Unusual anomeric rearrangement of para-nitrobenzoylxanthate d-glycosides: a new direct stereoselective access to α-thioglycosides from pyranose sugars

Article abstract of DOI:10.1016/j.tet.2006.03.024

A mild and general procedure for the synthesis of α-thioglycosides from glycopyranoses is described. The method involves the treatment of pyranose reductive sugar with sodium hydride, carbon disulfide, and p-nitrobenzoyl chloride, as a key step, to yield

Full text of DOI:10.1016/j.tet.2006.03.024

Tetrahedron 62 (2006) 4784–4794
Unusual anomeric rearrangement of para-nitrobenzoylxanthate
D-glycosides: a new direct stereoselective access to
a-thioglycosides from pyranose sugars
a
Adjou Ane, Solen Josse, Sebastien Naud, Vivien Lacone, Sandrine Vidot,
b
b
b
b
´
´
ˆ
Anaıs Fournial,b Anirban Kar,b Muriel Pipelierb and Didier Dubreuilb,
*
¨
a
`
Laboratoire de Synthese Organique, Faculte des Sciences et des Techniques, 22 BP 582 Abidjan 22,
´
ˆ
Cote d’Ivoire
Universite de Nantes, CNRS, Laboratoire de Synthese Organique, UMR 6513, Faculte des Sciences et des Techniques,
b
´
`
2 rue de la Houssiniere, BP 92208, 44322 Nantes Cedex 3, France
´
`
Received 19 January 2006; revised 2 March 2006; accepted 7 March 2006
Available online 31 March 2006
Abstract—A mild and general procedure for the synthesis of a-thioglycosides from glycopyranoses is described. The method involves the
treatment of pyranose reductive sugar with sodium hydride, carbon disulfide, and p-nitrobenzoyl chloride, as a key step, to yield p-nitroben-
zoyl-a-D-thioglycopyranose intermediates with high stereoselectivity, in a one-pot-two-step process. The interest of the strategy highlights
a direct stereoselective access to ether-protected 1-thiol-a-D-glycopyranose derivatives (Gal, Glc, and Man) from pyranoses in the absence
of anomeric ‘Lewis acid’ promoters.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
sulfoxide donors remain among efficient donors. The modu-
lation of their reactivity with various promoters allows the
anomeric substitution by nucleophilic partners including
thiol-derivatives.1,14
The thiosaccharides, in which the oxygen of the glycosidic
bond is replaced by a sulfur atom, are receiving considerable
attention in glycobiology as potential enzyme substrates or
inhibitors due to their resistance to acid/base or enzyme-
mediated hydrolysis.1–3 They have recently been highlighted
as potent new therapeutic agents, for example, in anti-
tumoral4,5 or anti-HIV treatment.6
However, base promoted S-alkylation of configurationally
pure anomeric a and b-glycosyl thiol, xanthate or thiourea,
by SN2 displacement of alkylating agents has been found
as one of the most elegant and powerful routes for the
preparation of a and b-1-thioglycosides, respectively.14,15
Indeed, it has been observed that the thioglycosyl anions
do not mutarotate under basic conditions1,16,17 and their
anomerization is very slow18 (Scheme 1).
Within the range of general glycosylation methods, a number
of glycosyl donors have been differentiated by the nature of
the anomeric groups with a critical effect upon the activation
step under acidic catalysis, neutral or basic conditons.7–13
In the course of the stereoselective thioglycosylation pro-
cess, halide, trichloroacetimidate, thio-alkyl or -aryl, and
The a and b-glycosyl thiolates are obtained from isolable
a and b-anomeric thiols, respectively,18–21 or by in situ
O
S
O
RX
SR
HO
OH
HO
OH
RO
OR
RO
RO
OR
RX
O
O
HO
OH
O
O
HO
base
SH
HO
S
RO
SAc
O
base
HO
HO
HO
OH
O
RO
RO
SAc
O
HO
SR
β
α
SH
Scheme 1.
Keywords: Stereoselective a-thioglycosylation; a-Glycopyranoside thiols; a-Galactoside thiol; Thiolo-thiono rearrangement; a-Thiogalactolipids.
* Corresponding author. Tel.: +33 2 51 12 54 20; fax: +33 2 51 12 54 02; e-mail: didier.dubreuil@univ-nantes.fr
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.03.024

A. Ane´ et al. / Tetrahedron 62 (2006) 4784–4794
4785
S-deacetylation of the corresponding anomeric thioacetates
in the presence of bases (Et2NH, MeONa,.).1,17,22,23 The
efficiency of the S-alkylation approach is overshadowed by
the variable yields often associated with the generation of
the anomeric thiolate and its subsequent reactivity with the
electrophilic partner in solution. The use of costly hindered
iminophosphorane bases has been recently proposed to min-
imize undesirable competing elimination and to avoid
a trans-esterification side reaction when other sensitive
O-ester protecting groups are present.23 Furthermore, the ac-
cess to configurationally pure a- and b-thioacetate (or xan-
thate and thiourea) anomers has been mainly performed by
preliminary catalyzed S-glycosylation from suitable acti-
vated 2,3,4,6-ester-protected glycosyl halide, acetate and
acetimidate donors in the presence of tetrabutylamonium
salt of thioacetic acid and potassium thioacetate, respec-
tively (or potassium ethyl xanthate and thiourea).24–30 The
attribute of the latter process, catalyzed by an ammonium
salt or Lewis acid promoters, strongly depends on the nature
of the activated donors and mostly affords high stereocontrol
to produce 1,2-trans-thio-D-glycosides (b-gluco, b-galacto
or a-manno) when a neighboring acyloxonium anomeric
participation can be involved. Alternatively, Michael-addi-
tion of thionucleophiles to sugar enones has also been prone
to achieve the access to thioglycosides.5
The results are discussed in terms of interpretation of an
original mechanism and a first application to the preparation
of a-thiogalactoconjugates following S-alkylation process.
2. Results and discussion
In our search for new thioglycosylation methods, we
investigated a stereoselective access to 1-thiol-a-D-galacto-
pyranose 1 (1,2-cis) derivatives from 2,3,4,6-tetra-O-benzyl-
D-galactose 4, via the 1-S-p-nitrobenzoyl-a-thiogalactopyra-
nose 2a (Scheme 3).
O
BnO
BnO
BnO
BnO
OBn
O
OBn
O
NO2
S
BnO
BnO
O
2
SH
OH
1
4
Scheme 3. Retrosynthesis of 1-thiol-a-D-galactopyranose 1.
The 1-S-p-nitrobenzoyl-a-thiogalactopyranose 2a resulted
from an in situ rearrangement of the 1-O-(S-p-nitrobenzoyl)-
dithiocarbonate-D-galactopyranose 3 formed by the treat-
ment of tetrabenzyl-galactopyranose
4 with sodium
hydride and carbon disulfide and subsequent addition of p-
nitrobenzoyl chloride to the resulting xanthate salt (Scheme
4). When 1.1 equiv of each reagent were used, in THF, the
1-S-p-nitrobenzoyl-a-thiogalactopyranose 2a and the 1-O-
p-nitrobenzoyl-b-galactopyranose 6b were identified as
the major products formed in the reaction and were isolated
in almost 50% yield. By-products, 2b, 7a, and 7b, were also
present in less than 10% overall yield and 25% of starting
material 4 remained.
Due to the relative difficulty of conveniently achieving 1,2-
cis glycosylation,11 the introduction of a thioacetate group in
a pure a-anomeric configuration in galacto or gluco series
(or b-configuration for mannosides) and its subsequent in
situ deacetylation for S-alkylation process has been pro-
moted.14 However, only a few syntheses of 1,2-cis thiogly-
cosides have been reported.14,24,31 Driguez and co-workers
have used a fair combination of ester-protected a-1-thiolace-
tate glycosides,31,32 derived from b-chloro and a-triphenyl-
metylthio-donors, to produce linear and branched
a-thiooligosaccharides. In their convergent approaches, the
authors performed the conversion of a-1-thiotrityl interme-
diatestoa-1-thioacetateglycosidesbysubsequentHg(OAc)2,
H2S, and Ac2O treatments. Alternatively, 2,3,4,6-tetra-
O-acetyl-1-thio-a-D-glucopyranose can be also produced al-
most exclusively by fair photochemical addition of thioacetic
acid, catalyzed by tert-butyl or cumene hydroperoxide, from
tetra-O-acetyl-1,5-anhydro-D-arabino-hex-1-enitol.33–35
We attempted to improve the preparation of the thioester 2a
using the following optimized proportion of reagents:
1.2 equiv of NaH, 3 equiv of CS2, and 1.2 equiv of
p-NO2BzCl in THF. The ratio between a-thioester 2a and
b-ester 6b was evaluated and the most significant results
are summarized in Table 1. When the reaction was run at
ꢀ
0 C, the thioester 2a and ester 6b were formed in almost
60% yield (entry 1), with 20% of galactopyranose 4 remain-
ing. After purification by chromatography on silica gel, com-
pounds 2a and 6b were isolated in a 7/3 ratio. No decrease in
the remaining initial pyranose 4 and no appearance of O-p-
nitrobenzoyl anomer 6a were observed when the reaction
was continued for 6 h after the addition of p-NO2BzCl,
which indicates that sodium hydride and the acid chloride
were consumed (entry 2). When the reaction was run entirely
at rt, 2a and 6b were produced in the same proportion (5/5)
in 67% yield (entry 3). The formation of the alkoxide at rtꢀfor
15 min prior to the addition of CS2 and p-NO2BzCl at 0 C,
increased the ratio in favor of 2a (8/2, entry 4). Finally, the
best selectivity leading to a 2a/6b ratio of 9/1 (entry 5) was
obtained when the alkoxide formation was carried out for
30 min. In these conditions, a 2a/6b mixture was isolated
in 78% yield and only 10% of galactopyranose 4 remained.
We describe here a mild and general procedure for the direct
access to novel S-p-nitrobenzoyl-a-D-thioglycopyranose
from ether-protected D-glycopyranose precursors, which
can be regarded as new potent intermediates in the prepara-
tion of a-glycoside thiolates. The method involves the treat-
ment of the reductive sugar with sodium hydride, carbon
disulfide, and p-nitrobenzoyl chloride, as a key step, to yield
in a one-pot-two step process the corresponding S-p-nitro-
benzoyl-a-D-thioglycopyranose with high stereoselectivity
(Scheme 2).
NaH, CS2,
O
O
O
1) base
2) RX
p-NO2BzCl
NO2
one-pot
no catalyst
We then applied the latter procedure to manno- and gluco-
pyranose rings. The results obtained in the manno series
seemed to lend weight to this unusual anomeric phenome-
non, which occurred in the absence of an activating catalyst.
S
α
OH
SR
O
Scheme 2.

4786
A. Ane´ et al. / Tetrahedron 62 (2006) 4784–4794
OBn
OBn
O
O
NO2
NaH, CS2
THF, 0°C
S
p-NO2BzCl
Na
4
BnO
O
S
O
S
BnO
S
O
5
3
BnO
BnO
OBn
O
BnO
BnO
OBn
O
NO2
NO2
O
BnO
+
BnO
S
O
2
6
O
major products
minor products
NO2
NO2
O
O
O
NO2
O
S
O
S
O
7
2
S
7
Scheme 4.
Table 1
difficult to rationalize but can be correlated to results usually
encountered in the literature for the preparation of a-gluco-
side derivatives, whereas galacto analogues are easier to pre-
pare in good yields.
Entry
NaH
CS2
p-NO2BzCI Yield % Ratio
of 2a+6b of 2a/6b
q (oC) t (min) q (oC)/60 min q (oC) t (min)
1
2
3
4
5
0
0
rt
rt
rt
15
15
15
15
30
0
0
rt
0
0
0
0
rt
0
0
60
360
60
60
60
60
61
67
70
78
7/3
7/3
5/5
8/2
9/1
2.1. Mechanism interpretation
In a preliminary study on the galactose series, the formation
of 1-O-(S-p-nitrobenzoyl)dithiocarbonate-D-galactopyrano-
ses 3 was first suggested as key isolable intermediates in
the transformation of tetrabenzyl-galactose 4 (1.1 equiv of
NaH, 3 equiv of CS2, and 1.1 equiv of p-NO2BzCl).36 How-
ever, recent advances in the elucidation of the mechanism
have highlighted some misunderstanding of this hypothesis,
mostly due to the spontaneous evolution of the reaction
products even in mild storage conditions.37 Therefore, the
analysis of the crude reaction mixture and the characteriza-
tion of the intermediates formed were not so straightforward.
Thus, by a similar one-pot rearrangement the targeted 1-S-p-
nitrobenzoyl-a-thiomannopyranose ester 9a was produced
as the sole product of the reaction from the tetrabenzyl-man-
nopyranose 8 in 70% yield (Scheme 5).
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
1) NaH, CS2
O
O
NO2
OH
2) p-NO2BzCl
8
S
70%
9
Although the reaction should a priori take into account a re-
arrangement of intermediates 3a and 3b (Scheme 4), these
latter appeared to be unstable and evolved differently in
the medium to give the anomers 2, 6, and 7, as shown by
1H NMR (400 MHz) analysis (Fig. 1, Table 2). A reference
experiment was initially recorded exposing galactose 4 to
the conditions described in entry 5 (Table 1) but at a lower
O
O
OBn
O
BnO
BnO
NO2
NO2
OBn
BnO
S
+
O
1) NaH, CS2
BnO
BnO
11
OH
ꢀ
2) p-NO2BzCl
BnO
10
temperature (ꢁ20 C) and concentrating the THF medium
OBn
50%
O
under vacuum only 20 min after the addition of the p-nitro-
benzoyl chloride (instead of 60 min). Usual workup with
dichloromethane/H2O and the concentration of the dried
organic layer were then achieved. The latter procedure
revealed the appearance in the crude reaction mixture of
all derivatives 2, 3, 6, and 7, which could be involved in
the transformation of the pyranose 4 (Fig. 1A). The evolu-
BnO
BnO
O
BnO
12
O
Scheme 5.
When tetrabenzyl-glucopyranose 10 was subjected to the
same reaction conditions, the results were confirmed but in
a slightly lower yield and ratio (Scheme 5) as the mixture
of a-thioester 11a and b-ester 12b was isolated in almost
50% yield, in a 6/4 ratio. The three homologue by-products,
previously described in the galacto series, were also identi-
fied in the gluco series (<3% from H NMR spectra of the
crude reaction mixture) but were not isolated. The difference
in the reactivity between the gluco and the galacto series is
1
tion of each derivative was then monitored using H NMR
analysis from the same sample kept for 60 min and 12 h,
in CDCl3 solution (Fig. 1B and C).
The presence of 1-O-(S-p-nitrobenzoyl)dithiocarbonate-
a-D-galactopyranose 3a (dH1¼7.00 ppm, d, J1,2¼3.3 Hz)
and thus of 1-S-p-nitrobenzoyl-a-thiogalactopyranose 2a
(dH1¼6.50 ppm, d, J1,2¼5.3 Hz) was unambiguously
1

A. Ane´ et al. / Tetrahedron 62 (2006) 4784–4794
4787
(A) = 20 min
(B) = 60 min
(C) = 12 h
7.00
6.50
6.00
5.50
ppm(t1)
Figure 1. Zone of 1H NMR spectra (5.3–7.1 ppm) showing the anomeric proton signals: evolution of the proportion of compounds 2, 3, 6, 7, and 14 with time:
20 min (A), 60 min (B), and 12 h (C).
Table 2
O
O
O
O
NO
2
NO2
NO2
O
NO
NO2
NO
NO
O
O
2
2
2
O
O
S
S
S
S
O
S
O
S
O
O
O
S
O
O
O
S
7
2
14
7
6
3
2
H1 (ppm)
J1–2 (Hz)
7.00
3.3
6.91
3.3
6.50
5.3
6.38
5.4
6.30
7.7
5.84
8.0
5.37
10.1
assigned (Fig. 1A–C). However, the appearance of a signal at
6.38 ppm (dH1), which increased after 60 min (Fig. 1B) and
disappeared after 12 h (Fig. 1C), revealed the existence of
a novel intermediate 14a (d, J1,2¼5.4 Hz) related to the re-
arrangement of 3a into thioester 2a. When repeating these
NMR investigations in order to validate this observation,
we have also observed, in some experiments, the total lack
of the intermediate 3a in favor of 14a (Fig. 2A). Despite
the difficulty in controlling the timing of the predominant
formation of 14a, this phenomenon was confirmed several
times during 1H NMR experiments, even when the same pro-
cedures leading to the data depicted in Fig. 1 were rigorously
reproduced.38 The identification of the 1-S-(S-p-nitroben-
zoyl)dithiocarbonate-1-thio-a-D-galactopyranose 14a (13C
NMR, dCO¼183.8, 178.4 ppm for the two carbonyls),
which is unstable on silica gel supports and in storage con-
ditions, was confirmed by the analysis of its hydrolysis prod-
uct, a-thiogalactopyranose 15a (dH1¼5.82 ppm, t, J1,2
¼
J1-SH¼5.3 Hz). The formation of the latter was observed to-
gether with thioester 2a (Fig. 2B) when silica gel was added
to the crude mixture of a reaction in which 14a was detected
as the major a-anomer, whereas 1-S-p-nitrobenzoyl-a-thio-
galactopyranose 2a remained stable on silica gel.
This evidence led us to propose a revised mechanism for
the stereoselective and concomitant formation of the a-
thioester 2a and b-ester 6b from tetrabenzyl-galactopyra-
nose 4 (Scheme 6). Our hypothesis is based on an original

4788
A. Ane´ et al. / Tetrahedron 62 (2006) 4784–4794
initiated under acidic catalysis in refluxing solvent (THF
14
(A)
or toluene) while, surprisingly, ꢀit occurred in situ between
the glycosides 3a and 14a at 0 C in the present case. Fur-
thermore, it is interesting to note that the thionoester 7a also
spontaneously rearranged into the thioester 2a, even when
ꢀ
(B) = (A) + silica gel
stored under argon at ꢁ10 C.
Logically, the formation of by-products 2b, 7a, and 7b
should then involve the participation of an oxonium interme-
diate 16, which could result from an inevitable partial degra-
dation of dithiocarbonate 3a. The addition of the released
oxathiocarbonyl 17 to oxonium 16 would then also explain
the presence of anomers 2 and 7. This comment takes into
account the significant increase in the H1 signal of 2b ob-
served in the NMR experiments (Fig. 1A, B), while no trace
of dithiocarbonate 3b was detected. As the formation of the
xanthate salt precursor (NaH, CS2) cannot be considered as
the determining step, if the dithiocarbonate 3b is formed, it
is too unstable to achieve its rearrangement into thioester 2b
and the appearance of the latter would then be understood as
coming from the oxonium 16 in the presence of 17.
7.0
6.8
6.6
6.4
6.2
6.0
5.8
5.6
Figure 2. 1H NMR spectra of crude reaction mixture after work-up: (A):
reaction conditions: 1.2 equiv NaH, rt, 30 min, CS2, 0 ꢀC, 60 min,
p-NO2BzCl, 0 ꢀC, 2 h; (B): (A)+silica gel.
and surprising one-pot-two-step stereospecific double
rearrangement of 1-O-(S-p-nitrobenzoyl)dithiocarbonate-
a-D-galactopyranose 3a into 1-S-p-nitrobenzoyl-a-thioga-
lactopyranose 2a, via the 1-S-(S-p-nitrobenzoyl)dithiocar-
bonate-1-thio-a-D-galactopyranose 14a.
In other end, according to Tsuboyama et al.,48 who has
described a one-step synthesis of S-1-(10-phenyl-1H-
tetrazolyl)-2,3,4,6-tetra-O-benzyl-a-D-glucopyranose in the
absence of catalytic activation by reacting S-S0-bis(1-
phenyl-1H-tetrazol-5-yl)-dithiocarbonate with tetrabenzyl-
glucopyranose, the predominant formation of 2a from an
oxonium ion 18 cannot be entirely ruled out.
p-NO2BzCl
O
unstable
3
6
O
Na
minor
13
NaH, CS2
4
+
p-NO2BzCl
O
O
NO2
3
O
major
major
O
S
S
2
major
S
The formation of 1-O-p-nitrobenzoyl-b-D-galactopyranose
6b should now be understood as a simple reaction of b-alco-
holate anomer 13b with the remaining p-nitrobenzoyl chlo-
ride reagent. Moreover, it should be noted that the protected
1-O-p-nitrobenzoyl anomer 6b is also of interest as it has al-
ready been reported as an efficient glycoside donor in the
usual stereoselective a-glycosylations.49
S
O
NO2
O
14
minor
O
NO2
- OCS
S
17
OBn
OBn
O
OBn
OBn
BnO
BnO
O
BnO
OBn
16
In conclusion to this mechanism study, it should be noted
that the direct access to a-(p-nitrobenzoyl)-thioglycopyra-
nose from pyranose sugars is quite remarkable and efficient
particularly as it occurs in the absence of activating pro-
moters with a high stereoselectivity.
18
+
+
+
7
7
2
2
Scheme 6.
The anomer counterpart 3b would not be able to achieve
such transformations and the total absence of a signal related
to the 1-O-(S-p-nitrobenzoyl)dithiocarbonate-b-D-galacto-
2.2. Thioalkylation process
1
pyranose anomer 3b in H NMR experiments (Figs. 1 and
The study of the galacto series was then continued to evalu-
ate the potential of the thioester 2a for S-alkylation reac-
tions. The de-esterification of 2a was first attempted to
obtain the corresponding a-thiol donor 15a, anticipating
that the corresponding thiolate anion could participate effi-
ciently in the SN2 displacement of electrophiles to generate
a variety of a-thioglycoconjugates or a-thioglycosides.
De-esterification of the thioester 2a was first carried out at
rt in THF with a catalytic amount of sodium methoxide
(1 M solution in MeOH). In these conditions, the desired
thiogalactopyranose 15a was obtained with a concomitant
formation of the disulfide 19 (Scheme 7).
2) prompted us to suspect its instability. In contrast, the
remarkable conservation of the a-stereochemistry during
a consecutive double rearrangement of 3a can be high-
lighted. The mechanism could be envisaged as following
a thiono/thiolo rearrangement of 3a giving the intermediate
14a, which could evolve through an anomeric pericyclic
process to form 2a.
Thiono/thiolo rearrangement, known as the Schronberg
¨
rearrangement39–41 in the case of thionocarbonates and as
Newman–Karnes rearrangement42–45 in the case of thiocar-
bamates, tends to usually occur at very high temperatures.
Thus, to best of our knowledge, only two examples of
such transformations have been previously mentioned on
pyranose sugars, from a secondary C-4 carbamate46 and an
anomeric xanthate.47 In both the cases, the process was
When the reaction was performed with an equimolar quan-
tity of MeONa in a 1/1 THF/ꢀMeOH mixture at lower temper-
ature50 (ꢁ40, ꢁ15, and 0 C), the thiol 15a was formed
1
quantitatively, as confirmed by H NMR analysis of the

A. Ane´ et al. / Tetrahedron 62 (2006) 4784–4794
4789
chromatography on silica gel. This inconvenience led us to
attempt the following deprotection step without purification.
BnO
BnO
OBn
BnO
BnO
OBn
O
MeONa
O
2
+
THF/MeOH
BnO
S
As predictable, attempts to achieve hydrogenolysis of the
benzyl ether groups on thiogalactosides in the presence of
Pd/C or Pd(OH)2 failed while the debenzylation of 23, 24,
and 25 by sodium in liquid ammonia55,56 was successful,
affording the targeted free a-thioglycosides 26, 27, and 28,
respectively (Scheme 9).
BnO
SH
2
15
19
Scheme 7.
crude mixture of the reaction. Nevertheless, significant deg-
radation occurred during flash chromatography on silica gel
since the purified thiol compound was finally isolated with
a maximum yield of 50%. This result suggested that thiol
15a should be used in the next step without further purifica-
tion. However, de-esterification of 2a in the presence of NaH
and imidazole (2 equiv) in acetonitrile, gave the disulfide 19
as the single product of the reaction (85% yield) and its sub-
sequent reduction into the desired thiol 15a was fully
achieved by treatment with tributylphosphine (1 equiv) in
wet THF.51
BnO
BnO
HO
HO
OBn
OH
O
O
Na, NH3
THF
liq.
HO
BnO
S
S
R
R
R =
PO(OEt)2
23
24
25
26
27
28
10
OH
10
OH
12
Scheme 9.
Alkylation of the thiogalactopyranose 15a was then attemp-
ted in the presence of three electrophiles, 10-diethoxy-
phosphoryl-1-O-tosyldecanol 20,52 1-bromodecanol 21, and
1-bromododecanol 22 (Scheme 8). The results are summa-
rized in Table 3.
Thus, the reaction sequence: disulfide reduction, thiol-alkyl-
ation, and Birch reduction, was carried out without subse-
quent purification and, after final chromatography on silica
gel, the free sugar analogues were obtained in almost 30%
overall yields from 2,3,4,6-tetra-O-benzyl-a,b-D-galacto-
pyranose.
OBn
RX =
OBn
O
Base, RX
DMF
20
PO(OEt)2
10
OH
10
TsO
15
BnO
3. Conclusion
Br
21
22
BnO
SR
Br
OH
12
RX = 20
RX = 21
RX = 22
23
24
25
We describe an original alternative for a-thioglycosylation,
which compares well with results related in the literature
following other methods starting from D-glycopyranose
precursors.
Scheme 8.
The purified thiol 15a treated with NaH (1 equiv), tosylate
20 (1.5 equiv), and crown-ether53 (1 equiv) gave the desired
alkylation product 23 as the major compound but the pres-
ence of the disulfide 19 and degradation products was also
observed (entry 1). The thiol 15a, generated in situ by reduc-
tion of the disulfide 19 (Fig. 3A) prior to the addition of
Cs2CO3 (1 equiv) and tosyl 20 (1.2 equiv) in DMF,54 gave
quantitatively the 1-S-diethyldecanphosphonate-a-thioga-
lactoside 23 (entry 2). When electrophiles 21 and 22 were
used, similar results were obtained to yield 1-(10-hydroxy-
decanyl)-a-thiogalactoside 24 and 1-(12-hydroxydode-
canyl)-a-thiogalactoside 25, respectively (entries 3 and 4).
Although the 1H NMR spectra of the crude products of the
reactions showed a quantitative formation of the desired
compounds (Fig. 3B), the thiogalactosides 23, 24, and 25
were recovered in moderate 25–30% yields after flash
The strategy involves, as a key step, the in situ double
consecutive rearrangements of 2,3,4,6-tetra-O-benzyl-1-O-
(S-p-nitrobenzoyl)dithiocarbonate-a-D-glycopyranoses into
the corresponding 1-S-p-nitrobenzoyl-a-D-thioglycopyrano-
ses. The latter rearrangement proceeds in the absence of
anomeric activation with a high a-stereoselectivity from
reductive sugars. As anticipated, the resulting a-glycoside
1-thioesters are expected to be involved as source of
a-anomeric thiolate anions for S-alkylations with a total
retention of the anomeric configuration. The study of the
influence of the ether protecting groups on the efficiency
of the methodology, in order to perform the access to
branched thioglycosides by convergent approaches, is cur-
rently in progress by exchanging benzyloxy groups with
para-methoxybenzyl, hydrolysis-sensitive substituents or
mixed ester–ether groups.
Table 3
Entry
Starting material
Base
RX
Crown-ether
Producta
Isolated yieldb (%)
1
2
3
4
15a
NaH
20
20
21
22
15-crown-5
None
None
23 maj.c
23 quant.
24 quant.
25 quant.
25
28
25
30
27 Reduction
27 Reduction
27 Reduction
Cs2CO3
Cs2CO3
Cs2CO3
None
Evaluated by 1H NMR.
After purification by flash chromotagraphy on silica gel.
With traces of side products.
a
b
c

4790
A. Ane´ et al. / Tetrahedron 62 (2006) 4784–4794
(A)
O
SH
5.82 ppm
H1
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
(B)
O
23
S
PO(OEt)2
5.45 ppm
H1
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
Figure 3. Crude NMR spectra of: (A) reduction of disulfide 19 into 15a with tributylphosphine in wet THF; (B) alkylation of thiol 15a into 23.
The usefulness of this strategy has been illustrated by the
first synthesis of three a-thiogalactoconjugates, which are
of interest as potential glycomimics and an extension to
the synthesis of thiofuranose analogues is underway. The
thioglycosylation process is also now being exploited for
the synthesis of thio-analogues of a-O-galactoceramides,57
which express anti-cancer and anti-malaria potentials.
with the aid of two-dimensional 1H, 1H (COSYDFTP) or 1H,
13C (INVBTP) experiments using standard Bruker pulse
programs. All reactions were monitored by TLC on com-
mercially available pre-coated plates (Kieselgel 60 F254
)
and the products were visualized with mostaıne solution
¨
(250 mL H2O, 10.5 g of (NH4)6Mo7O24$4H2O, 0.5 g of
Ce(SO4)2, and 15 mL of H2SO4). Kieselgel 60, 230–400
mesh (Merck) was used for column chromatography. Optical
ꢀ
rotations were measured at 20ꢂ1 C on Perkin Elmer 341 in
4. Experimental section
4.1. General methods
the indicated solutions whose concentrations are expressed
in grams per 100 mL. Mass spectra were measured by CI
with NH3 on a quad. Hewlett Packard 5989A. HRMS were
measured on an LCT spectrometer from Micromass (Lok-
spray, channel 2795 from Waters, flow: MeOH/H2O 50/50:
0.2 mL/min) and were performed at the Institut de Chimie
des Substances Naturelles, CNRS, Gif-sur-Yvette, France.
FTIR spectra were obtained in the 500–4000 cmꢁ1 range
on a Bruker Vector 22 FT-IR spectrometer using NaCl pellets.
Solvents were purified and dried by standard methods prior
to use.58 All reactions were carried out under argon. 1H and
13C NMR spectra were recorded on a Bruker AC 400 at rt
with TMS as internal standard for 1H spectra. Coupling con-
stants J are given in Hertz. All assignments were confirmed

A. Ane´ et al. / Tetrahedron 62 (2006) 4784–4794
4791
2
4.2. General procedure for the preparation of 1-S-p-nitro-
benzoyl-2,3,4,6-tetra-O-benzyl-1-thio-a-D-glycopyranose
3J2–1¼8.0), 4.41 (d, 1H, CH2(OBn), Jgem¼11.6), 4.46 (d,
2
1H, CH2(OBn), Jgem¼11.6), 4.65 (d, 1H, CH2(OBn),
2Jgem¼11.6), 4.72–4.76 (m, 3H, CH2(OBn)), 4.87 (d, 1H,
2
To a stirred suspension of sodium hydride (0.14 g,
3.43 mmol) in 10 mL of THF was added a solution of
2,3,4,6-tetra-O-benzyl-a,b-D-glycopyranose (1.57 g, 2.86
mmol) in 10 mL of dry THF at rt under argon. After
30 min, carbon disulfide (0.52 mL, 8.60 mmol) was added
CH2(OBn), Jgem¼11.2), 4.96 (d, 1H, CH2(OBn),
2Jgem¼11.6), 5.84 (d, 1H, H1, J1–2¼8.0), 7.13–7.36 (m,
3
3
20H, CH(OBn)), 8.10 (d, 2H, CHar, J¼7.0), 8.21 (d, 2H,
CHar, J¼7.0); 13C NMR (100 MHz, CDCl3) d 68.1 (C6),
3
73.0 (CH2(OBn)), 73.2 (C4), 73.7, 74.6 (2CH2(OBn)), 75.0
(C5), 75.4 (CH2(OBn)), 77.8 (C2), 82.7 (C3), 95.5 (C1),
123.6 (CHar), 127.8–128.6 (CH(OBn)), 131.3 (CHar),
134.8 (Cqar), 137.8–138.5 (Cq(OBn)), 150.9 (Cqar), 163.3
(CO); IR n (cmꢁ1) 1732 (C]O), 1266 (O–CO); [a]2D0 –8.2
(c 1.1, CH2Cl2); HRMS m/z calcd for C41H39NO9Na
712.2523, found 712.2547.
ꢀ
dropwise to the reaction mixture at 0 C and stirring was
continued for 1 h at the same temperature. The reaction mix-
ture was then treated with p-nitrobenzoyl chloride (0.64 g,
ꢀ
3.43 mmol) and was stirred for another 1 h at 0 C. The sol-
vent was removed under vacuum and the residue was dis-
solved in CH2Cl2. The resulted solution was washed with
brine, dried over MgSO4, concentrated, and purified by flash
chromatography.
4.2.4. 1-O-p-Nitrothiobenzoyl-2,3,4,6-tetra-O-benzyl-a-
D-galactopyranose (7a). Isolated in less than 3% yield dur-
ing synthesis of thioester 2a. H NMR (400 MHz, CDCl3)
d 3.45 (m, 1H, H6a), 3.55 (m, 1H, H6b), 3.94 (m, 2H, H3,
H5), 4.05 (m, 1H, H4), 4.29 (m, 2H, H2, CH2(OBn)), 4.36
1
4.2.1. 1-S-p-Nitrobenzoyl-2,3,4,6-tetra-O-benzyl-1-thio-
a-D-galactopyranose (2a). Synthesized following the
general procedure from 2,3,4,6-tetra-O-benzyl-a,b-D-galac-
2
(d, 1H, CH2(OBn), Jgem¼11.6), 4.55 (d, 1H, CH2(OBn),
1
topyranose 4 in 63% yield. H NMR (400 MHz, CDCl3)
d 3.53 (m, 1H, H6a), 3.61 (m, 1H, H6b), 3.64 (dd, 1H, H3,
2Jgem¼11.6), 4.63 (d, 1H, CH2(OBn), Jgem¼12.7), 4.71
2
2
(d, 1H, CH2(OBn), Jgem¼12.7), 4.76 (s, 2H, CH2(OBn)),
3
3J3–4¼2.8, J3–2¼10.0), 3.97 (m, 1H, H5), 4.03 (m, 1H,
4.93 (d, 1H, CH2(OBn), 2Jgem¼12.1), 6.91 (d, 1H, H1, 3J1–
2
H4), 4.37 (d, 1H, CH2(OBn), Jgem¼11.7), 4.43 (d, 1H,
¼3.3), 7.15–7.32 (m, 20H, CH(OBn)), 8.11 (m, 4H,
2
3
2
CH2(OBn), Jgem¼11.7), 4.48 (dd, 1H, H2, J2–3¼10.0,
CHar); 13C NMR (100 MHz, CDCl3) d 68.3 (C6), 72.8
(CH2(OBn)), 73.0 (C5), 73.8 (CH2(OBn)), 74.3 (C4), 75.1,
75.8 (2CH2(OBn)), 78.3 (C3), 97.7 (C1), 123.5 (CHar),
128.0–128.6 (CH(OBn)), 129.9 (CHar).
3J2–1¼5.3), 4.59 (d, 1H, CH2(OBn), Jgem¼11.3), 4.71 (s,
2
2
2H, CH2(OBn)), 4.74 (d, 1H, CH2(OBn), Jgem¼11.7),
2
4.84 (d, 1H, CH2(OBn), Jgem¼11.7), 4.96 (d, 1H,
2
3
CH2(OBn), Jgem¼11.3), 6.50 (d, 1H, H1, J1–2¼5.3),
7.22–7.36 (m, 20H, CH(OBn)), 8.12 (d, 1H, CHar,
4.2.5. 1-O-p-Nitrothiobenzoyl-2,3,4,6-tetra-O-benzyl-b-
D-galactopyranose (7b). Isolated in less than 3% yield dur-
ing synthesis of thioester 2a. H NMR (400 MHz, CDCl3)
3J¼9.0), 8.28 (d, 1H, CHar, J¼9.0); 13C NMR (100 MHz,
3
CDCl3) d 68.3 (C6), 73.3, 73.6 (2CH2(OBn)), 74.0 (C5),
74.5 (C4), 75.1 (2CH2(OBn)), 75.4 (C2), 80.6 (C3), 84.1
(C1), 123.9 (CHar), 127.5–128.7 (CH(OBn)), 137.7–138.5
1
3
3
d 3.62 (m, 2H, 2H6), 3.74 (dd, 1H, H3, J3–2¼9.7, J3–4
¼
2.3), 3.81 (m, 1H, H5), 4.05 (m, 1H, H4), 4.29 (m, 1H,
H2), 4.40 (d, 1H, CH2(OBn), Jgem¼11.5), 4.48 (d, 1H,
(Cq(OBn)), 141.7, 150.7 (Cqar), 188.3 (CO); IR n (cmꢁ1
)
2
1671 (C¼O); [a]2D0 +141.1 (c 1.0, CH2Cl2); HRMS m/z calcd
2
CH2(OBn), Jgem¼11.5), 4.60–4.79 (m, 4H, 2CH2(OBn)),
for C41H39NO8SNa 728.2294, found 728.2303.
2
4.87 (d, 1H, CH2(OBn), Jgem¼11.4), 4.96 (d, 1H,
2
3
CH2(OBn), Jgem¼11.3), 6.30 (d, 1H, H1, J1–2¼7.7),
7.20–7.36 (m, 20H, CH(OBn)), 8.17 (m, 4H, CHar); 13C
NMR (100 MHz, CDCl3) d 68.3 (C6), 73.1 (CH2(OBn)),
73.4 (C4), 73.7 (CH2(OBn)), 74.7 (C5), 74.9, 75.4
(2CH2(OBn)), 78.1 (C2), 82.6 (C3), 99.6 (C1), 123.3
(CHar), 127.9–128.5 (CH(OBn)), 130.1 (CHar), 138.0,
138.4 (Cq(OBn)), 142.1, 150.2 (Cqar), 206.5 (CS).
4.2.2. 1-S-p-Nitrobenzoyl-2,3,4,6-tetra-O-benzyl-1-thio-
b-D-galactopyranose (2b). Isolated in less than 3% yield
during synthesis of thioester 2a. 1H NMR (400 MHz,
3
CDCl3) d 3.59 (m, 2H, 2H6), 3.72 (dd, 1H, H3, J3–2
9.1, J3–4¼2.4), 3.80 (m, 1H, H5), 4.04 (m, 2H, H2, H4),
¼
3
3
4.40 (d, 1H, CH2(OBn), Jgem¼11.7), 4.46 (d, 1H,
2
CH2(OBn), Jgem¼11.7), 4.63 (d, 1H, CH2(OBn),
2Jgem¼11.5), 4.75 (m, 3H, CH2(OBn)), 4.89 (d, 1H,
4.2.6. 1-S-p-Nitrobenzoyl-2,3,4,6-tetra-O-benzyl-1-thio-
a-D-mannopyranose (9a). Obtained in 60% yield as the
only product of the reaction following the general procedure
from 2,3,4,6-tetra-O-benzyl-a,b-D-mannopyranose 8. 1H
NMR (400 MHz, CDCl3) d 3.72 (m, 2H, H6a, H5), 3.81
(m, 2H, H6b, H3), 3.87 (m, 1H, H2), 4.12 (m, 1H, H4), 4.53
(m, 4H, 2CH2(OBn)), 4.65 (d, 1H, CH2(OBn), 2Jgem¼12.1),
2
CH2(OBn), Jgem¼10.8), 4.94 (d, 1H, CH2(OBn),
2Jgem¼11.5), 5.37 (d, 1H, H1, J1–2¼10.1), 7.24–7.35 (m,
3
3
20H, CH(OBn)), 8.04 (d, 2H, CHar, J¼8.8), 8.28 (d, 2H,
CHar, J¼8.8); 13C NMR (100 MHz, CDCl3) d 68.2 (C6),
3
72.9 (CH2(OBn)), 73.7 (C2 or C4, CH2(OBn)), 74.9, 75.9
(2CH2(OBn)), 77.2 (C2 or C4), 78.0 (C5), 82.4 (C1), 84.4
(C3), 124.1 (CHar), 127.8–128.6 (CH(OBn), CHar), 137.9,
138.0, 138.2, 138.6 (Cq(OBn)), 141.4, 150.8 (Cqar), 188.1
(CO); HRMS m/z calcd for C41H39NO8SNa 728.2294,
found 728.2289.
2
4.76 (d, 1H, CH2(OBn), Jgem¼12.4), 4.91 (d, 2H,
2
3
CH2(OBn), Jgem¼11.0), 6.41 (d, 1H, H1, J1–2¼1.7),
7.17–7.19, 7.25–7.34, 7.44–7.46 (m, 20H, CH(OBn)), 8.08
(d, 2H, CHar, J¼8.8), 8.31 (d, 2H, CHar, J¼8.8); 13C
NMR (100 MHz, CDCl3) d 69.0 (C6), 71.9, 72.0, 73.6
(3CH2(OBn)), 74.3 (C4), 75.4 (CH2(OBn)), 76.6 (C2), 77.2
(C5), 80.2 (C3), 80.9 (C1), 124.0 (CHar), 127.6–128.7
(CH(OBn)), 137.8–138.3 (Cq(OBn)), 141.2, 150.8 (Cqar),
187.5 (CO); IR n (cmꢁ1) 1675 (C]O); MS (IC+, NH3)
723 (M+18); [a]2D0 +72.1 (c 1.0; CH2Cl2).
3
3
4.2.3. 1-O-p-Nitrobenzoyl-2,3,4,6-tetra-O-benzyl-b-D-
galactopyranose (6b). Formed along with 2a in 7% yield.
1H NMR (400 MHz, CDCl3) d 3.62 (m, 2H, 2H6), 3.71
3
3
(dd, 1H, H3, J3–4¼2.7, J3–2¼9.6), 3.79 (m, 1H, H5), 4.03
3
3
(d, 1H, H4, J4–3¼2.7), 4.12 (dd, 1H, H2, J2–3¼9.6,

4792
A. Ane´ et al. / Tetrahedron 62 (2006) 4784–4794
2
4.2.7. 1-S-p-Nitrobenzoyl-2,3,4,6-tetra-O-benzyl-1-thio-
a-D-glucopyranose (11a). Obtained following the general
procedure from 2,3,4,6-tetra-O-benzyl-a,b-D-glucopyra-
nose 10 in 36% yield. 1H NMR (400 MHz, CDCl3)
d 3.62–3.83 (m, 5H, H3, H4, H5, 2H6), 4.01 (dd, 1H, H2,
(d, 1H, CH2(OBn), Jgem¼11.5), 4.71 (d, 1H, CH2(OBn),
2Jgem¼11.7), 4.72 (d, 1H, CH2(OBn), Jgem¼11.5), 4.81
2
2
(d, 1H, CH2(OBn), Jgem¼11.7), 4.92 (d, 1H, CH2(OBn),
2Jgem¼11.4), 5.82 (dd, 1H, H1, J1–SH¼3.9, J1–2¼5.3),
7.22–7.37 (m, 20H, CH(OBn)); 13C NMR (100 MHz,
CDCl3) d 68.7 (C6), 70.5 (C5), 72.7–73.6 (4CH2(OBn)),
74.9 (C4), 76.0 (C2), 78.8 (C3), 79.8 (C1), 127.6–128.5
(CH(OBn)), 138.0, 138.1, 138.6, 138.7 (Cq(OBn)); MS
(IC+, NH3) 574 (M+18); [a]D20 +125.3 (c 1.0, CH2Cl2);
HRMS m/z calcd for C34H36O5SNa 579.2181, found
579.2194.
3
3
3
3J2–1¼5.2, J2–3¼9.0), 4.44–4.99 (m, 8H, 4CH2(OBn)),
3
6.49 (d, 1H, H1, J1–2¼5.2), 7.13–7.14 (m, 2H, CH(OBn)),
7.24–7.32 (m, 18H, CH(OBn)), 8.15 (d, 2H, CHar,
3
3J¼8.0), 8.31 (d, 2H, CHar, J¼8.0); 13C NMR (100 MHz,
CDCl3) d 68.1 (C6), 73.2, 73.7 (2CH2(OBn)), 75.2 (C3 or
C4 or C5), 75.4, 75.9 (2CH2(OBn)), 77.2 (C3 or C4 or C5),
78.7 (C2), 83.1 (C1), 83.7 (C3 or C4 or C5), 123.8–124.0
(CHar), 127.9–128.8 (CH(OBn), CHar), 137.4, 137.9,
138.1, 138.6 (Cq(OBn)), 141.5, 150.8 (Cqar), 188.0 (CO);
4.2.11. Bis[2,3,4,6-tetra-O-benzyl-a-D-galactopyrano-
syl]disulfide (19). To a solution of thioester 2a (1.29 g,
1.83 mmol) in 20 mL of dry CH3CN was added imidazole
(0.25 g, 3.67 mmol) followed by sodium hydride (0.15 g,
3.67 mmol). The reaction mixture was stirred for 2 h and
the solvent was removed. The crude product was diluted in
EtOAc, washed with brine, dried over MgSO4, and concen-
trated under reduced pressure. It was then purified by flash
chromatography (15% EtOAc/petroleum ether) to afford
IR
C41H39NO8SNa 728.2294, found 728.2307.
n
(cmꢁ1
)
1672 (C¼O); HRMS m/z calcd for
4.2.8. 1-O-p-Nitrobenzoyl-2,3,4,6-tetra-O-benzyl-b-D-
glucopyranose (12b). Formed along with 11a in 24% yield.
1H NMR (400 MHz, CDCl3) d 3.68–3.84 (m, 6H, H2, H3, H4,
H5, 2H6), 4.46–4.91 (m, 8H, 4CH2(OBn)), 5.87–5.91 (m,
1H, H1), 7.16–7.32 (m, 20H, CH(OBn)), 8.12 (m, 2H,
CHar), 8.25 (m, 2H, CHar); 13C NMR (100 MHz, CDCl3)
d 68.1 (C6), 73.6, 75.0 (2CH2(OBn)), 75.7 (C2 or C3 or C4
or C5, 2CH2(OBn)), 77.2, 80.7, 85.0 (C2 or C3 or C4 or
C5), 95.1 (C1), 123.5 (CHar), 127.9–128.5 (CH(OBn)),
131.1 (CHar), 134.6 (Cqar), 137.8–138.3 (Cq(OBn)), 150.8
(Cqar), 163.1 (CO); IR n (cmꢁ1) 1739 (C¼O), 1268 (O–
CO); MS (ICꢁ, NH3) 689 [M]; [a]2D0 –34.2 (c 1.0,
1
1.73 g of disulfide 19 as a white solid (85%). H NMR
(400 MHz, CDCl3) d 3.57 (dd, 1H, H6a, 2J6a–6b¼9.0, 3J6a–5
¼
5.2), 3.67 (t, 1H, H6b, 2J6b–6a¼3J6b–5¼9.0), 3.79 (dd, 1H, H3,
3J3–2¼9.9, 3J3–4¼2.3), 4.02 (d, 1H, H4, 3J4–3¼2.3), 4.17 (dd,
3
3
3
1H, H5, J5–6a¼5.2, J5–6b¼9.0), 4.29 (dd, 1H, H2, J2–1
¼
5.3, 3J2–3¼9.9), 4.35 (d, 1H, CH2(OBn), 2Jgem¼11.6), 4.46
2
(d, 1H, CH2(OBn), Jgem¼11.6), 4.57 (d, 1H, CH2(OBn),
2Jgem¼11.2), 4.60 (d, 1H, CH2(OBn), Jgem¼11.6), 4.68
2
2
ꢀ
CH2Cl2); mp 74–76 C; HRMS m/z calcd for C41H39NO9Na
712.2523, found 712.2531.
(d, 1H, CH2(OBn), Jgem¼11.6), 4.79 (d, 1H, CH2(OBn),
2Jgem¼11.6), 4.93 (d, 1H, CH2(OBn), Jgem¼11.2), 5.40
2
3
(d, 1H, H1, J1–2¼5.3), 7.24–7.35 (m, 20H, CH(OBn));
4.2.9. 2,3,4,6-Tetra-O-benzyl-1-S-(S-p-nitrobenzoyl)-
dithiocarbonate-1-thio-a-D-galactopyranose (14a). 1H
NMR (400 MHz, CDCl3) d (analysis of the crude product)
13C NMR (100 MHz, CDCl3) d 68.2 (C6), 70.6 (C5), 72.6,
73.4, 73.6, 75.1 (4CH2(OBn)), 74.9 (C4), 76.7 (C2), 79.4
(C3), 87.1 (C1), 127.6–128.4 (CH(OBn)), 138.1–138.8
(Cq(OBn)); MS (ES+) 1133.5 (M+Na); [a]2D0 +270.5 (c
1.0, CH2Cl2).
3
6.38 (d, 1H, H1, J1–2¼5.4); 13C NMR (100 MHz, CDCl3)
d 183.8, 178.4 (CO).
4.2.10. 2,3,4,6-Tetra-O-benzyl-1-thio-a-D-galactopyra-
nose (15a). Procedure A: To a solution of thioester 2a
(0.845 g, 1.20 mmol) in 8 mL of a mixture of dry THF/
MeOH (1/1) was added a solution of sodium methoxide
(1 M in MeOH, 1.12 mL, 1.12 mmol). The reaction was
stirred for 1 h and neutralized with Dowex acidic resin.
The resin was filtered off and the filtrate was concentrated
under reduced pressure to give the thiogalactopyranose
15a (100% on NMR spectrum of the crude product). This
was used immediately for the next step.
4.3. General procedure for the preparation of thiogalac-
topyranosides (23), (24), and (25)
A solution of the thiogalactopyranose 15a (0.70 g,
1.26 mmol), from the crude product of the disulfide reduc-
tion, in 10 mL of DMF was treated with cesium carbonate
(0.41 g, 1.26 mmol). After 10 min at rt, the electrophile
was added to the reaction mixture (10-diethoxyphos-
phoryl-1-O-tosyldecanol 20 (0.68 g, 1.5 mmol) for the prep-
aration of 23, 10-bromodecan-1-ol 21 (0.36 g, 1.5 mmol) for
the preparation of 24, and 10-bromododecan-1-ol 22 (0.40 g,
1.5 mmol) for the preparation of 25). The solution was
stirred at rt for 3 h then the reaction mixture was diluted
with Et2O and washed with brine. The organic layer was
dried over MgSO4 and then concentrated under vacuum.
The crude product can be purified by flash chromatography
at this step (15% EtOAc/petroleum ether) to afford 0.29 g of
23 (28%) or 0.22 g of 24 (25%). In the case of 25, crude
product was directly run in the next step.
Procedure B:
A solution of disulfide 19 (0.250 g,
0.22 mmol) in 3 mL of wet THF was treated with tributyl-
phosphine (0.055 mL, 0.22 mmol). After 3 h at rt, the sol-
vent was removed under vacuum and the residue was
dissolved in EtOAc, washed with brine, dried over MgSO4
then concentrated under reduced pressure to afford the thio-
galactopyranose 15a (100% on NMR spectrum of the crude
1
product). This was used immediately for the next step. H
NMR (400 MHz, CDCl3) d 1.81 (d, 1H, SH, JSH-1¼3.9),
3
3
3
3.52 (d, 2H, 2H6, J6–5¼6.4), 3.80 (dd, 1H, H3, J3–4¼2.7,
4.3.1. 2,3,4,6-Tetra-O-benzyl-1-S-diethyldecanphos-
phonate-1-thio-a-D-galactopyranoside (23). 1H NMR
3J3–2¼9.8), 3.95 (d, 1H, H4, J4–3¼2.7), 4.24 (dd, 1H, H2,
3
3J2–3¼9.8, J2–1¼5.3), 4.38 (m, 1H, H5), 4.43 (d, 1H,
(400 MHz, CDCl3)
2CH3(OEt)), 2.45–2.54 (m, 2H, CH2S), 3.53 (m, 2H, 2H6),
d
1.17–1.75 (m, 24H, 9CH2,
3
2
CH2(OBn), Jgem¼11.9), 4.47 (d, 1H, CH2(OBn),
2Jgem¼11.9), 4.57 (d, 1H, CH2(OBn), Jgem¼11.4), 4.66
3.81 (dd, 1H, H3, J3–4¼2.4, J3–2¼9.9), 3.92 (d, 1H, H4,
2
3
3

A. Ane´ et al. / Tetrahedron 62 (2006) 4784–4794
4793
3J4–3¼2.4), 4.06–4.11 (m, 4H, 2CH2(OEt)), 4.26–4.31 (m,
14H, 7CH2), 1.87 (m, 2H, CH2), 2.51–2.68 (m, 2H,
CH2S), 3.54 (t, 2H, CH2OH, J¼7.7), 3.61 (dd, 1H, H3,
3
2H, H2, H5), 4.40 (d, 1H, CH2(OBn), 2Jgem¼11.8), 4.47 (d,
2
3
1H, CH2(OBn), Jgem¼11.8), 4.57 (d, 1H, CH2(OBn),
3J3–2¼10.1, J3–4¼3.3), 3.73 (m, 2H, H6), 3.92 (m, 1H,
2
3
3
2Jgem¼11.5), 4.68 (d, 1H, CH2(OBn), Jgem¼11.7), 4.70
H4), 4.07 (dd, 1H, H2, J2–1¼5.6, J2–3¼10.1), 4.18 (m,
2
3
(d, 1H, CH2(OBn), Jgem¼11.8), 4.74 (d, 1H, CH2(OBn),
1H, H5), 5.37 (d, 1H, H1, J1–2¼5.6); 13C NMR (75 MHz,
2
2Jgem¼11.7), 4.83 (d, 1H, CH2(OBn), Jgem¼11.8), 4.94
CD3OD) d 26.5, 26.9, 30.0, 30.3, 30.5, 30.6, 30.7, 30.8,
33.6 (9CH2), 62.6 (C6), 63.0 (CH2OH), 69.7 (C2), 71.0
(C4), 72.2 (C3), 72.5 (C5), 87.5 (C1).
2
3
(d, 1H, CH2(OBn), Jgem¼11.5), 5.45 (d, 1H, H1, J1–2
¼
5.5), 7.21–7.39 (m, 20H, CH(OBn)); 13C NMR (100 MHz,
CDCl3) d 16.7, 16.8 (2CH3(OEt)), 22.5, 22.6, 25.2, 26.6,
29.1, 29.3, 29.4, 29.6, 30.7, 30.9 (10CH2), 61.5, 61.6
(2CH2(OEt)), 69.2 (C6), 69.8 (C5), 72.6, 73.5, 73.5, 74.9
(4CH2(OBn)), 75.3 (C4), 76.4 (C2), 79.7 (C3), 83.8 (C1),
127.6–128.5 (CH(OBn)), 138.2, 138.4, 138.8, 139.0
(Cq(OBn)); 31P NMR (80 MHz, CDCl3) d 32.61; [a]2D0
+79.3 (c 1.0, CH2Cl2).
4.4.3. (12-Hydroxydodecanyl)-1-thio-a-D-galactopyrano-
side (28). H NMR (400 MHz, CD3OD) d 1.30–1.35 (m,
1
16H, 8CH2), 1.41 (m, 2H, CH2), 1.63 (m, 2H, CH2), 2.51–
2.65 (m, 2H, CH2S), 3.54 (t, 2H, CH2OH, J¼6.3), 3.60
3
3
3
(dd, 1H, H3, J3–2¼9.9, J3–4¼3.5), 3.71 (m, 2H, H6), 3.88
3
3
(m, 1H, H4), 4.07 (dd, 1H, H2, J2–1¼5.3, J2–3¼9.9), 4.18
(m, 1H, H5), 5.37 (d, 1H, H1, 3J1–2¼5.3).
4.3.2. 2,3,4,6-Tetra-O-benzyl-(10-hydroxydecanyl)-1-
thio-a-D-galactopyranoside (24). 1H NMR (400 MHz,
CDCl3) d 1.16–1.60 (m, 16H, 8CH2), 2.44–2.57 (m, 2H,
3
References and notes
CH2S), 3.53 (m, 2H, 2H6), 3.62 (t, 2H, CH2OH, J¼6.6),
3
3
3.81 (dd, 1H, H3, J3–4¼2.8, J3–2¼9.9), 3.92 (d, 1H, H4,
3J4–3¼2.8), 4.28 (m, 2H, H5, H2), 4.40 (d, 1H, CH2(OBn),
1. Driguez, H. Top. Curr. Chem. 1997, 187, 85–116.
2. Andrews, J. S.; Pinto, B. M. Carbohydr. Res. 1995, 270, 51–62.
3. Witczak, Z. J.; Chhabra, R.; Chen, H.; Xie, X.-Q. Carbohydr.
Res. 1997, 301, 167–175.
4. Witczak, Z. J. Curr. Med. Chem. 1999, 6, 165–178.
5. Witczak, Z. J.; Kaplon, P.; Markus Dey, P. Carbohydr. Res.
2003, 338, 11–18.
6. Comber, R. N.; Friedrich, J. D.; Dunshee, D. A.; Petty, S. L.;
Secrist, J. A., III. Carbohydr. Res. 1994, 262, 245–255.
7. Toshima, K.; Tatsuta, K. Chem. Rev. 1993, 93, 1503–1531.
8. Garegg, P. J. Adv. Carbohydr. Chem. Biochem. 1997, 52, 179–
210.
2
2Jgem¼11.8), 4.47 (d, 1H, CH2(OBn), Jgem¼11.8), 4.57
2
(d, 1H, CH2(OBn), Jgem¼11.5), 4.68 (d, 1H, CH2(OBn),
2
2Jgem¼11.7), 4.70 (d, 1H, CH2(OBn), Jgem¼11.8), 4.74
2
(d, 1H, CH2(OBn), Jgem¼11.7), 4.83 (d, 1H, CH2(OBn),
2
2Jgem¼11.8), 4.94 (d, 1H, CH2(OBn), Jgem¼11.5), 5.45
3
(d, 1H, H1, J1–2¼5.5), 7.22–7.40 (m, 20H, CH(OBn));
13C NMR (100 MHz, CDCl3) d 25.8, 29.0–29.5, 23.9
(9CH2), 63.1 (CH2OH), 69.2 (C6), 69.8 (C5), 72.6, 73.5,
74.9 (4CH2(OBn)), 75.3 (C4), 76.4 (C2), 79.7 (C3), 83.7
(C1), 127.7–128.4 (CH(OBn)), 138.2, 138.4, 138.7, 138.9
(Cq(OBn)); IR n (cmꢁ1) 3420 (OH), 2925 (CH2), 2854
(CH2); [a]2D0 +109.8 (c 1.0, CH2Cl2); HRMS m/z calcd for
C44H56O6SNa 735.3695, found 735.3735.
9. Hanessian, S.; Lou, B. Chem. Rev. 2000, 100, 4443–4464 and
ref. cited therein.
10. Jung, K. H.; Muller, M.; Schmidt, R. R. Chem. Rev. 2000, 100,
4423–4442.
11. Demchenko, A. V. Synlett 2003, 1225–1239.
4.4. General procedure for the debenzylation of thioglyco-
sides
´
12. Codee, J. D. C.; Litjens, R. E. J. N.; van den Bos, L. J.; Over-
A solution of liquid ammoniaꢀ was treated with sodium
(0.057 mg, 2.40 mmol) at ꢁ78 C. The thiogalactopyrano-
side 23, 24 or 25 (crude product of the thioalkylation step)
in 2 mL of THF was added to the reaction mixture. After
kleeft, H. S.; van der Marel, G. A. Chem. Soc. Rev. 2005, 34,
769–782.
13. Garegg, P. J. Adv. Carbohydr. Chem. Biochem. 2004, 59, 69–
134.
14. Pachamuthu, K.; Schmidt, R. R. Chem. Rev. 2005.
15. Driguez, H. ChemBioChem. 2001, 2, 311–318.
16. Orgeret, C.; Seillier, E.; Gautier, C.; Defaye, J.; Driguez, H.
Carbohydr. Res. 1992, 224, 29–40.
17. Moreau, V.; Norrild, J. C.; Driguez, H. Carbohydr. Res. 1997,
300, 271–277.
ꢀ
1 h 30 at ꢁ78 C, the reaction mixture was neutralized
with NH4Cl (0.128 g, 2.40 mmol) before evaporation of
the solvent. The crude product was purified by flash chroma-
tography to afford the deprotected thioglycosides 26, 27, and
28 in 55% yield from disulfide 19 (i.e., over three steps).
4.4.1. 1-S-Diethyldecanphosphonate-1-thio-a-D-galacto-
pyranoside (26). H NMR (400 MHz, CD3OD) d 1.30–
18. Hashimoto, H.; Shimada, K.; Horito, S. Tetrahedron: Asymme-
try 1994, 5, 2351–2366.
1
1.41, 1.52–1.63, 1.73–1.82 (m, 24H, 2CH3(OEt), 9CH2),
2.50–2.67 (m, 2H, CH2S), 3.60 (dd, 1H, H3, J3–2¼9.8,
19. Witczak, Z. J.; Sun, J.; Mielguj, R. Bioorg. Med. Chem. Lett.
1995, 5, 2169–2174.
20. Pasetto, P.; Chen, X.; Drain, C. M.; Franck, R. W. Chem. Com-
mun. 2001, 81–82.
21. Hummel, G.; Hindsgaul, O. Angew. Chem., Int. Ed. 1999, 38,
1782–1784.
22. Blanc-Muesser, M.; Driguez, H. J. Chem. Soc., Perkin Trans. 1
1988, 3345–3351.
3
3J3–4¼2.4), 3.71 (m, 2H, 2H6), 3.89 (d, 1H, H4, J4–3
¼
3
2.4), 4.05–4.12 (m, 6H, H2, 2CH2(OEt)), 4.18 (m, 1H, H5),
3
5.36 (d, 1H, H1, J1–2¼5.3); 13C NMR (100 MHz,
CD3OD) d 16.7, 16.8 (2CH3(OEt)), 30.0–31.5 (10CH2),
62.6 (C6), 63.0, 63.1 (2CH2(OEt)), 69.8 (C2), 70.9 (C4),
72.2 (C3), 72.6 (C5), 87.4 (C1); 31P NMR (80 MHz,
CD3OD) d 34.34; [a]2D0 +174,0 (c 0.3, MeOH).
23. Xu, W.; Springfield, S. A.; Koh, J. T. Carbohydr. Res. 2000,
325, 169–176.
4.4.2. (10-Hydroxydecanyl)-1-thio-a-D-galactopyrano-
side (27). H NMR (300 MHz, CD3OD) d 1.39–1.66 (m,
24. Blanc-Muesser, M.; Defaye, J.; Driguez, H. Carbohydr. Res.
1978, 67, 305–328.
1

4794
A. Ane´ et al. / Tetrahedron 62 (2006) 4784–4794
25. Horton, D.; Wolfrom, M. L. J. Organomet. Chem. 1962, 27,
1794–1800.
42. Newman, M. S.; Karnes, H. A. J. Organomet. Chem. 1966, 31,
3980–3984.
26. Matta, K. L.; Girotra, R. N.; Barlow, J. J. Carbohydr. Res. 1975,
43, 101–109.
27. Holick, S. A.; Chiu, S.-H. L.; Anderson, L. Carbohydr. Res.
1976, 50, 215–225.
28. Blanc-Muesser, M.; Defay, J.; Driguez, H. J. Chem. Soc.,
Perkin Trans. 1 1982, 15–18.
29. Tejima, S.; Maki, T.; Akagi, M. Chem. Pharm. Bull. 1964, 12,
528–532.
43. Brown, S.; Bernardo, M. M.; Li, Z.-H.; Kotra, L. P.; Tanaka, Y.;
Fridman, R.; Mobashery, S. J. Am. Chem. Soc. 2000, 122,
6799–6800.
44. Percec, V.; Bera, T. K.; De, B. B.; Sanai, Y.; Smith, J.; Holerca,
´
M. N.; Barboiu, B.; Grubbs, R. B.; Frechet, J. M. J. J. Organo-
met. Chem. 2001, 66, 2104–2117.
45. Nishide, K.; Miyamoto, T.; Kumar, K.; Ohsugi, S.-I.; Node, M.
Tetrahedron Lett. 2002, 43, 8569–8573.
30. Sakata, M.; Haga, M.; Tejima, S.; Akagi, M. Chem. Pharm.
Bull. 1964, 12, 652–656.
46. Mikkelsen, L. M.; Skrydstrup, T. J. Organomet. Chem. 2003,
68, 2123–2128.
31. Ratajczkack, F.; Greffe, L.; Cottaz, S.; Driguez, H. Synlett
2003, 1253–1254.
32. Greffe, L.; Jensen, M. T.; Chang-Pi-Hin, F.; Fruchard, S.;
O’Donohue, M. J.; Svensson, B.; Driguez, H. Chem. Eur. J.
2002, 8, 5447–5455.
33. Gadelle, A.; Defaye, J.; Pedersen, C. Carbohydr. Res. 1990,
200, 497–498.
34. Araki, Y.; Matsuura, K.; Ishido, Y.; Kushida, K. Chem. Lett.
1973, 383–386.
47. Pougny, J. R. J. Carbohydr. Chem. 1986, 5, 529–535.
48. Tsuboyama, K.; Takeda, K.; Torrii, K.; Ebihara, M.; Shimizu, J.;
Suzuki, A.; Sato, N.; Ogura, H. Chem. Pharm. Bull. 1990, 38,
636–638.
49. Jutten, P.; Scharf, H.-D.; Raabe, G. J. Organomet. Chem. 1991,
¨
56, 7144–7149.
50. Kartha, K. P. R.; Cura, P.; Aloui, M.; Readman, S. K.; Ruther-
ford, T. J.; Field, R. A. Tetrahedron: Asymmetry 2000, 11, 581–
593.
35. Igarashi, K.; Honma, T. J. Organomet. Chem. 1970, 35, 606–
610.
36. Josse, S.; Le Gal, J.; Pipelier, M.; Cleophax, J.; Olesker, A.;
51. Kim, S.-H.; Augeri, D.; Yang, D.; Kahne, D. J. Am. Chem. Soc.
1994, 116, 1766–1775.
52. Nixon, C. M.; Le Claire, K.; Odobel, F.; Bujoli, B.; Talham, D.
R. Chem. Mater. 1999, 11, 965–976.
53. Scheffler, G.; Behrendt, M. E.; Schmidt, R. R. Eur. J. Org.
Chem. 2000, 2000, 3527–3539.
54. Dugave, C.; Menez, A. Tetrahedron: Asymmetry 1997, 8,
1453–1465.
55. Holick, S. A.; Anderson, L. Carbohydr. Res. 1974, 34, 208–
213.
56. Crich, D.; Li, H. J. Organomet. Chem. 2000, 65, 801–805.
57. Vo-Hoang, Y.; Micouin, L.; Ronet, C.; Gachelin, G.; Bonin, M.
ChemBioChem 2003, 4, 27–33.
`
Pradere, J.-P.; Dubreuil, D. Tetrahedron Lett. 2002, 43, 237–
239.
37. Thus, in our previous communication, some mistakes were
made concerning the attribution of the NMR data of compound
3, which should be identified in fact as compound 2. This con-
fusion has led to a wrong mechanism interpretation.
38. Attempt to run NMR experiment just after the addition of the
reagents, without workup, failed.
39. Schonberg, A.; Vargha, C. V. Chem. Ber. 1930, 63.
¨
40. Al-Kazimi, H. R.; Tarbell, D. S.; Plant, D. J. Am. Chem. Soc.
1955, 77, 2479–2482.
41. Powers, D. H.; Tarbell, D. S. J. Am. Chem. Soc. 1956, 78, 70–71.
58. Perrin, D. D.; Amarego, W. L. F. Purification of Laboratory
Chemicals, 3rd ed.; Pergamon: Boston, 1988.