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saccharide acceptor 9 by using two different sialyl donors: C5À which possessed two hydroxy groups at the 3- and 4-positions
[
8b,9]
NHAc sialic acid donor 7 and C5Àazide donor 8.
Sialylation
of glucosamine, was also prepared by cleavage of the Fmoc
group of compound 25.
with C5ÀNHAc donor 7 afforded compound 2 in 64% yield,
with an a/b selectivity of 2:1. On the other hand, C5Àazide
donor 8 showed higher reactivity: Sialylation of compound 9
with azidosialic acid donor 8 gave compound 3 in improved
yield (90%), with lower a-selectivity (a/b=1.5:1) compared
with the reaction with C5ÀNHAc sialic acid donor 7. Separation
of the a and b isomers by column chromatography on silica
gel was difficult; therefore, we explored a more-efficient
method of synthesizing the tetrasaccharide.
With the donors and acceptors in hand, we next investigat-
ed the synthesis of the tetrasaccharide (Table 1). Glycosylation
of C5’ÀNHAc donor 12 and acceptor 15 did not proceed at all
(Table 1, entry 1). Glycosylation of compound 12 with the less-
hindered C2ÀNHAc acceptor 27 yielded the desired tetrasac-
charide (29) in low yield (Table 1, entry 2), whereas the reaction
of compound 12 with 3,4-di-OH acceptor 28 only gave trace
amounts of tetrasaccharide 30 (Table 1, entry 3). On the other
hand, the glycosylation reaction between C5Àazide sialylated
disaccharide donor 13 and acceptor 16 provided the desired
product (5) in 50% yield (Table 1, entry 4). However, this yield
was unsatisfactory, and the preparation of C5Àazide sialic acid
Next, we investigated the “[2+2]” pathway, in which the tet-
rasaccharide structure was constructed through a glycosylation
reaction between disaccharides Sia(a2,3)Gal and Sia(a2,6)Glc-
NAc. First, a-sialylation of 2-O-benzoyl-6-O-benzyl galactose de-
rivative 21 was performed by using the C5ÀNHAc and the C5À required several reaction steps. Thus, we investigated a simpler
[8b,9]
azide sialyl trifluoroacetimidates (7 and 8) as donors.
Thus,
and more-efficient route to the tetrasaccharide.
the desired disaccharides (22 and 23) were obtained in satis-
factory yields and excellent selectivities (compound 22: 86%
yield, a only; 23: quantitative yield, a/b=19:1; Scheme 3).
Thus, galactose acceptor 21 showed higher reactivity than 2,6-
di-O-benzoylated acceptor 18. Disaccharides 22 and 23 were
converted into donors 12 and 13, respectively.
These results revealed that modifying the C5-nitrogen atom
of the sialic acid dramatically affected the outcome of the gly-
cosylation reaction between the sialylated saccharides. It is
possible that the hydrogen-bonding network that was formed
by the C5ÀNHAc moieties of sialic acid decreased their reactivi-
ty. Although these hydrogen-bonding effects were reported by
[
12]
For the synthesis of the sialyl glucosamine unit, sialylation
Kononov et al. to be essential for the sialylation reaction to
with glucosamine acceptor 24 was performed by using C5À proceed, the authors did not report that a hydrogen bond in-
NHAc and C5Àazide sialyl donors 7 and 8 to afford sialylated
disaccharides 25 and 26, respectively, in good yields and selec-
tivities (compound 25: 95% yield, a only; compound 26: 89%
yield, a/b=10:1). After protecting the C4 position of glucosa-
mine, the fluorenylmethyloxycarbonyl (Fmoc) group was
cleaved to give disaccharide acceptors 15 and 16. C2ÀNHAc
acceptor 27 was prepared from compound 25 to decrease the
steric hindrance introduced by the 2,2,2-trichlorethoxycarbonyl
volving NHAc, some distance from the reactive site, also affect-
ed the outcome of the glycosylation reaction. In view of these
considerations, we investigated a synthesis of the tetrasacchar-
ide through glycosylation of the N,N-diacetyl sialyl disaccharide
donor (14) and acceptor (17; Scheme 4). Compounds 14 and
17 were readily prepared from compounds 19 and 25, respec-
tively, as described below: After the acetylation of compound
19 by using isopropenyl acetate and catalytic amounts of p-
[
11a]
(
Troc) group at the C2 position of glucosamine. Acceptor 28,
TsOH·H O,
(N-phenyl)trifluoroacetimidate was introduced to
2
Scheme 3. Synthesis of the sialylated disaccharide; reagents and conditions: a) compound 7 or 8, TMSOTf, EtCN, À788C, 4 molecular sieves (compound 22:
6% yield, a only; compound 23: quantitative yield, a/b=19:1; compound 25: 95% yield, a only; compound 26: 89% yield, a/b=10:1); b) Ac O, pyridine;
c) (1,5-cyclooctadiene)bis(methyldiphenylphosphine)iridium(I)PF , H , THF, water, I ; d) N-phenyltrifluoroacetimidoyl chloride, K CO , acetone (compound 12:
quantitative yield in three steps; compound 13: 84% yield in three steps); e) 15% Et N, CH Cl (compound 15: 83% yield in two steps; compound 16: 83%
8
2
6
2
2
2
3
3
2
2
yield in two steps; compound 27: 84% yield in three steps; compound 28: 98% yield); f) zinc–copper couple, 1,4-dioxane, acetic acid. Ac
dride, Bn=benzyl.
2
O=acetic anhy-
Chem. Asian J. 2016, 11, 1436 – 1440
1438
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