(4:1, v/v), 100 °C, 16 h, Ac2O (excess), MeOH–CH2Cl2 (1:1, v/v), 0 °C,
1 h; ix, MeOH–MeONa, 24 h; x, LiI (10 equiv.), pyridine, 120 °C, 3 h
O
O
O
R1
O
R2O
OBn
O
AcO
HO
NPhth
OAc
OH
NPhth
11
12 R1 = OMe, R2 = H
13 R1 = SPh, R2 = Ac
Fig. 2 Key intermediates 5–13 involved in the synthesis of target molecules
1–4
Chem. Commun., 1997
23

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OBn
O
OPiv
O
Removal of both the phthalimido and acetate groups from 20
was accomplished by treatment with hydrazine hydrate in
ethanol (1:9, v/v) at 80 °C followed by N-acetylation to give 23
in 65% yield. Condensation of sialic acid donor 10 with 23 at
240 °C followed by O-acetylation gave 24 in 35% yield (based
on 23 consumed). The synthesis of 4 from 24 was achieved by
a sequence of reactions similar to those described for the
preparation of 3 from 21. The structures of 1–4 were confirmed
by 1H and 13C NMR spectroscopy.†
Our preliminary examination of Galb1,4(6-sulfo)
GlcNAcb1,3 Galb1,4(6-sulfo) GlcNAcb-O-Me (3) and Neu-
Aca2,3Galb1,4(6-sulfo)GlcNAcb1,3Galb1,4(6-sulfo)
GlcNAcb-O-Me (4) indicated that both of these compounds
were equally active as acceptors for human colon tumour a1,3-
l -fucosyltransferase.
HO
HO
i, ii, iii, iv
12
O
OMe
AcO
NPhth
OAc
19
v
13
20
vi
OAc
O
OR
OR
OAc
O
AcO
AcO
AcO
O
O
O
OMe
NHAc
O
O
AcO
AcO
NHAc
OAc
OAc
21 R = Bn
22 R = H
vii
viii, ix
These investigations were supported by Grant No. CA 63218
awarded by the National Cancer Institute.
3
Scheme 2 Reagents and conditions: i, MeOH–CH2Cl2 (1:1, v/v), MeONa,
0 °C, 2 h, 85%; ii, DMP, PTS, room temp., 1.5 h, 89%; iii, pyridine–Ac2O
(2:1, v/v), room temp., 12 h, 89%; iv, 70% aq. AcOH, 65 °C, 2.5 h, 66%;
v, 13 (0.95 equiv.), NIS (3.0 equiv.)–triflic acid, 220 °C, 1 h, 54%; vi,
EtOH–hydrazine hydrate (4:1, v/v), 100 °C, 16 h, pyridine–Ac2O (2:1,
v/v), room temp., 12 h, 84%; vii, 10% Pd–C, H2, MeOH, 16 h; 50%; viii,
SO3–pyridine complex in DMF (10 equiv.), 0 °C, 16 h; ix, MeOH–MeONa,
16 h; Na+ resin, 35% from 22
Footnote
† Selected data for 1: [a]D 7 (c 1.5, H2O) [lit.,12 212.2 (c 0.5, H2O)]; 13
C
NMR (D2O, 100.6 MHz): d 101.86 (C-1AAA), 101.72 (C-1A), 101.45 (C-1B),
98.81 (C-1), 81.04 (C-3A), 77.49 (C-3AAA), 73.89 (C-4B), 73.85 (C-4), 59.90
(C-6AAA and C-6A), 59.09 (C-6B), 58.85 (C-6), 54.19 (C-2B), 53.99 (C-2). For
2: [a]D +186 (c 0.2, H2O); 1H NMR (D2O, 400 MHz): d 4.84 (d, J = 12 Hz,
20
i
OBn
O
OPiv
O
OBn
O
OPiv
O
HO
HO
HO
O
OMe
O
O
HO
HO
NHAc
NHAc
23
OH
OH
10 ii, iii
OAc
OR
OPiv
OR
OPiv
O
OAc
AcO
CO2Me
O
OAc
O
O
O
O
O
OMe
NHAc
AcO
AcHN
O
O
AcO
AcO
NHAc
OAc
OAc
OAc
24 R = Bn
25 R = H
iv
v, vi
4
Scheme 3 Reagents and conditions: i, EtOH–hydrazine hydrate (9:1, v/v), 80 °C, 1 h, MeOH–Et3N–Ac2O (4:2:1), room temp., 2 h, 65%; ii, 10 (2.50 equiv.),
NIS (3.0 equiv.)–triflic acid, MeCN, 240 °C, 1 h; iii, pyridine–Ac2O (2:1, v/v), room temp., 12 h, 35% based on 23 consumed; iv, 10% Pd–C, H2 MeOH,
24 h; v, SO3–pyridine complex in DMF (10 equiv.), room temp., 2 h; vi, MeOH–MeONa, 48 h; H2O, 4 h, Na+ resin, 56% from 24
Selective sulfation of 18 with SO3–pyridine complex in
pyridine at 5 °C provided the 3-O-sulfo compound which upon
removal of its phthalimido group (MeOH–hydrazine hydrate,
100 °C) and N-acetylation followed by de-O-acetylation
(MeOH–MeONa) gave the known compound 1 (55% from
18).4
A similar NIS–triflic acid reaction of 18 with sialic acid
donor 10 provided the crude pentasaccharide. The conversion of
this intermediate into target compound 2 (23% from 18) was
then carried out in 4 steps: (i) LiI–pyridine (methyl ester to
acid), (ii) MeOH–hydrazine hydrate (phthalimido group re-
moval), (iii) Ac2O–MeOH–CH2Cl2 (N-acetylation) and (iv)
MeOH–MeONa (de-O-acetylation).
H-1B), 4.69 (d, J = 11.0 Hz, H-1), 4.50 (d, J = 8.0 Hz, H-1AAA), 4.41 (d,
J = 8.0 Hz, H-1A), 2.71 (dd, J = 4.6 Hz, H-3BBe), 1.99 and 1.88 (each s,
33NAc), 1.75 (t, J = 1.2 Hz, H-3BBa); 13C NMR: d 101.86 (C-1AAA), 101.73
(C-1A), 101.55 (C-1B), 98.79 (C-1), 81.04 (C-3A), 77.49 (C-3AAA), 74.49
(C-4B), 74.15 (C-4), 61.58 (C-9BB), 59.99 (C-6AAA), 59.91 (C-6A), 59.09
(C-6B), 58.86 (C-6), 54.17 (C- 2B), 53.99 (C-2), 50.68 (C-5B), 38.63
(C-3BB); m/z 1128.5 (M 2 Na)2. For 3: [a]D +21 (c 0.6, H2O); 13C NMR:
d 101.84 (C-1AAA), 101.67 (C-1A), 101.56 (C-1B), 100.94 (C-1), 81.46 (C-3A),
76.88 (C-3AAA), 74.33 (C-4B), 74.05 (C-4), 67.63 (C-6BA), 67.36 (C-6), 60.11
(C-6AAA), 60.02 (C-6A), 56.19 (OMe), 54.15 (C-2B), 53.91 (C-2); m/z 942.9 (M
2 Na)2. For 4: [a]D +24 (c 0.7, H2O); 13C NMR: d 101.84 (C-1AAA), 101.60
(C-1A), 101.15 (C-1B), 100.92 (C-1), 98.73 (C-2BB), 81.50 (C-3A), 76.79
(C-3AAA), 74.29 (C-4B), 74.02 (C-4), 67.29 (C-6B), 67.08 (C-6), 61.52 (C-9BB),
60.01 (C-6A and C-6AAA), 56.17 (OMe), 54.09 (C-2B), 53.06 (C-2), 50.60
(C-5BB), 38.57 (C-3BB).
The synthesis of 3 and 4 (Schemes 2 and 3) involved the
glycosylation of 8 with fluoride 9 under conditions similar to
those described for the preparation of 15 (from 5), followed by
acetylation to give donor 13 along with some 1?3 linked
disaccharide. Condensation of 13 with 19 under NIS–triflic acid
conditions at 220 °C provided 20 in 54% yield. The formation
of 21 from 20 was achieved by the treatment with hydrazine
hydrate in ethanol (1:4, v/v) at 100 °C followed by acetylation
with pyridine–acetic anhydride in 84% yield. The removal of O-
benzyl (10% Pd–C) gave diol 22 which on sulfation with SO3–
pyridine complex in DMF and followed by de-O-acetylation
gave compound 3 in 35% yield (from 22).
References
1 R. K. Jain, R. Vig, R. D. Locke, A. Mohammad and K. L. Matta, J. Chem.
Soc., Chem. Commun., 1996, 65.
2 T. Mukaiyama, Y. Murai and S. Shoda, Chem. Lett., 1981, 431;
T. Mukaiyama, Y. Hashimoto and S. Shoda, Chem. Lett., 1983, 935.
3 G. Catelani, F. Colonna and A. Marra, Carbohydr. Res., 1988, 182,
297.
4 G. V. Reddy, R. K. Jain, R. D. Locke and K. L. Matta, Carbohydr. Res.,
1996, 280, 261.
Received, 5th August 1996; Com. 6/05439K
24
Chem. Commun., 1997