Syntheses of α- and β-glycosyl donors with a disaccharide β-D-Gal-(1→3)-D-GalNAc backbone

Article abstract of DOI:10.1023/A:1020428329743

The synthesis of thioglycoside glycosyl donors with a disaccharide β-D-Gal-(1 → 3)-D-GalNAc backbone was studied using the glycosylation of a series of suitably protected 3-monohydroxy- and 3,4-dihydroxyderivatives of phenyl 2-azido-2-deoxy-1-thio-α- and 1-thio-β -D-galactopyranosides by galactosyl bromide, fluoride, and trichloroacetimidate. In the reaction with the monohydroxylated glycosyl acceptor, the process of intermolecular transfer of thiophenyl group from the glycosyl acceptor onto the cation formed from the molecule of glycosyl donor dominated. When glycosylating 3,4-diol under the same conditions, the product of the thiophenyl group transfer dominated or the undesired (1 → 4), rather than (1 → 3)-linked, disaccharide product formed. The aglycon transfer was excluded when 4-nitrophenylthio group was substituted for phenylthio group in the galactosyl acceptor molecule. This led to the target disaccharide, 4-nitrophenyl 2-azido-4,6-O-benzylidene-2-deoxy-3-O-(2,3,4,6-tetra-O-acetyl-β -D-galactopyranosyl)-1-thio-β-D-galactopyranoside, in 57% yield. This disaccharide product bears nonparticipating azido group in position 2 of galactosamine and can hence be used to form α-glycoside bond. Azido group and the aglycon nitro group were simultaneously reduced in this product and then trichloroacetylated, which led to the β-glycosyl donor, 4-trichloroacetamidophenyl 4,6-di-O-acetyl-2-deoxy-3-O-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl) -1-thio-2-trichloroace-tamido-β-D-galactopyranoside, in 62% yield. The resulting glycosyl donor was used in the synthesis of tetrasaccharide asialo-GM₁.

Full text of DOI:10.1023/A:1020428329743

Russian Journal of Bioorganic Chemistry, Vol. 28, No. 5, 2002, pp. 419–429. Translated from Bioorganicheskaya Khimiya, Vol. 28, No. 5, 2002, pp. 462–473.
Original Russian Text Copyright © 2002 by Cheshev, Kononov, Tsvetkov, Shashkov, Nifantiev.
Syntheses of a- and b-Glycosyl Donors with a Disaccharide
b-D-Gal-(1 3)-D-GalNAc Backbone
1
P. E. Cheshev, L. O. Kononov, Yu. E. Tsvetkov, A. S. Shashkov, and N. E. Nifantiev
Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninskii pr. 47, Moscow, 119991 Russia
Received August 17, 2001; in final form, September 6, 2001
Abstract—The synthesis of thioglycoside glycosyl donors with a disaccharide β-D-Gal-(1
3)-D-GalNAc
backbone was studied using the glycosylation of a series of suitably protected 3-monohydroxy- and 3,4-dihy-
droxyderivatives of phenyl 2-azido-2-deoxy-1-thio-α- and 1-thio-β-D-galactopyranosides by galactosyl bro-
mide, fluoride, and trichloroacetimidate. In the reaction with the monohydroxylated glycosyl acceptor, the pro-
cess of intermolecular transfer of thiophenyl group from the glycosyl acceptor onto the cation formed from the
molecule of glycosyl donor dominated. When glycosylating 3,4-diol under the same conditions, the product of
the thiophenyl group transfer dominated or the undesired (1
4), rather than (1
3)-linked, disaccharide
product formed. The aglycon transfer was excluded when 4-nitrophenylthio group was substituted for phe-
nylthio group in the galactosyl acceptor molecule. This led to the target disaccharide, 4-nitrophenyl 2-azido-
4,6-O-benzylidene-2-deoxy-3-O-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)-1-thio-β-D-galactopyranoside,
in 57% yield. This disaccharide product bears nonparticipating azido group in position 2 of galactosamine and
can hence be used to form α-glycoside bond. Azido group and the aglycon nitro group were simultaneously
reduced in this product and then trichloroacetylated, which led to the β-glycosyl donor, 4-trichloroacetami-
dophenyl 4,6-di-O-acetyl-2-deoxy-3-O-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)-1-thio-2-trichloroace-
tamido-β-D-galactopyranoside, in 62% yield. The resulting glycosyl donor was used in the synthesis of tet-
rasaccharide asialo-GM1.
Key words: aglycon transfer, asialo-GM1, galactosamine, 4-nitrophenyl thiogalactosides, phenyl thiogalacto-
sides
1
INTRODUCTION
Disaccharide β-D-Gal-(1 3)-D-GalNAc is a
participating azido group in position 2 of galac-
tosamine residue, which allows its use as an α-glycosyl
donor. The type (II) glycosyl donor bearing 2-partici-
pating group necessary for the efficient β-glycosylation
can be obtained from (I) by the reduction of the azido
group and the subsequent acylation of the resulting
amine.
2
structural block of many natural glycoconjugates. In
particular, this block is a fragment of the structures of
the group A specific oligosaccharides and of glycolip-
ids of globo and ganglio series when being linked
through α- and β-glycoside bonds, respectively. In the
majority of previous studies devoted to the obtaining of
various oligosaccharides bearing chains of the men-
tioned types [1–3], the synthetic block on the basis of
OAc
OAc
β-D-Gal-(1
3)-D-GalNAc was not used; instead,
OAc
O
OAc
O
galactosamination followed by glycosylation with var-
ious oligosaccharides with the galactose residue on the
reducing end was used.
SArH
O
AcO
AcO
N3
In this work, we consider a possibility of a prepara-
tive synthesis of the selectively protected thioglycoside
α- and β-glycosyl donors (I) and (II) with the β-D-Gal-
I
(I)
(1
3)-D-GalNAc backbone for their subsequent
OAc
OAc
use in the synthesis of oligosaccharide chains of natural
glycoconjugates. The type (I) disaccharide has a non-
OAc
OAc
O
O
SArH
O
AcO
1
Please send correspondence to phone/fax: +7 (095) 135-8784;
AcO
NHC(O)CCl3
e-mail: nen@ioc.ac.ru.
2
Abbreviations: All, allyl; Bn, benzyl; CSA, (±)-camphor-10-sul-
fonic acid; DMAP, 4-dimethylaminopyridine; NIS, N-iodosuc-
cinimide; Np, p-nitrophenyl; and Tf, trifluorometanesulfonyl.
(II)
II
1068-1620/02/2805-0419$27.00 © 2002 MAIK “Nauka /Interperiodica”

420
CHESHEV et al.
OH
HO
OSiButPh2
O
OAc
OAc
O
1, 2
AcO
(III)
(IV)
OAc
OH
OSiButPh2
O
OAc
OAc
O
OAc
O
3
+ (IV)
O
OC(NH)CCl3
AcO
AcO
AcO
AcO
(V)
(VI)
1, MeONa + MeOH; 2, ButPh2SiCl, Et3N, DMF; 3, BF3 · Et2O, CH2Cl2.
Scheme 1.
RESULTS AND DISCUSSION
chemical shift value of H3 was practically unchanged.
The β-configuration of glycoside bond in (VI) was con-
firmed by the characteristic value of spin-spin coupling
constant J1, 2 8.3 Hz.
At present, the most useful and often applied prepar-
ative method for the synthesis of D-galactosamine
derivatives is based on the reaction of azidonitration of
galactal or its derivatives [4]. Two variants of the use of
this method for the obtaining of (1–3)-linked galacto-
sylgalactosamine are possible. The first of them is
based on the azidonitration of galactal and the subse-
quent galactosylation of the azido derivative, and the
second, on the azidonitration of galactosylgalactal [5].
The efficiency of the use of the second approach partic-
ularly depends on the yield in which the stage of obtain-
ing of the target derivative of galactosylgalactal pro-
ceeds.
Next, we studied the approach based on the galacto-
sylation of the 2-azido-2-deoxy-D-galactose deriva-
tives. As the first group of acceptors, we used phenyl
thioglycosides (IX) and (X), which were obtained by
the interaction of azido chloride (VII) with thiophenol
(Scheme 2).
By the action of sodium thiophenolate in anhydrous
THF, β-chloride (VII) [4] was converted into the corre-
sponding phenyl α-thioglycoside (VIII) in 62% yield;
the displacement reaction proceeded stereoselectively
with the inversion of configuration, which was con-
firmed by the characteristic value of spin–spin coupling
constant (J1, 2 = 5.2 Hz) of (VIII). The relatively low
yield could be explained by the concomitant side reac-
tion of the azido group reduction to amino group, which
proceeded under the thiophenol action. The resulting
thioglycoside (VIII) was deacetylated and converted
quantitatively into the benzylidene derivative (IX) and,
then, into 6-O-silylated diol (X) in 91% yield.
In the synthesis of galactosylgalactal, we applied
3,4,5-tri-O-acetyl-D-galactal (III) as the starting com-
pound. Its deacetylation with sodium methylate in
methanol and selective silylation at O6 with tert-butyl-
diphenylsilyl chloride led to the known 3,4-diol (IV)
[6] (yield 80%, Scheme 1). The allyl hydroxyl group at
C3 of galactal is known to be particularly active, and
the glycosylation of 3,4-diols proceed at O3 with a high
regioselectivity. It is also known that, due to the pres-
ence of double bond, the glycosylation of glycals is
very sensitive to the type of the donor and the promo-
tion conditions used and often proceeds in rather low
yields [7]. In our case, the BF3 · Et2O-catalyzed glyco-
An attempt of glycosylating monohydroxyderiva-
tive (IX) with acetobromogalactose (XVII) under the
conditions of Helferich reaction [activation by
sylation of acceptor (IV) with a mixture of α- and β- HgBr2 /Hg(CN)2 salts] in dry acetonitrile led to the
2,3,4,6-tetra-é-acetyl-D-galactopyranosyl trichloroac-
etamidates (V) [8] in dichloromethane (Scheme 1) led
to the target disaccharide (VI) in yield 35%, which does
not allow to consider the approach with the use of this
disaccharide as preparative. The double bond in the
acceptor molecule substantially restricts the possibili-
ties of the further optimization of the disaccharide (VI)
synthesis. The presence of just (1–3)-bond in the disac-
charide (VI) molecule unequivocally followed from a
complete degradation of all the reagents without the
formation of the glycosylation product (Table 1, exper-
iment 1). The reaction in dichloromethane in the pres-
ence of silver triflate (experiment 2) resulted in a com-
plex mixture of substances, which lacked the target gly-
cosylation product and contained phenyl 2,3,4,6-tetra-
O-acetyl-1-thio-β-D-galactopyranoside (XIX) as the
major product (yield 24%); the latter is the product of
the thiophenyl aglycon transfer from the glycosyl
comparison of 1H NMR spectra of (VI) and its O-acetyl acceptor to the cation formed from the glycosyl donor
derivative, in which the resonance of H4 shifted to low molecule. The structure of (XIX) was elucidated by
field by 1.35 ppm (δ 4.15
5.50 ppm), whereas the means of NMR spectroscopy. In particular, the charac-
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 28 No. 5 2002

SYNTHESES OF α- AND β-GLYCOSYL DONOR
421
Ph
O
O
O
HO
OAc
N3
OAc
OAc
O
OAc
O
SPh
(IX)
1
2
AcO
Cl
AcO
N3
OH
HO
OSiButPh2
O
N3
SPh
(VIII)
(VII)
N3
SPh
(X)
5
Ph
O
O
O
HO
OAc
OAc
O
N3
S
NO2
AcO
(XII)
2
N3
S
NO2
OH
HO
OSiButPh2
O
(XI)
N3
S
NO2
(XIII)
Ph
OAc
OAc
OAc
O
OAc
O
O
O
O
AcO
S
NO2
AcO
5
2, 3
N3
N3
S
NO2
HO
Cl
N3
(XV)
(XIV)
(XVI)
1, PhSH/NaH, THF; 2, MeONa, MeOH; 3, PhCH(OMe)2, CSA, CH3CN; 4, ButPh2SiCl, DMAP, Py;
5, Np-SH, Bu4NHSO4, NaHCO3, EtOAc/H2O.
Scheme 2.
teristic spin–spin coupling constant J1, 2 of 10.5 Hz con- mixture was observed when glycosylating acceptor
(IX) in other solvents, under different temperature con-
ditions, or with the use of other glycosylating agents,
including trichloroacetimidate (V) in dichloromethane
under promotion by BF3 · Et2O (Table 1, experiment 3)
and fluoride (XVIII) in toluene under promotion by
AgOTf/SnCl2 (Table 1, experiment 4).
firms its β-configuration.
We could presume that the process of aglycon trans-
fer was brought about by the predominant attack of the
glycosyl cation formed from bromide (XVII) on the
sulfur atom in aglycon rather than on hydroxy group at
C3 [9]. Probably, azido group at C2 decreases the reac-
tivity of hydroxyl at C3, and this becomes lower than
that of the sulfur atom in aglycon.
Our result of glycosylation with galactosyl fluoride
(XVIII) differed from that obtained in [10] where the
A similar pattern with the predominance of (XIX) authors specially claimed that no products of aglycon
rather than the glycosylation products in the reaction transfer arise at the glycosylation of thioglycosides by
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 28 No. 5 2002

422
CHESHEV et al.
Table 1. Results of glycosylation reactions
Experi-
ment no.
Reagents
Promoter
Solvent
Temperature, °C
Product
Yield, %
1
2
(IX) + (XVII)
(IX) + (XVII)
(IX) + (V)
Hg(CN)2/HgBr2
AgOTf
CH3CN
CH2Cl2
CH2Cl2
Toluene
CH2Cl2
Toluene
CH2Cl2
Toluene
CH2Cl2
CH2Cl2
Toluene
20
–
–
–40…–30
–30…–20
10…15
(XIX)
(XIX)
(XIX)
(XXIII)
(XXIII)
(XIX)
(XIX)
(XX)
24
3
BF3 · Et2O
40*
30*
48**
56
4
(IX) + (XVIII) AgOTf/SnCl2
5
(X) + (XVII)
(X) + (XVII)
(X) + (V)
AgOTf
–40…–30
–40…–30
–30…–20
0…10
6
AgOTf
7
BF3 · Et2O
AgOTf/SnCl2
30*
20*
57
8
(X) + (XVIII)
9
(XVI) + (XVII) AgOTf
(XII) + (XVII) AgOTf
(XIII) + (XVII) AgOTf
–30…–20
–30…–20
–30…–20
10
11
(XXI)
(XXIV)
48
37
* An approximate estimate of yield by TLC data.
** Incomplete acceptor conversion; yield is calculated from the reacted acceptor.
glycosyl fluorides. The transfer of thiophenyl aglycon derivative (the spectrum not shown). The resonance of
was previously observed when using 4,6-O-isopropy- H3 is shifted to a low field by 1.1 ppm (δ 3.94
lidene-N-trichloroacetylated derivatives of galac- 4.04 ppm) when going from (XXIII) to its O-acetyl
tosamine; and it was shown [11] that the transfer pro- derivative, whereas the chemical shift of H4 was prac-
cess is characteristic of just glycosyl acceptors with tically unchanged. The (1–4)-linking was also con-
galacto- rather than gluco-configuration.
firmed by a low-field signal from C4 (77.5 ppm) of the
galactosamine residue in the 13C NMR spectrum of dis-
accharide (XXIII) (Table 3).
We could hope that the reactivity of hydroxy group
at C3 would be higher in the case of diol (X) in compar-
ison with monohydroxy derivative (IX); for example, it
would be due to the absence of conformational rigidity
provided with the fused dioxane ring in the benzylidene
derivative (IX). In this case, the use of the more reactive
acceptor (X) might help decrease the yield of the trans-
fer product and provide for efficient glycosylation.
The variation of temperature conditions of the reac-
tion (from –30 to –10°ë) and the use of toluene as the
solvent led only to changes in the conversion degree of
the starting acceptor (X) and in the increased yield of
the isomeric product (XXIII) rather than to the forma-
tion of the target product with the β-(1–3)-bond. At the
same time, the use of the mixture of galactosyl trichlo-
roacetimidates (V) and galactosyl fluoride (XVIII) as
glycosylating agents (Table 1, experiments 7, 8) led
only to the aglycon transfer product (XIX). These
results were difficult to predict, because the equatorial
hydroxy group at C3 is usually more reactive in the
However, the glycosylation of diol (X) with aceto-
bromogalactose (XVII) (Table 1, experiments 5, 6)
resulted in the formation of one disaccharide product,
namely β-(1–4)-linked (XXIII), which is a derivative
of the structural unit of isogangliooligosaccharide
chains. The presence of just (1–4)-bond in (XXIII)
unequivocally followed from a comparison of the H galactosamine derivatives than the axial hydroxy group
NMR spectra of disaccharide (XXIII) and its O-acetyl at C4.
1
N3
R1
OAc
OAc
OR3
OAc
O
OAc
O
OR2
OAc
HO
OAc
O
O
O
R
OR2
AcO
R1
O
AcO
O
AcO
OAc
AcO
N3
AcO
R2
–PhCH–
–PhCH–
R3
R2
TBDPS
TBDPS
R1
β-SC6H4NO2
(XXI) α-SC6H4NO2
R1
(XXIII) α-SPh
(XXIV) α-SC6H4NO2
R
(XX)
α/β-OC(NH)CCl3
α-Br
α-F
(V)
(XVII)
(XVIII)
(XIX) β-SPh
Ac
Ac
(XXII) β-SC6H4NO2
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 28 No. 5 2002

SYNTHESES OF α- AND β-GLYCOSYL DONOR
423
1
Table 2. Parameters of H NMR spectra of (IV), (VI), (IX), (X), (XII), (XIII), (XVI), (XX)–(XXVI), and (XXVIII)
(CDCl3; δ, ppm; J, Hz)
Com- Resi-
H1
H2
H3
H4
H5
H6a H6b J1, 2
J2, 3
J3, 4
J4, 5 J5, 6a J5, 6b J6a, 6b
pound
due
(IV)
*
*
6.37 4.73 4.39 4.15 3.94
6.38 4.58 4.46 4.17 4.00
4.65 5.22 5.05 5.42 3.95
3.90–4.08
3.90–4.05
4.10–4.20
6.2
6.3
8.7
5.5
5.4
5.2
5.5
8.9
9.9
7.9
5.4
7.9
9.2
7.8
5.3
7.9
5.4
7.8
4.6
3.6
3.4
7.7
7.8 11.7
(VI)
Gal
GalN 5.78
GalN 5.72 4.28 3.92 4.27 4.43
10.8
10.4
10.3
(IX)
(X)
3.90–4.30
4.02
3.98–4.11
3.95
2.9
2.4
3.2
4.2
2.9
3.4
3.1
3.5
3.6
3.1
2.6
3.4
2.3
3.4
2.8
1.6
3.0
0.9
4.5
9.3
3.2
4.7 11.0
(XII)** GalN 5.87 4.30 4.11 4.28 3.92
(XIII) GalN 5.90 4.31 3.87 4.23 4.20
(XVI)*** GalN 4.74 3.95 3.92 4.51 3.93
10.0
4.3
4.38
12.4
(XX)
GalN 4.58 3.85 3.57 4.34 4.37 3.55 4.05
10.0
10.3
10.7
10.4
11.0
10.8
10.6
10.4
10.4
10.3
Gal
GalN 6.06 4.68 3.95 4.49
Gal 4.88 5.36 5.10 5.47 4.02
GalN 4.58 3.70 3.67 5.42 3.87 4.09 4.11
4.78 5.24 5.02 5.38 3.92
4.15
6.6
6.7 11.4
(XXI)
(XXII)
4.05–4.32
4.05–4.32
6.4
7.4
6.6
5.7
6.5
6.5
6.1
6.4
6.5
8.1
Gal
(XXIII) GalN 5.67 4.03 3.94 4.09 4.53
Gal
(XXIV) GalN 5.86 4.05 3.88 3.99 4.31
Gal 4.68 5.15 3.98 5.28 3.64 3.64 3.81
GalN 4.94 4.20 5.30 5.40 3.96
(XXVI) GalN 5.26 3.83 4.42 5.48 3.88
4.70 5.15 4.97 5.34 3.90
3.98–4.22
7.3
3.98
5.9
4.78 5.19 5.04 5.34 3.78 3.71 3.96
3.84–3.96
6.9 10.9
6.7
1.5
3.3
6.7 10.4
6.6 11.7
(XXV)
4.10–4.24
4.05–4.20
4.05–4.20
10.3 10.8
10.1 11.7
Gal
(XXVIII) Glc
Gal
4.65 5.07 4.89 5.23 3.85
7.5
7.4
7.8
8.3
7.8
10.5
9.6 10.2
4.46 3.45 3.60 4.03 3.42 3.45 3.67
4.48 3.62 3.45 4.08 3.40
3.70–3.86
4.18–4.29
8.8
2.6
3.1
3.4
GalN 5.10 3.86 4.27 5.45 3.82
Gal
4.55 5.08 4.90 5.37 3.87 4.05 4.25
10.6
Other signals: CH-Ph 5.58–5.78; SPh 7.20–7.60; SPh-NO 7.50–8.15; CH=CH 5.9–6.1; CH=CH 5.3–5.5; SPhNHCOCl 8.4; NHCOCl
3
2
2
2
3
6.8 (J
10 Hz).
NH, 2
* Galactal residue. ** The spectrum was measured in acetone-d . *** The spectrum was measured in CDCl + ~10 vol % of acetone-d .
6
3
6
1
spin coupling constants J1, 2 5.4 and 10 Hz in the H
NMR spectra of (XI) and (XV), respectively (Table 2).
To avoid the undesired process of the aglycon
transfer, we tried to use 4-nitrophenyl analogues (XII),
(XIII), and (XVI) instead of the phenyl thioglycosides.
We might expect that the introduction of electron-with-
drawing nitro group into aglycon could substantially
decrease the nucleophilicity of its sulfur atom and,
thereby, would inhibit the aglycon transfer process [12].
4-Nitrophenyl thioglycosides (XI) and (XV) were
deacetylated and converted into benzylidene deriva-
tives (XII) and (XVI) in the total yields of 72 and 66%,
respectively. In addition, 6-O-silyl derivative (XIII)
was obtained from (XI) in total yield of 90% (Scheme 2).
The target β-(1–3)-linked disaccharide (XX) was
obtained by the glycosylation of p-nitrophenyl β-
thioglycoside (XVI) with acetobromogalactose (XVII)
in dichloromethane in the presence of silver triflate in
yield of 57% (Table 1, experiment 9). The β-configura-
tion of galactose residue was confirmed by the charac-
teristic value of spin–spin coupling constant (J1, 2 7.9
The 4-nitrophenyl thioglycoside acceptors were
obtained from chlorides (VII) and (XIV) [4] (Scheme
1) according to the procedure [13]. Under the condi-
tions of phase-transfer catalysis in the two-phase sys-
tem ethyl acetate–1 M Na2CO3, chlorides (VII) and
(XIV) reacted with p-nitrophenol with the formation of
the corresponding glycosides (XI) and (XV) and the
complete inversion of configuration of the anomeric
1
Hz) in the H NMR spectrum of (XX) (Table 2). The
presence of (1–3)-glycoside bond was confirmed by the
center, which was confirmed by the characteristic spin- low-field chemical shift of C3 in the galactosamine res-
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 28 No. 5 2002

424
CHESHEV et al.
Table 3. Parameters of 13C NMR spectra of (IV), (VI), (IX), (X), (XII), (XIII), (XVI), (XX)–(XXVI), and (XXVIII)
(CDCl3; δ, ppm)
Compound
(IV)
Residue
C1
C2
C3
C4
C5
C6
*
144.4
145.5
98.1
103.3
100.3
71.0
61.0
61.2
60.5
60.8
61.9
60.1
68.8
58.6
67.1
61.6
68.1
61.9
69.6
61.8
69.8
51.3
53.6
68.9
81.7
80.5
55.4
68.6
64.5
68.8
70.7
68.9
70.3
68.8
70.7
70.2
80.3
71.0
77.2
71.2
79.3
70.6
70.6
70.8
71.0
71.0
70.6
74.8
70.8
82.9
81.5
73.5
70.5
65.6
63.8
66.9
74.9
69.9
75.2
69.8
74.4
74.7
67.1
75.4
64.7
68.1
66.7
77.5
66.6
77.8
66.8
66.9
68.9
66.8
76.1
72.5
69.0
66.8
76.4
76.6
73.3
69.2
70.4
69.4
70.8
70.2
70.2
71.0
69.1
71.2
75.6
70.9
72.1
70.4
73.2
70.7
74.8
75.5
71.0
75.0
73.2
71.2
70.8
63.6
62.4
61.1
63.5
64.2
64.4
64.4
69.1
69.0
61.5
68.7
61.5
62.7
61.0
63.6
60.7
64.1
61.0
61.7
62.6
61.1
68.9
68.3
61.0
62.0
(VI)
*
Gal
(IX)
GalN
GalN
GalN
GalN
GalN
GalN
Gal
87.1
(X)
87.5
(XII)**
(XIII)
(XVI)***
(XX)
85.5
85.5
84.6
85.1
102.3
85.8
(XXI)
GalN
Gal
102.3
85.6
(XXII)
(XXIII)
(XXIV)
GalN
Gal
101.4
87.6
GalN
Gal
102.0
85.9
GalN
Gal
102.5
86.5
(XXV)
GalN
GalN
Gal
(XXVI)
85.0
100.6
102.7
102.3
99.3
(XXVIII)
Glc
Gal
GalN
Gal
100.5
Other signals: CH-Ph 100.4–101.2; SPh 127.2–132.3; SPh-NO 123.8–141.5; COCCl 159.5–161.6.
2
3
For footnotes *,**, and ***, see Table 2.
idue (80.3 ppm) in the 13C NMR spectrum of (XX)
(Table 3). The use of toluene instead of dichlo-
romethane resulted in a substantial reduction of the gly-
cosylation product yield.
used for (X). Only the isomeric product of β-(1–4)-
linking (XXIV) was obtained in this case in yield of
37% (Table 1, experiment 11). The characteristic J1, 2
value (7.8 Hz) in the 1H NMR spectrum (Table 2) con-
firmed the β-configuration of galactose residue in
(XXIV), whereas (1–4)-bond followed from the low-
field position of the C4 resonance of galactosamine res-
idue (77.7 ppm) in its 13C NMR spectrum (Table 3).
Therefore, among the studied ways of synthesis of
the type (I) disaccharides, the scheme based on the
reaction (XVI) + (XVII) (Table 1, experiment 9) seems
to be optimal. After the debenzylidenation of disaccha-
ride (XX) and subsequent acetylation, the complete
acetate (XXII) was obtained in the quantitative yield.
This can be used as the α-glycosyl donor for, e.g.,
obtaining the structures related to group-A-specific oli-
gosaccharides.
The galactosylation of p-nitrophenyl α-thioglyco-
side (XII) with bromide (XVII) (experiment 10) led to
48% yield of the corresponding disaccharide (XXI).
The β-configuration of its galactose residue was
deduced from the characteristic spin–spin coupling
1
constant (J1, 2 7.9 Hz) in the H NMR spectrum of
(XXI) (Table 2). The presence of (1–3)-glycoside bond
was confirmed by the low-field chemical shift of C3 in
the galactosamine residue (77.2 ppm) in the 13C NMR
spectrum of (XXI) (Table 3).
The regioselectivity of the glycosylation at O3 and
O4 was comparatively studied in the cases of nitrophe-
nyl thioglycosides of 2-deoxy-2-azidogalactose and
phenyl thioglycoside (X). To this end, diol (XIII), an
Next, for the obtaining of the type (II) β-glycosyl
analogue of (X), was galactosylated with bromide donor, it was necessary to convert the azido group in
(XVII) in toluene under the conditions similar to those disaccharide (XXII) into the participating amide group.
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SYNTHESES OF α- AND β-GLYCOSYL DONOR
425
OAc
OAc
O
1(2), 3
(XV)
S
NHC(O)CCl3
AcO
NHC(O)CCl3
(XXV)
OAc
OAc
OAc
OAc
O
O
2, 3
(XXII)
S
NHC(O)CCl3
O
AcO
AcO
NHC(O)CCl3
(XXVI)
1, SnCl2, EtOH; 2, Zn, HOAc; 3, CCl3COCl, Et3N, CH2Cl2.
Scheme 3.
The nitro group of the aglycon should also be reduced azide and nitro groups to amines was confirmed by the
1
in order to increase the nucleophilicity of the sulfur
atom and, in this manner, enhance the reactivity of the
type (II) glycosyl donor. With this end in view, we stud-
ied various methods of simultaneous reduction of the
aromatic nitro group in aglycon and azido group at C2
in sugar moiety followed by the trichloroacetylation of
the two resulting amine groups. The conditions of these
reactions were chosen when applying monosaccharide
(XV) as the substrate (Scheme 3). The presence of a
sulfur atom in (XV) and (XXII) precludes the use of
catalytic hydrogenation for the reduction of the aro-
matic nitro and aliphatic azido groups. Of the other
available approaches to the reduction of these groups,
we chose and studied the following systems: a saturated
solution of hydrogen sulfide in aqueous pyridine [14], a
solution of sodium sulfide in methanol [15], a suspen-
sion of nickel boride in a borate buffer [16], tin(II) chlo-
ride [12, 17], tin(II) chloride/sodium borohydride [18],
and zinc in acetic acid [19].
presence in the H NMR spectrum of disaccharide
(XXVI) of the resonances of NH of aliphatic (6.8 ppm,
d, JNH, 2 10 Hz) and aromatic (8.4 ppm, s) amide groups
(Table 2).
An efficient use of the disaccharide donor (XXVI)
was demonstrated by the example of glycosylation of
the known [20] acceptor (XXVII): an asialo-GM1 tet-
rasaccharide derivative (XXVIII), was obtained in 67%
yield (Scheme 4). The β-configuration of galac-
tosamine residue in (XXVIII) was confirmed by a char-
acteristic spin–spin coupling constant (J1, 2 = 8.3 Hz)
for H1 of GalN residue in 1H NMR spectrum (Table 2).
The presence of (1–3)-glycoside bond between the
galactosamine residue and the galactose residue in the
acceptor lactose block followed from the low-field shift
of the C3 resonance (81.5 ppm) of the galactose residue
in the 13C NMR spectrum of tetrasaccharide (XXVIII)
(Table 3).
Thus, a preparative method of the synthesis of α-
and β-glycosyl donors on the basis of disaccharide
According to TLC data, the reduction by hydrogen
or sodium sulfide, as well as with a nickel boride sus-
pension resulted in complex mixtures, which were not
studied further. The use of tin(II) chloride and the sub-
sequent trichloroacetylation of intermediate diamine
resulted in the target product (XXV) in 44% yield. The
reduction of the azido and nitro groups to amines was
confirmed by the presence in the 1H NMR spectrum of
amide (XXV) of the resonances of NH of aliphatic
(6.8 ppm, d, JNH, 2 10 Hz) and aromatic (8.4 ppm, s)
amide groups (Table 2). The use of the tin(II) chlo-
ride/sodium borohydride system did not result in any
substantial changes in the reaction pattern (TLC data).
The most successful was the reduction by zinc in acetic
acid: in this case, the yield of the target product was
62%.
β-D-Gal-(1
3)-D-GalNAc was developed. The
efficiency of using the β-glycosyl donor in the prepara-
tion of oligosaccharide chains of natural glycoconju-
gates was demonstrated by the example of the synthesis
of the carbohydrate chain of the asialo-GM1 ganglio-
side derivative.
EXPERIMENTAL
The purification procedures for solvents and
reagents and the measurement conditions of the NMR
spectra and physicochemical constants are given in
[21]. The 1H and 13C NMR spectra were registered on a
Bruker DRX-500 or a Bruker AM-300 instrument at
The required β-glycosyl donor (XXVI) was 25°ë. The optical rotation was measured on a digital
obtained in a total yield of 61% when using the reduc- polarimeter Jasco DIP-360 at 18–25°ë. For TLC, the
tion of disaccharide (XXII) with zinc in acetic acid, fol- precoated plates with Kieselgel-60 (Merck) were used;
lowed by N-acylation (Scheme 3). The reduction of the the substances were detected by spraying with 10 vol %
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 28 No. 5 2002

426
CHESHEV et al.
OH
OBn
OBn
O
O
O
OAll
BnO
BnO
BnO
(XXVI)
BnO
(XXVII)
NIS/TfOH, CH2Cl2
OAc
OAc
OAc
O
OAc
O
O
O
AcO
AcO
NHC(O)CCl3
BnO
OBn
O
OBn
O
O
OAll
BnO
BnO
BnO
(XXVIII)
Scheme 4.
of orthophosphoric acid in ethanol or, for amines, by a 10 : 1), and disaccharide (VI) was isolated; white foam;
ninhydrin solution (3 g/l in a 30 : 1 butanol–acetic acid yield 97 mg (35%); Rf 0.31 (10 : 1 dichloromethane–
mixture, followed by heating at ~150°ë. For column
chromatography, Silica gel 60 (0.063–0.2 mm, Fluka)
or Silasorb 600 (20 µm, Chemapol) was used.
diethyl ether); [α]D +57.5° (c 2, CHCl3).
Phenyl
2-azido-3,4,6-tri-O-acetyl-2-deoxy-1-
thio-a-D-galactopyranoside (VIII). Thiophenol
(968 µl, 23.74 mmol) was slowly added dropwise to a
intensively stirred cooled to –10°ë suspension of
sodium hydride (343 mg, 8.58 mmol of 60% suspen-
sion in an oil) in dry THF (15 ml) under argon. After a
gas evolution ceased, the reaction mixture was a white
suspension. It was heated to +5°ë, and (VII) [4] (1 g,
2.86 mmol) was then added to it. The mixture was
stirred for 16 h at this temperature, diluted with dichlo-
romethane (200 ml), and washed with a saturated
NaHCO3 solution (2 × 250 ml). The organic phase was
evaporated and filtered through a silica gel layer. The
unreacted thiophenol was eluted with dichloromethane,
and the reaction products, with a 10 : 1 dichlo-
romethane–diethyl ether mixture. Thioglycoside (VIII)
was obtained as white foam; yield 750 mg (62%); Rf
0.62 (10 : 1 dichloromethane–diethyl ether); it was fur-
ther used without any additional purification.
1,5-Anhydro-6-O-(tert-butyl)diphenylsilyl-2-deoxy-
D-lyxo-hex-1-enitol (IV). DMAP (5 mg) was added to
a stirred and cooled to 0°ë solution of galactal (III) [4]
(420 mg, 2.9 mmol), ButPh2SiCl (Fluka, 736 µl,
2.9 mmol), and triethylamine (808 µl, 5.8 mmol) in dry
DMF. The reaction mixture was stirred for 16 h at
20°ë, diluted with ethyl acetate (150 ml), washed with
water (200 ml), and evaporated. A flash chromatogra-
phy of the residue (10 : 1 dichloromethane–diethyl
ether) afforded diol (IV); yield 883 mg (80%), white
foam; Rf 0.52 (10 : 1 dichloromethane–diethyl ether);
[α]D +50.9° (c 2.2, CHCl3).
1,5-Anhydro-6-O-(tert-butyl)diphenylsilyl-2-deoxy-
3-O-2,3,4,6-tetra-O-acetyl-b-D-galactopyranosyl)-D-
lyxo-hex-1-enitol (VI). A solution of glycosyl acceptor
(IV) (150 mg, 0.39 mmol) and trichloroacetimidate (V)
[8] (202 mg, (0.41 mmol) in anhydrous dichlo-
romethane (3 ml) was stirred under argon with the pre-
liminarily heated molecular sieves MS-4 Å (200 mg)
for 1 h at 20°ë. The reaction mixture was then cooled
to –80°ë, treated with BF3 · Et2O (3 µl, and, after
30 min, with a saturated solution of NaHCO3 (2 ml).
The mixture was diluted with dichloromethane (50 ml)
and washed with a solution of NaHCO3 (100 ml). The
Phenyl
2-azido-4,6-O-benzylidene-2-deoxy-1-
thio-a-D-galactopyranoside (IX). A solution of
(VIII) (180 mg, 0.46 mmol) in absolute methanol
(4 ml) was deacetylated with 0.1 ml of 1 M MeONa
solution in methanol. After 20 min, the solution was
neutralized with cation-exchange resin KU-2 (ç+), the
resin was filtered off, washed with methanol, and fil-
trate was evaporated. The resulting crystalline deacety-
organic phase was evaporated, chromatographed in a lated product was coevaporated with toluene (to
dichloromethane–diethyl ether gradient (from 20 : 1 to remove methanol), dried in a vacuum of an oil pump,
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SYNTHESES OF α- AND β-GLYCOSYL DONOR
427
and used in the reaction of benzylidenation with α,α- romethane–diethyl ether); white foam; yield 76 mg
dimethoxytoluene (105 µl) and CSA (5 mg) in dry ace- (90%); Rf 0.37 (3 : 1 toluene–ethyl acetate); [α]D
tonitrile (5 ml) without additional treatment. The reac-
tion mixture was kept for 16 h at 20°ë, neutralized with
triethylamine, and evaporated. After a chromatography
(3 : 1 toluene–ethyl acetate mixture), (IX) was obtained
as a white foam; yield 170 mg (quantitative); Rf 0.54
(3 : 1 toluene–ethyl acetate); [α]D +134.9° (c 0.5, CHCl3).
+149.8° (c 2, CHCl3).
4-Nitrophenyl
2-azido-4,6-O-benzylidene-2-
deoxy-1-thio-b-D-galactopyranoside (XVI). Under
the conditions similar to those used for the synthesis of
(XII), crude (XIV) (105 mg) was obtained from (XIV)
[4] (86 mg, 0.25 mmol), p-nitrothiophenol (114 mg,
0.74 mmol), and Bu4NHSO4 (70 mg, 0.25 mmol) in
2 ml of ethyl acetate and 2 ml of 1 M Na2CO3. (XV)
was then deacetylated and benzylidenated as described
above to give (XVI); white foam; yield 70 mg (66%);
Rf 0.37 (10 : 1 dichloromethane–diethyl ether); [α]D –
24.2° (c 2, CHCl3).
Phenyl 2-azido-5-O-(tert-butyl)diphenylsilyl-2-
deoxy-1-thio-a-D-galactopyranoside (X). A solution
of (VIII) (750 mg, 1.92 mmol) in absolute methanol
(10 ml) was deacetylated with 0.2 ml of 1 M solution of
MeONa in methanol and then treated as described
above. Without any additional treatment, the resulting
product of deacetylation was dissolved in dry pyridine
(10 ml) and treated with ButPh2SiCl (748 µl, 2.9 mmol,
Fluka) and then with DMAP (5 mg). The reaction mix-
ture was kept for 18 h at 20°ë, evaporated, and coevap-
orated several times with toluene to remove pyridine
traces (odor). After the flash chromatography (10 : 1
dichloromethane–diethyl ether), diol (X) was obtained
as a white foam; yield 867 mg (91%); Rf 0.50 (3 : 1 tol-
uene–ethyl acetate); [α]D +127.8° (c 2, CHCl3).
General glycosylation procedure for obtaining
disaccharides (XX), (XXI), (XXIII), and (XXIV). A
mixture of acetobromogalactose and glycosyl acceptor
was trice coevaporated with toluene to remove water
traces, dissolved in freshly distilled dry dichlo-
romethane or toluene (see Table 1) under argon, and
transferred by argon pressure to the reaction flask con-
taining the preliminarily heated molecular sieves MS-
4 Å. The reaction mixture was stirred for 2–14 h at
20°ë, cooled to –40°ë, and treated with silver triflate.
The glycosylation was carried out within the tempera-
ture range from –40 to –20°ë in dependence on the
type of glycosyl donor and glycosyl acceptor (see Table
1), monitoring the reaction course by TLC. When glyc-
osyl acceptor was completely consumed, a saturated
solution of sodium bicarbonate (1–2 ml) and 2 M
sodium thiosulfate (1–2 ml) were added, the reaction
mixture was heated to 20°ë, diluted with dichlo-
romethane, and filtered through a layer of Celite. The
filtrate was washed with a saturated solution of sodium
bicarbonate, the aqueous phase was extracted with
dichloromethane, and the organic layers were com-
bined and evaporated. The reaction products were iso-
lated by column chromatography.
4-Nitrophenyl
2-azido-4,6-O-benzylidene-2-
deoxy-1-thio-a-D-galactopyranoside (XII). Two ml
of 1 M Na2CO3 were added to a solution of (VII)
(100 mg, 0.29 mmol), p-nitrothiophenol (133 mg,
0.86 mmol), and Bu4NHSO4 (97 mg, 0.29 mmol) in
ethyl acetate (2 ml). The reaction mixture was stirred at
40°ë for 5 h (until the disappearance of the starting
chloride monitored by TLC in a 10 : 1 dichlo-
romethane–diethyl ether mixture). The reaction mix-
ture was then diluted with ethyl acetate (100 ml),
washed with a saturated solution of NaHCO3 (2 ×
100 ml), filtered through a layer of cotton wool, and
evaporated. The residue was filtered through a layer of
silica gel, unreacted p-nitrophenol was eluted with 10 : 1
toluene–ethyl acetate mixture, and the product with 3 : 1
toluene–ethyl acetate mixture. Crude glycoside (XI)
(123 mg) was obtained; it was deacetylated and treated
as described above for (IX). The resulting triol was
benzylidenated without any additional purification with
α,α-dimethoxytoluene (60 µl) and CSA (5mg) in dry
acetonitrile (3 ml), and the reaction mixture was treated
as described above for (IX). After chromatography (3 : 1
toluene–ethyl acetate), (XII) was obtained; white foam;
yield 88 mg (72%); Rf 0.44 (10 : 1 dichloromethane–
diethyl ether); [α]D +134.9° (c 2, CHCl3).
4-Nitrophenyl
2-azido-4,6-O-benzylidene-2-
deoxy-3-O-(2,3,4,6-tetra-O-acetyl-b-D-galactopyra-
nosyl)-1-thio-b-D-galactopyranoside (XX). The
reaction of glycosyl acceptor (XVI) (200 mg,
0.47 mmol) and acetobromogalactose (XVII) (230 mg,
0.56 mmol) was promoted by silver triflate (173 mg,
0.67 mmol). Upon completion of the reaction (2.5 h),
the mixture was subjected to the standard treatment and
chromatography in 20 : 1 to 10 : 1 gradient of dichlo-
romethane in diethyl ether to give (XX); white foam;
yield 201 mg (57%), Rf 0.33 (10 : 1 dichloromethane–
diethyl ether); [α]D –48.0° (c 2, CHCl3).
4-Nitrophenyl 2-azido-6-O-(tert-butyl)diphenyl-
silyl-2-deoxy-1-thio-a-D-galactopyranoside (XIII).
Thioglycoside (XI) (50 mg, 0.15 mmol) in absolute
methanol (2 ml) was deacetylated with 0.05 ml of 1 M
solution of MeONa in methanol and then, without addi-
tional purification, silylated in 2 ml of dry pyridine with
ButPh2SiCl (62 µl, 0.22 mmol) and DMAP (1 mg) for
4-Nitrophenyl
2-azido-4,6-O-benzylidene-2-
deoxy-3-O-(2,3,4,6-tetra-O-acetyl-b-D-galactopyra-
nosyl)-1-thio-a-D-galactopyranoside (XXI). The
reaction of glycosyl acceptor (XII) (100 mg,
0.23 mmol) and acetobromogalactose (XVII) (115 mg,
0.28 mmol) was promoted by silver triflate (86 mg,
16 h at 20°ë as described above. Diol (XIII) was iso- 0.34 mmol). Upon completion of the reaction (2 h), the
lated by flash chromatography (10 : 1 dichlo- mixture was subjected to the standard treatment and
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 28 No. 5 2002

428
CHESHEV et al.
chromatography in 20 : 1 to 10 : 1 gradient of dichlo- romethane (3 ml), and the solution was dropwise
romethane in diethyl ether to give (XXI); white foam; treated with trichloroacetic anhydride (380 µl,
yield 85 mg (48%), Rf 0.57 (10 : 1 dichloromethane– 2.07 mmol) under stirring on an ice–water bath. After
20 min, methanol (1 ml) was added to the reaction mix-
ture; it was diluted with dichloromethane (100 ml) and
washed with a saturated soda solution (100 ml). The
aqueous phase was extracted with dichloromethane
(2 × 30 ml) and the extracts were combined and evapo-
rated. The residue was separated with column chroma-
tography in 3 : 1 toluene–ethyl acetate system to give
(XXV); while foam; yield 106 mg (44%); Rf 0.40 (2 : 1
toluene–ethyl acetate).
diethyl ether); [α]D +57.9° (c 0.5, CHCl3).
Phenyl 2-azido-6-O-(tert-butyl)diphenylsilyl-2-
deoxy-4-O-(2,3,4,6-tetra-O-acetyl-b-D-galactopyra-
nosyl)-1-thio-a-D-galactopyranoside (XXIII). The
reaction of glycosyl acceptor (X) (150 mg, 0.3 mmol)
and acetobromogalactose (XVII) (140 mg, 0.34 mmol)
was promoted by silver triflate (105 mg, 0.4 mmol).
Upon completion of the reaction (1.5 h), the mixture
was subjected to the standard treatment and chromatog-
raphy in 3 : 1 toluene–ethyl acetate system to give
(XXIII); white foam; yield 138 mg (56%), Rf 0.40 (3 : 1
toluene–ethyl acetate); [α]D +99.8° (c 2, CHCl3).
4-Nitrophenyl 2-azido-6-O-(tert-butyl)diphenyl-
silyl-2-deoxy-3-O-(2,3,4,6-tetra-O-acetyl-b-D-galac-
topyranosyl)-1-thio-a-D-galactopyranoside (XXIV).
The reaction of glycosyl acceptor (XIII) (76 mg,
0.13 mmol) and acetobromogalactose (XVII) (65 mg,
0.16 mmol) was promoted by silver triflate (49 mg,
0.19 mmol). Upon completion of the reaction (2 h), the
mixture was subjected to the standard treatment and
chromatography in 7 : 1 to 5 : 1 toluene–ethyl acetate
gradient to give (XXIV); white foam; yield 44 mg
(37%), Rf 0.40 (9 : 4 toluene–ethyl acetate); [α]D
+108.4° (c 2, CHCl3).
4-Nitrophenyl 2-azido-4,6-di-O-acetyl-2-deoxy-
3-O-(2,3,4,6-tetra-O-acetyl-b-D-galactopyranosyl)-
1-thio-b-D-galactopyranoside (XXII). A solution of
(XX) (100 mg, 0.13 mmol) in 90% acetic acid (3 ml)
was kept for 3 h at 80°ë. The reaction mixture was
cooled to 20°ë, evaporated, and coevaporated with tol-
uene to remove the acetic acid odor. The residue was
dissolved in dry pyridine (2 ml) and treated dropwise
with acetic anhydride (1 ml). The reaction mixture was
kept for 18 h at 20°ë, treated with methanol, evapo-
rated, and many times coevaporated with toluene to
remove the pyridine odor. After flash chromatography
(5 : 1 dichloromethane–diethyl ether), per-O-acetyl
derivative (XXII) was obtained; white foam; yield
99 mg (100%), Rf 0.38 (5 : 1 dichloromethane–diethyl
ether); [α]D +10.9° (c 2, CHCl3).
Method b. A solution of (XV) (190 mg, 0.41 mmol)
in THF (4 ml) was successively treated under intensive
stirring with drops of acetic acid (1.2 ml) and with zinc
dust (2.6 g). The reaction mixture was stirred 16 h at
20°ë and filtered through Celite. Filtrate was diluted
with dichloromethane (75 ml) and washed with a satu-
rated solution of sodium bicarbonate (100 ml) until gas
evolution ceased. The aqueous layer was extracted with
dichloromethane (2 × 20 ml), and the organic layers
were combined and evaporated. The residue was twice
coevaporated with toluene, dried in an oil pump vac-
uum, dissolved in dry dichloromethane (3 ml), and
treated with triethylamine (290 µl) and, under stirring
on an ice bath and dropwise, with trichloroacetyl chlo-
ride (115 µl). After 20 min, methanol (1 ml) was added
to the reaction mixture; it was diluted with dichlo-
romethane (70 ml), washed with a saturated solution of
sodium bicarbonate (100 ml), and evaporated. (XXV)
was isolated from the residue by column chromatogra-
phy in 10 : 1 dichloromethane–diethyl ether system;
white foam; yield 177 mg (62%); Rf 0.54 (10 : 1 dichlo-
romethane–diethyl ether); [α]D –15.5° (c 1, CHCl3).
4-Trichloroacetamidophenyl 2-deoxy-4,6-di-O-
acetyl-3-O-(2,3,4,6-tetra-O-acetyl-b-D-galactopyra-
nosyl)-1-thio-2-trichloroacetamido-b-D-galactopy-
ranoside (XXVI). Acetic acid (0.75 ml) and, gradually,
zinc dust (1.7 g) were added under intensive stirring to
a solution of (XXII) (198 mg, 0.26 mmol) in THF
(4 ml). The reaction mixture was stirred overnight at
20°ë and filtered through a layer of Celite. The filtrate
was diluted with dichloromethane (150 ml) and washed
4-Trichloroacetamidophenyl 2-deoxy-3,4,6-tri- with a saturated soda solution (200 ml) until gas evolu-
O-acetyl-1-thio-2-trichloroacetamido-b-D-galacto- tion ceased. The aqueous layer was reextracted with
pyranoside (XXV). Method a. Tin(II) chloride dihy- dichloromethane (2 × 50 ml), and extracts were com-
drate (463 mg, 2.05 mmol) was gradually added under bined and evaporated. The residue was twice coevapo-
intensive stirring to a solution of (XV) (160 mg, rated with toluene, dried in an oil pump vacuum, and
0.34 mmol) in ethanol preliminarily dried by azeotro- dissolved in dry dichloromethane (4 ml). Triethylamine
pic distillation with benzene. The reaction mixture was (220 µl) and, under stirring on an ice bath and drop-
heated to 40°ë, stirred for 2 h at this temperature, wise, trichloroacetyl chloride (88 µl) were added. After
diluted with dichloromethane (100 ml), and washed 20 min, methanol (1 ml) was added to the reaction mix-
with a saturated solution of soda (100 ml). The organic ture; it was diluted with dichloromethane (150 ml),
phase was separated, and the aqueous phase was washed with a saturated solution of sodium bicarbonate
extracted with dichloromethane (2 × 30 ml). The (200 ml), and evaporated. The aqueous layer was
organic phase and extracts were combined, evaporated, extracted with dichloromethane (2 × 50 ml), and
trice coevaporated with toluene, and dried in a vacuum extracts were combined and evaporated. (XXVI) was
of an oil pump. The residue dissolved in dry dichlo- isolated from the residue by column chromatography in
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SYNTHESES OF α- AND β-GLYCOSYL DONOR
429
4. Lemieux, R.U. and Ratcliffe, R.M., Can. J. Chem., 1979,
10 : 3 dichloromethane–diethyl ether system; white
foam; yield 160 mg (62%); Rf 0.37 (10 : 3 dichlo-
romethane–diethyl ether); [α]D +11.3° (c 2, CHCl3).
vol. 57, pp. 1244–1251.
5. Look, G.C., Ichijawa, Y., Shen, G.-J., Cheng, P.-W., and
Wong, C.-H., J. Org. Chem., 1993, vol. 58, pp. 4326–
4330.
6. Koseki, K., Griffith, D.A., and Danishefsky, S.J., J. Am.
Chem. Soc., 1992, vol. 114, pp. 8331–8333.
7. Danishefsky, S.J., Gervay, J., Peterson, J.M.,
McDonald, F.E., Koseki, K., Griffith, D.A., Oriyama, T.,
and Marsden, S.P., J. Am. Chem. Soc., 1995, vol. 117,
pp. 1940–1953.
Allyl O-(2,3,4,6-tetra-O-acetyl–b-D-galactopyra-
nosyl)-(1–3)-O-(4,6-di-O-acetyl-2-deoxy-2-trichlo-
roacetamido-b-D-galactopyranosyl)-(1–4)-O-(2,3,6-
tri-O-benzyl-b-D-galactopyranosyl)-(1–4)-
2,3,6-
tri-O-benzyl-b-D-galactopyranoside (XXVIII). A
solution of (XXVII) [17] (100 mg, 0.108 mmol) and
(XXVI) (79 mg, 0.08 mmol) in anhydrous dichlo-
romethane (3 ml) was stirred under argon with the pre-
liminarily heated molecular sieves MS-4 Å (200 mg)
for 2 h at 20°ë. N-Iodosuccinimide (27 mg) was then
added, and the mixture was stirred for additional
15 min at 20°ë. The reaction mixture was cooled to
−30°ë, treated with 5% solution of TfOH in dichlo-
romethane (50 µl and, after 30 min, 150 µl), and stirred
for 1.5 h at –30 to –20°ë. A saturated solution of
sodium bicarbonate (1 ml) was added, the mixture was
filtered through a Celite layer, and the filtrate was
diluted with dichloromethane (100 ml) and washed
with NaHCO3 solution (100 ml). The organic phase was
evaporated, and the residue was separated by column
chromatography in 10 : 1 to 5: 1 gradient of dichlo-
romethane in diethyl ether to give white foam of
(XXVIII); yield 90 mg (67%); Rf 0.34 (5 : 1 dichlo-
romethane–diethyl ether); [α]D +10.6° (c 2, CHCl3).
8. Schmidt, R.R. and Stumpp, M., Liebigs Ann. Chem.,
1983, pp. 1249–1256.
9. Nilsson, S., Lohn, H., and Norberg, T., Glycoconjugate
J., 1991, vol. 8, p. 9.
10. Nicolaou, K.C. and Ueno, H., Preparative Carbohydrate
Chemistry, Hanessian, S., Ed., Marcel Dekker Inc.,
1997, pp. 313–338.
11. Belot, F. and Jaquinet, J.-C., Carbohydr. Res., 1996,
vol. 290, pp. 79–86.
12. Cao, S., Hernandes-Mateo, F., and Roy, R., Carbohydr.
Chem., 1998, vol. 17, pp. 609–631.
13. Kim, J.M. and Roy, R., Carbohydr. Chem., 1997, vol. 16,
pp. 1281–1292.
14. Adachi, T., Yoshihisa, Y., and Ichizo, I., Synthesis, 1977,
pp. 45–46.
15. Belinka, B.A. and Hassner, A., J. Org. Chem., 1979,
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ACKNOWLEDGMENTS
This work was supported by Russian Foundation
for Basic Research, project nos. 99-03-33047a and
00-03-32815a.
17. Bellamy, F.D. and Ou, K., Tetrahedron Lett., 1984,
vol. 25, pp. 839–842.
18. Satoh, T., Mitsuo, N., Nishiki, M., Inoue,Y., and Ooi,Y.,
Chem. Pharm. Bull., 1981, vol. 29, pp. 1443–1445.
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