Rearrangement of 1-O-(thio-p-nitrobenzoyl)thiocarbonyl galactoside: A novel access to α-thioglycoside derivatives

Article abstract of DOI:10.1016/S0040-4039(01)02122-0

The synthesis of galactosides thiolate and thioester is described by direct S-glycosylation process from 1-O-(thio-p-nitrobenzoyl)thiocarbonyl galactoside. Three novel anomeric groups are presented as potent glycoside activators: O-(thio-p-nitrobenzoyl)th

Full text of DOI:10.1016/S0040-4039(01)02122-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 237–239
Rearrangement of 1-O-(thio-p-nitrobenzoyl)thiocarbonyl
galactoside: a novel access to a-thioglycoside derivatives
Solen Josse,a Julien Le Gal,a Muriel Pipelier,a Jeannine Cle´ophax,b Alain Olesker,b
Jean-Paul Prade`rea and Didier Dubreuila,*
aLaboratoire de Synthe`se Organique associe´ au CNRS, UMR 6513, Faculte´ des Sciences et des Techniques,
2, rue de la Houssinie`re, BP 92208, F-44322 Nantes Cedex 3, France
bInstitut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, F-91198 Gif-sur-Yvette, France
Received 8 October 2001; accepted 8 November 2001
Abstract—The synthesis of galactosides thiolate and thioester is described by direct S-glycosylation process from 1-O-(thio-p-
nitrobenzoyl)thiocarbonyl galactoside. Three novel anomeric groups are presented as potent glycoside activators: O-(thio-p-
nitrobenzoyl)thiocarbonyl, O-(imidazolyl)thiocarbonyl and S-thio-p-nitrobenzoyl. © 2002 Elsevier Science Ltd. All rights
reserved.
The diastereoselective synthesis of thioglycosides is an
important goal not only because they are the most
commonly used shelf-stable glycoside donors1 but also
they have shown significant potential as competitive
inhibitors of oligosaccharide processing enzymes.2
Thus, several reports have highlighted a renewed inter-
est in the synthesis of 1-thioglycosides.2,3 The straight-
forward stereospecific construction of 1-thioglycosides
from configurationally pure glycosyl thiolates, which is
essentially independent of neighbouring group effects,
makes their access more attractive.2–4 Glycosyl thiolates
mostly result in basic S-deacetylation of thioacetate
glycosyl donors obtained by usual S-glycosylation from
activate glycosides (Scheme 1).4
The synthesis of the 2,3,4,6-tetra-O-benzyl-1-O-(thio-p-
nitrobenzoyl)thiocarbonyl a- and b- -galactopyrano-
D
sides 3 was achieved, in 80% overall yield, following
two efficient steps from the galactopyranose tetrabenzyl
15 (Scheme 2). Thus, carbon disulfide reacted with the
galactopyranose 1 in the presence of sodium hydride to
give the xanthate salt intermediate 2 which was
quenched in situ by p-nitrobenzoyl chloride (1.1 equiv.)
yielded the xanthate 3. The stable anomers 3a and 3b
were isolated by flash chromatography on silica gel in
7/3 ratio.6
The treatment of the (thio-p-nitrobenzoyl)thiocarbonyl
galactopyranoside 3a by 1 equiv. of imidazole in dry
1,2-dichloroethane solution, in the presence of DBU (1
equiv.), afforded, as single product of the reaction, the
This work reports the stereospecific original access to
a-thiogalactoside derivatives by the rearrangement of
the hitherto unknown 1-O-(thio-p-nitrobenzoyl)thio-
carbonyl galactoside as an alternative avoiding the use
of osidic activators generally required for the prepara-
tion of 1-thioglycoside donors (Scheme 1).
1-S-(2%-chloro)ethyl a-
-thioglycoside 4a7 in 30% yield
D
(Scheme 3). The reaction yield was significantly
increased to 50% when supplementary amount of DBU
(1 equiv.) and imidazole (1 equiv.) were added. The
presence of DBU seems to be essential for the reaction
Scheme 1.
* Corresponding author. Tel.: 02-51-12-54-20; e-mail: dubreuil@chimie.univ-nantes.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02122-0

238
S. Josse et al. / Tetrahedron Letters 43 (2002) 237–239
Scheme 2.
Scheme 3.
thioester intermediate 6b or from the thiolate 7b, in
favour of the corresponding a-anomers. In the same
conditions as precedently used for the rearrangement
as the glycoside 3a was recovered quantitatively on
treating with just an excess of imidazole in 1,2-
dichloroethane. It is interesting to note that compound
4a can be regarded as a protected a-thiogalactoside
tethered to a reactive spacer arm.8
of 3a (imidazole
2 equiv., DBU 2 equiv., 1,2-
ClCH2CH2Cl), the 1-S-thio-p-nitrobenzoyl a-galac-
topyranoside 6a9 was isolated in 70% yield from the
1-O-(thio-p-nitrobenzoyl)thiocarbonyl b-glycoside 3b.
This latter result seems to be in favour of a mutaro-
tational equilibrium at the level of the thiolate interme-
diate 7b, instead of an anomeric effect from 6b. As it
seems admitted that alkylation of glycosyl thiolates
mainly occurs with retention of the anomeric configura-
tion,4 the formation of an oxonium intermediate from
the imidazole carbamate 5a can also be advocated
directing the introduction of the p-nitrobenzoyl car-
boxythiolate to the a-face of the cyclic oxycarbonium.
However, the resulting major formation of the interme-
diate 6a, expected in this case, would not unambigu-
ously explained the obtention of the chloroethyl
thioglycoside 4a, as 6a remains stable under the above
conditions.
Based on the literature data4 the stereospecific forma-
tion of the thioglycoside 4a from the glycoside precur-
sor 3a should take into account the nucleophilic
substitution from a galactoside thiolate 7a, generated in
situ, with the 1,2-dichloroethane exhibiting an unusual
electrophilic reactivity. Following this hypothesis, a
possible reaction mechanism has been proposed. The
activation of imidazole by DBU allowed its addition to
the thiocarbonyl function of the p-nitrobenzoyl xan-
thate 3a leading to the 1-O-(imidazolyl)thiocarbonyl
a- -galactoside 5a. This intermediate represents an
D
interesting new osidic activator displaced in situ by the
released p-nitrobenzoylthiolate to afford the 1-S-thio-
p-nitrobenzoyl b-galactoside 6b. The latter thioester
intermediate can be finally deacetylated into a reactive
glycoside thiolate in the presence of a second equivalent
of imidazole, prior to react with 1,2-dichloroethane.
Therefore, the stereochemistry of the unique thiogly-
coside reaction product 4a, suggests a the occurrence of
a previous anomeric equilibrium, either from the
These results prompted us to attempt the preparation
of galactoside thiol derivatives from the thio-p-
nitrobenzoyl thiocarbonyl a-glycoside 3a in absence of
1,2-dichloroethane solvent (Scheme 4).

S. Josse et al. / Tetrahedron Letters 43 (2002) 237–239
239
Scheme 4.
Thus, in acetonitrile, the treatment of galactoside 3a
with imidazole (2 equiv.) and DBU (2 equiv.), followed
by hydrolysis, led exclusively to the a-galactoside thiol
8a in 85% yield (H1: 5.39 ppm, d, 1H, J1–2=5.49 Hz).
Same experimental conditions applied in the presence
of an excess of methyl iodide afforded a 1/1 mixture of
the corresponding thiomethyl a- -galactoside 9a (H1:
5.40 ppm, d, 1H, J1–2=5.50 Hz) and its thiol precursor
8a, in 70% yield.
7.22–7.36 (m, 20H, CH OBn); 8.13 (d, 2H, J=9.2, CH
p-NO2-Ph); 8.27 (d, 2H, J=9.2, CH p-NO2-Ph). 13C
NMR† 100 MHz (CDCl3): l 68.3 (C6); 72.9, 73.3, 73.6,
75.1 (CH2 OBn); 74 (C5); 74.5 (C4); 75.4 (C2); 80.6 (C3);
84.1 (C1); 123.9 (CH p-NO2-Ph); 127.5–128.7 (CH OBn
and CH p-NO2-Ph); 138.5, 137.7, 137.8 (Cq OBn); 141.7,
150.7 (Cq p-NO2-Ph); 161.7 (CꢀO); 199.3 (CꢀS).
D
1
b-Anomer: H NMR† (CDCl3): l 3.59 (m, 2H, J=6.7, H6a,
H6b); 3.71 (dd, 1H, J3–4=2.7, J3–2=9.6, H3); 3.79 (t, 1H,
J=6.7, H5); 4.04 (d, 1H, J4–3=2.7, H4); 4.13 (dd, 1H,
In conclusion to this work, we have designed a new
access to glycosides thiolate and thioester. a-Galac-
toside thiol derivatives are stereospecifically produced,
in one pot procedure, from protected 1-O-(thio-p-
nitrobenzoyl)thiocarbonyl a-galactoside in the presence
of imidazole and DBU. Therefore, the p-nitrobenzoyl
a-thiogalactoside ester can be isolated from the b-
anomer precursor. The effect of base and solvent in the
stereochemistry of the rearrangement, as well as, the
influence of xanthate type anomeric group, are under
evaluation. The application to other glycosidic deriva-
tives is also in due course to achieve the synthesis of
oligothioglycosides in absence of any osidic catalysts.
J
2–1=8, J2–3=9.6, H2); 4.44 (m, 2H, CH2 OBn); 4.76 (m,
6H, CH2 OBn); 5.83 (d, 1H, J1–2=8, H1); 7.33 (m, 20H,
CH OBn); 8.09 (d, 2H, J=9, CH p-NO2-Ph); 8.23 (d, 2H,
3J=9.4, CH p-NO2-Ph). 13C NMR† (CDCl3): l 68 (C6); 73
(C4); 73.1, 73.6, 74.9, 75.4 (CH2 OBn); 74.5 (C5); 77.8 (C2);
82.7 (C3); 95.4 (C1); 123.6, 131.3 (CH p-NO2-Ph); 128 (CH
OBn); 134.7, 150.8 (Cq p-NO2-Ph); 137.7, 138.1, 138.4 (Cq
OBn); 163.2 (CꢀO); 201.1 (CꢀS).
7. 1-S-(2%-Chloro)ethyl-2,3,4,6-tetra-O-benzyl-a-D-galactopy-
ranoside 4a: ICMS (NH3) [M+18]=636; 1H NMR† 400
MHz (CDCl3): l 2.87 (m, 2H, H8a, H8b); 3.5 (m, 2H,
J6a–5=6, J6a–6b=10, H6a, H6b); 3.64 (m, 2H, H7a, H7b);
3.75 (dd, 1H, J3–2=10, J3–4=3, H3); 3.9 (d, 1H, J4–3=2,
H4); 4.24 (t, 1H, J5–6a=6, H5); 4.27 (dd, 1H, J2–1=5,
J
J
2–3=10, H2); 4.97–4.94 (m, 8H, CH2 OBn); 5.47 (d, 1H,
References
1–2=5.2, H1); 7.23–7.38 (m, 20H, CH OBn). 13C NMR†
100 MHz (CDCl3): l 32.2 (C8); 43.4 (C7); 69.2 (C6); 70.3
(C5); 72.8, 73.5, 73.6, 74.9 (CH2 OBn); 75.1 (C4); 76.2 (C2);
79.4 (C3); 84.6 (C1); 127.6–128.5 (CH OBn); 138.0, 138.2,
138.6, 138.7 (Cq OBn).
1. Garegg, P. J. Adv. Carbohydr. Chem. Biochem. 1997, 52,
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science; Driguez, H.; Thiem, J., Eds.; Springer: Berlin,
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H.; Henrissat, B.; Shulein, M.; Davies, G. J. Biochemistry
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Chem. Commun. 1996, 61, 1489–1500.
9. 1-S-Thio-(p-nitrobenzoyl)-2,3,4,6-tetra-O-benzyl-a-D-
galactopyranoside 6a: 1H NMR† 400 MHz (CDCl3): l
3.52–3.63 (m, 1H, H6); 3.98 (dd, 1H, J3–4=4, J3–2=12,
H3); 4.09–4.11 (m, 2H, H5, H4); 4.28 (dd, 1H, J2–1=4,
J2–3=12, H2); 4.39 (d, 1H, J=12, CH2 OBn); 4. (d, 1H,
J=12, CH2 OBn); 4.61 (d, 1H, J=12, CH2 OBn); 4.74 (s,
2H, CH2 OBn); 4.78 (d, 1H, J=12, CH2 OBn); 4.83 (d,
1H, J=12, CH2 OBn); 4.98 (d, 1H, J=12, CH2 OBn); 6.59
(d, 1H, J1–2=4, H1); 7.24–7.39 (m, 20H, CH OBn); 8.12
(d, 2H, J=8, CH p-NO2-Ph); 8.27 (d, 2H, J=8, CH
p-NO2-Ph). 13C NMR† 100 MHz (CDCl3): l 68.4 (C6);
72.7 (C4 or C5); 73.0, 73.6, 73.8 (CH2 OBn); 74.4 (C4 or
C5); 75.1 (CH2 OBn); 75.5 (C2); 78.3 (C3); 92.9 (C1); 123.7
(CH p-NO2-Ph); 127.7–128.6 (CH OBn); 131.1 (CH p-
NO2-Ph); 135.6 (Cq p-NO2-Ph); 137.8, 138.0, 138.4, 138.5
(Cq OBn); 150.8 (Cq p-NO2-Ph); 163.4 (CꢀO).
6. 1-O-(Thio-p-nitrobenzoyl)thiocarbonyl-2,3,4,6-tetra-O-ben-
zyl-
a-Anomer: H NMR† 400 MHz (CDCl3): l 3.52 (dd, 1H,
6a–6b=9.3, J6a–5=5.5, H6a); 3.63 (m, 2H, H6b, H3); 3.97 (t,
D-galactopyranoside 3:
1
J
1H, J5–6b=9.5, J5–6a=6.7, H5); 4.03 (d, 1H, H4); 4.39 (m,
2H, CH2 OBn); 4.48 (dd, 1H, J2–3=10.1, J2–1=5.4, H2);
4.57–4.97 (m, 6H, CH2 OBn); 6.50 (d, 1H, J1–2=5.2, H1);
† l (chemical shifts) in ppm and J (coupling constants) in Hz.