Synthesis of S- and C-galactofuranosides via a galactofuranosyl iodide. Isolable 1-galactofuranosylthiol derivative as a new glycosyl donor

Article abstract of DOI:10.1016/j.carres.2012.08.021

The use of the easily available persilylated derivative 1 for the synthesis of C- and S-Galf derivatives has been investigated. By anomeric iodination of 1 with TMSI, followed by in situ coupling with C- and S-nucleophiles under very mild conditions and in the absence of promoters, derivatives with value as glycomimetics or as precursors of glycobiological tools were synthesized. Among them, the synthesis of the isolable 1-galactofuranosylthiol 15 is remarkable, as it paves the way for alternative approaches for S-galactofuranosyl derivatives.

Full text of DOI:10.1016/j.carres.2012.08.021

Carbohydrate Research 362 (2012) 70–78
Contents lists available at SciVerse ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Synthesis of S- and C-galactofuranosides via a galactofuranosyl iodide.
Isolable 1-galactofuranosylthiol derivative as a new glycosyl donor
⇑
Luciana Baldoni, Carla Marino
CIHIDECAR-CONICET, Dpto. de Química Orgánica, Facultad de Ciencias Exactas y Naturales, UBA, Buenos Aires (1428), Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 August 2012
Received in revised form 26 August 2012
Accepted 27 August 2012
Available online 5 September 2012
The use of the easily available persilylated derivative 1 for the synthesis of C- and S-Galf derivatives has
been investigated. By anomeric iodination of 1 with TMSI, followed by in situ coupling with C- and
S-nucleophiles under very mild conditions and in the absence of promoters, derivatives with value
as glycomimetics or as precursors of glycobiological tools were synthesized. Among them, the synthesis
of the isolable 1-galactofuranosylthiol 15 is remarkable, as it paves the way for alternative approaches for
S-galactofuranosyl derivatives.
Keywords:
Per-tert-butyldimethylsilyl-b-
galactofuranose
Ó 2012 Elsevier Ltd. All rights reserved.
D-
Galactofuranosyl iodide
C-Galactofuranosylation
S-Galactofuranosylation
1. Introduction
We have also investigated the glycosylation of 1 by in situ activa-
tion with TMSI as the galactofuranosyl iodide 2 (Scheme 1). We
The important role of carbohydrates and glycoconjugates in bio-
chemical processes has prompted the development of glycomimet-
ics as tools for studying these processes and as potential
therapeutic agents.1,2 These analogues, in which one or more
oxygen atoms of the sugar have been replaced by a carbon, sulfur,
or other heteroatoms, are very similar to the natural substrates in
most of their biological properties and conformations but also
present some useful differences. For example, they can interact
with the active site of glycosidases, but be resistant to the
hydrolysis.2,3
demonstrated the effectiveness of this mild glycosylation method
for the synthesis of several -Galf-containing molecules, being
the first report of the use of a galactofuranosyl iodide as glycosyl
D
donor.10 Also the 1,2-cis fused bicyclic
a-D-galactofuranosyl thio-
carbamate was synthesized from 1 via iodide 2.12
Obtaining derivative 1, a new galactofuranosil donor of proven
usefulness in O-glycosylation reactions via iodide 2, led us to ex-
plore further applications. Due to their potential as glycobiological
tools, we chose to synthesize S- and C-galactofuranosides from the
in situ generated galactofuranosyl iodide 2.
The occurrence of galactofuranose in pathogenic microorgan-
isms plays, in many cases, a major role in triggering their antigenic
response. This fact has motivated a great deal of interest in the syn-
2. Results and discussion
thesis of
D-Galf precursors and the development of efficient glyco-
2.1. C-Galactofuranosylation
sylation methods for these precursors.4 In this context, we have
synthesized alkyl, aryl, and heteroaryl 1-thio-b-D-galactofurano-
C-Glycosyl compounds are highly desired synthetic targets as
precursors of stable and biologically active glycomimetics,2,13
although for the C-galactofuranosylation only a few strategies have
been described. For instances, the b-cyano derivatives 3 have been
synthesized by reduction of the corresponding 1-b-nitromethyl
sides,5 thiourethanes,6 nucleosides,7 and thiodisaccharides.8,9
These compounds have been evaluated as inhibitors of the exo
b-
D
-galactofuranosidase from Penicillium fellutanum.
More recently, we have reported the synthesis of a new precur-
sor, per-O-TBS-b- -galactofuranose (1), obtained as a crystalline
product in just one high yield step from
-galactose.10 The same
derivative,14 or by condensation of per-O-benzoyl-
D-Galf with
D
TMSCN promoted by BF3ꢀOEt2.15 By hydrolysis of nitrile function
of 3 (R = Bz), the methyl ester 4 was also synthesized.15 The intro-
duction of carbon substituents at C-1 was also achieved by olefin-
ation of protected derivatives of galactono-1,4-lactone. By further
elaboration phosphonates of the type of 5 were accessed.16
D
procedure was extended to other sugars and from the resulting
per-O-TBS-furanoses, acetylated derivatives were synthesized.11
⇑
Corresponding author. Tel./fax: +54 11 45763352.
E-mail address: cmarino@qo.fcen.uba.ar (C. Marino).
0008-6215/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.carres.2012.08.021

L. Baldoni, C. Marino / Carbohydrate Research 362 (2012) 70–78
71
O
HO
or
O
O
O
O
O
O
O
HO
OTBS
OTBS
or
OTBS
OTBS
OTBS
OTBS
I
OTBS
O
OTBS
O
OTBS
EtN(iPr)2
CH2OTBS
CH2OTBS
TMSI
OTBS
OTBS
OTBS
OTBS
?
SR
CH2R
O
OTBS
O
OTBS
CH2OTBS
CH2OTBS
or
2
1
OTBS
OTBS
OTBS
CH2OTBS
OTBS
CH2OTBS
Scheme 1. Galactofuranosides via galactofuranosyl iodide 2.
During the last years, the glycosyl iodides have been revalued as
glycosyl donors.17 Gervay-Hague and Hadd reported the C-glyco-
sylation of glycopyranosyl iodides with simple anionic nucleo-
philes such as diethyl malonate or nBu4NCN in basic medium,18
or with vinyl magnesium bromide.19 An interesting example of
the latter, is the synthesis of a C-glycosidic analogue of the immu-
nogenic bacterial glycolipid BbGL2, synthesized by C-vinylation of
a galactosyl iodide and subsequent olefin cross metathesis as key
steps.19
course, therefore other reaction conditions were investigated. It
is worth to mention that by treatment of 1 with TMSI followed
by addition of a base (EtN(iPr)2 or DBU), glycal 7 was obtained in
quantitative yield. In first instance, we decided to exclude the
EtN(iPr)2 in the second step of the reaction, in order to prevent
the 1,2-elimination. Moreover, as Lewis acid promoters have been
used for the condensation of glycopyranosyl iodides with less
reactive acceptors,21 we expected that the mild acidic medium,
generated during reaction of the iodide 2, would promote the
C-glycosylation. Under these conditions, after 24 h of reaction at
room temperature compound 8 was obtained as an anomeric mix-
Within the C-glycosides, the 3-C-glycosylprop-1-enes, such as 6,
represent a family of powerful precursors due to the versatility of
the double bond.20 Lay and co-workers studied the O-, S-, N-, and
ture (3:1 ba ratio) which could not be separated by column chro-
C-glycosylation of 2-amino-2-deoxy-
D
-glucopyranosyl iodides
matography. When the C-glycosylation was conducted in the
presence of different concentrations of Lewis acids (ZnI2 or
TMSOTf), the yields of 8 were lowered by formation of the anhydro
derivative 9.10 The best results were obtained carrying out the
reaction in the absence of a base or a Lewis acid promoter, at room
temperature during 24 h, affording compound 8 with 69% yield.
The 13C NMR spectrum of 8 showed the signals corresponding
to the aglycone (d 135.4, 116.6, and 37.5) and the signals for C-1
and C-2 (84.5 and 83.2 ppm), were shielded by the effect of the
C-aglycone. The 1H NMR spectrum of 8 also exhibited the signals
corresponding to the aglycone protons (d 5.85, 5.08, and 2.35)
and a shielded and complex signal for H-1 (multiplet, 3.92 ppm),
as a result of the coupling with the H-2 and the aglycone protons.
Furthermore, in the 1H–1H COSY spectrum the H-1 signal corre-
lated with the –CH2CH@CH2 signal. Although NOE measurements
did not provide information about the anomeric configuration,
the low field signals for C-2 and C-4 (d P80 ppm) observed in
the 13C NMR spectrum for the major component, were consistent
and particularly for the C-glycosylation, allyltrimethylsilane (ally-
lTMS) was used as C-nucleophile, using BF3ꢀEt2O as promoter.21
On this basis, we decided to investigate the synthesis of the
C-glycoside 6 (Fig. 1) using the conditions optimized for O-
glycosylations via the galactofuranosyl iodide.10 Therefore, the
per-O-TBS-derivative 1 was treated with 1.2 equiv of TMSI in anhy-
drous CH2Cl2 at 0 °C. When monitoring by TLC showed complete
consumption of 1, allylTMS (1.3 equiv) and EtN(iPr)2, were added.
After 24 h of reaction, a main product (Rf = 0.79 10:1 hexane/
EtOAc) was isolated by column chromatography (66%). The 1H
NMR spectrum of this product showed no signals corresponding
to the aglycone, and the most deshielded signal, a singlet at
6.02 ppm, correlated with a signal at 129.0 ppm in a HSQC NMR
experiment. This signal, together with another one at 137.4 ppm,
confirmed the presence of a C-C double bond, and as no 13C–1H
correlation was observed for C-2, suggested the glycal structure
of 7 for the compound (Scheme 2). The other 1H and 13C NMR sig-
nals showed d and multiplicities in agreement with this structure.
For other analogue glycopyranosyl iodide donors, the formation of
glycals was also observed.18,22
with a b configuration.15,23 The signals corresponding to the
a-ano-
mer were also assigned.
Deprotection of 8 was accomplished with nBu4NF (TBAF) in THF
with quantitative yield.24 After column chromatography purifica-
tion the NMR spectra of compound 6 showed signals correspond-
Our results seem to indicate that the allylation of iodide 2 with
a weak nucleophile like allyl TMS does not follow the expected
ing to both anomers in a 4:1 b/a ratio.
CN
COOCH3
O
O
O
O
2.2. S-Galactofuranosylation
OR
OBz
OR
PO(OH)2
OH
C
R2
OH
OR
OBz
OR
OR
CH2OR
Thiodisaccharides are generally synthesized by reaction of
glycosyl donors with thiols or thiolate anions, or by condensation
of 1-thioaldose donors with acceptors bearing good leaving
groups.3b In the case of galactofuranose, thioglycosides have been
obtained from per-O-acylated derivatives by SnCl4 or BF3ꢀOEt2 pro-
moted glycosylation with thiol.5,25 Their use as glycosyl donors has
OR
CH2OR
OBz
CH2OBz
OH
CH2OH
5
R = H
R = F
3
R = Ac
R = Bz
6
4
Figure 1. Synthetic C-galactofuranosides.

72
L. Baldoni, C. Marino / Carbohydrate Research 362 (2012) 70–78
I
OTBS
TMSI, 4Å MS
O
OTBS
O
OTBS
O
OTBS
H
EtN(iPr)2
CH2Cl2, 0 °C
(with or without
acceptor)
OTBS
OTBS
CH2OTBS
OTBS
OTBS
CH2OTBS
OTBS
OTBS
CH2OTBS
rt
1
2
66 %
7
without
TMS
promoter
rt
O
OH
O
OTBS
O
TBAF
THF
OTBS
OH
TBSO
OTBS
OTBS
OH
CH2OH
OTBS
CH2OTBS
O
H2C
9
99 %
8
6
(β/α 3:1) 69 %
Scheme 2. Synthesis of 3-C-(b-D-galactofuranosyl)prop-1-ene via the galactofuranosyl iodide 2.
also been investigated,26 and the MoO2Cl2 has been proved a useful
catalyst in the case of labile acceptors.9 On the other hand, as a 1-
thioGalf derivative was not available, the construction of intergly-
cosidic S-linkages has been performed by in situ generation of such
a thioaldose from an isothiourea derivative.9
The S-glycosylation of 1 proceeded with less stereospecificity
than in the case of the thioglycosylation by different promoters
of perbenzoylated Galf,5,8,9 in which the anchimeric assistance
operates, and even lower than in the O-glycosylations of 1 with
simple alcohols.10 However, the yield was excellent and it was pre-
dicted that the diastereoselectivity should be increased using bulky
thiols as acceptors. To verify this hypothesis, we studied the reac-
For studying the S-glycosylation of 1 via the glycosyl iodide, we
first chose to use 4-methylthiophenol as a model acceptor. Follow-
ing the protocol for the O-glycosylation via the glycosyl iodide,10
compound 10 was isolated in ꢁ60% yield. In the presence of Et-
N(iPr)2 (1.2 equiv), which improves the nucleophilicity of the thio-
phenol, 10 was obtained in 95% yield as an anomeric mixture in a
tion of 2 with the 6-thio-D
-galactopyranose derivative 11.27 Com-
pound 11 was selected as we had previously observed that
iodide 2 reacts more favorably with isopropylidene derivatives
than with acylated ones.10 The efficiency of the glycosylation of 2
with 11 was sensitive to the concentration of the base. In the pres-
ence of a stoichiometric amount of EtN(iPr)2 (1.2 equiv), disaccha-
ride 12 was obtained in 65% yield. Glycal 7 and the disulfide
formed by dimerization of 11 were present in the reaction mixture.
The reduction of the amount of EtN(iPr)2 (0.6 equiv) had no effect
in the yield of 12 and with an excess the proportion of disulfide
was increased. Therefore, the amount of base used had to be bal-
anced so that it was enough to neutralize the mild acidic medium
to avoid byproducts of recombination of 1, but did not generate
1:2
a
/b ratio (Scheme 3). The 1H NMR spectrum of the anomeric
mixture of 10 showed signals corresponding to H-1 of both ano-
mers (2 d, d 5.41 and 5.24) with similar J1,2 (3.1 Hz and 3.5 Hz,
respectively). The compound which showed the more deshielded
C-1 signal (93.2 ppm with a cross peak with the doublet at
5.24 ppm) and the signals for C-4 and C-2 over de 80 ppm (d 85.4
and 84.9, respectively) was assigned as the b-anomer.23 The signal
at d 5.41, which showed in the HSQC spectrum a cross peak at
91.5 ppm, was assigned to the
a-anomer.
O
OTBS
I
OTBS
O
OTBS
O
OTBS
S
CH
3
4-methylthiophenol
TMSI, 4Å MS
CH Cl 0 °C
i
EtN( Pr)
2
2,
2
OTBS
OTBS
CH OTBS
OTBS
OTBS
OTBS
OTBS
rt
2
CH OTBS
2
CH OTBS
2
10
95 %
1
2
SH
O
O
i
EtN( Pr)
rt
2
O
O
O
11
S
O
O
O
O
OTBS
O
O
OTBS
OTBS
CH OTBS
2
12 65 %
Scheme 3. S-Galactofuranosylation via glycosyl iodide 2.

L. Baldoni, C. Marino / Carbohydrate Research 362 (2012) 70–78
73
other undesired products such as 7 or the disulfide mentioned be-
fore. Remarkably, under the reaction conditions, the newly formed
thioglicoside does not undergo activation, therefore it could not act
as a glycosyl donor as might occur in a product obtained by a tri-
chloroacetimidate glycosylation in the presence of TMSOTf.28 As
expected, with this bulky acceptor the stereospecificity of the reac-
tion was excellent and only the 1,2-trans anomer was obtained.
The configuration of 12 was established as b due to the presence
of a doublet with a small coupling constant (3.1 Hz) at d 5.15 for
H-10 in 1H NMR spectrum, in addition to the signals corresponding
to C-20 and C-40 above 80 ppm (80.7 and 89.5 ppm, respectively).
the HRMS was identified as a mixture of the b-disulfide 19
(3%) and 1 (10–12%), as a result of recombination of iodide 2
with –TMS or –TBS during the reaction.
The presence of the –SH functionality was further confirmed by
standard acetylation, affording the derivative 16. The 1H NMR
spectrum of 16 showed two singlets at 2.34 and 2.33 ppm corre-
sponding to the SC(O)CH3 of each anomer.32 Also, the anomeric sig-
nals (d 5.93, J = 3.6 Hz, H-1a and d 5.85, J = 1.5 Hz, H-1b) were
simplified being doublets instead of the double doublets, and
deshielded with respect to the analogue signals of 15. The 13C
NMR spectrum of 16 exhibited the signals corresponding the
SC(O)CH3 at 30.97 and 30.93 ppm, and signals at d 194.73 and
194.69 for the carbonyl group of each anomer.
2.2.1. Synthesis and applications of 1-thio-D-galactofuranose
(15)
The deprotection of 15 was accomplished with TBAF. The NMR
spectra showed that the product was a mixture mainly formed by a
compound with b-configuration, but the dC-1 (93.2 ppm), deshield-
ed with respect to dC-1 of 15, and corresponded to an S-substituted
aglycone. These data, together with the absence of signals corre-
sponding to -SH in the 1H NMR spectrum and the presence of an
ion at m/z 413.0558 in the ESI-HRMS spectrum (M+Na), confirmed
the disulfide structure 18. The minor components of the mixture
Taking into account that a-glycosylthiols, such as 14, are stere-
oselectively synthesized from 1,6-anhydrosugars by reaction with
(TMS)2S promoted by TMSOTf29 (Scheme 4), and as the anhydro-
derivative 9 can be readily prepared,10 we decided to evaluate this
compound as a synthetic precursor by studying the reaction of 9
with (TMS)2S/TMSOTf. However, under the numerous reaction
conditions assayed (solvents, temperature, amount of reagents),
the 1,6-anhydro ring of 9 resisted the opening. Probably, this 6-
membered ring fused to the furanose is less strained than the 5-
membered ring fused to the pyranose as in 13, disfavoring the
opening.30
In the course of this study, Schmidt described the use of (TMS)2S
not only for the opening of 1,6- and 1,2-anhydrosugars but also as
S-nucleophile in trichloracetimidate glycosylations.31 With the
(TMS)2S in hand, we decided to use this compound as acceptor in
the glycosylation of 1 via the glycosyl iodide 2. The use of the base
in the second step of the reaction was also avoided, as in the C-
galactofuranosylation, because also in this case the glycal was ob-
tained. Thus, once formed 2 by treatment of 1 with TMSI, was
added (TMS)2S (1.3 equiv). After 16 h of reaction at room temper-
ature compound 15 was obtained as an anomeric mixture in a
were disulfides with
units, formed from 15
a
a
configuration in one or both of the Galf
. Free thioaldose 17 was not detected.
As mentioned above, compound 15 represents a valuable syn-
thon. To demonstrate its usefulness, we studied reactions that
would allow installing an S-Galf interlinkage, in a precursor of a
thiodisacharide. The Michael-type addition of glycosyl thiols to su-
gar enones provides an efficient route to S-disaccharides.33,34 The
addition of thioaldoses to the hex-3-enopyranosid-2-ulose 2035
36–38
´
has been extensively studied by Varelas group.
Particularly
for the construction of S-furanosyl linkage, the elusive 1-thiofuranoses
were generated in situ from the corresponding isothiourea deriva-
tives.8,9 Now, with the thioaldose 15 in hand, we investigated the
Michael addition to the enone 20. Compound 15 was treated with
triethylamine and the enone 20, at a low temperature in order to
prevent the elimination of the enone 6-OAc group. Compounds
21 and 22 were obtained as major products, together with a
small amount of 23 (Scheme 6). The formation of the
2:1 b
a ratio (Scheme 5). By column chromatography purification,
although fractions enriched in the b-anomer were obtained, com-
plete anomeric resolution could not be achieved. Compound 15,
obtained in 66% yield was stable and it could be stored for several
months in the freezer.
a-linked thiodisaccharide 23 may be attributed to the presence
of 15 in the starting material. Compared with the O-glycosides,
a
The 1H NMR spectrum of 15 showed two double doublets corre-
sponding to the anomeric signals (d 5.28 and 5.11) coupled with
two doublets at d 2.59 (J = 9.2 Hz) and 2.25 (J = 10.0 Hz), character-
istic of the –SH groups,29b which in turn did not correlate with any
carbon in a HSQC experiment. The 13C NMR spectrum of 15 showed
S-glycosides are quite stable, so the anomeric configuration of
the glycosylthiols is maintained during glycosylation reactions.29b
Compounds 21 and 22 result from the addition of 15 to the respec-
tive
a or b faces of 20. In the case of thioaldopyranoses and the
arabinofuranosyl isothiourea derivative the addition occurs
diastereoselectively from the face of the enone opposite to the
axially oriented anomeric subtituent.8,36 However, for the per-
protected
a and b anomeric carbons (d 81.6 and 85.3, respectively),
as expected for S-sugars.5,23 Together with 15, a faster moving
fraction was isolated, which on the basis of the NMR spectra and
O-benzoylated isothioureide of D-Galf, loss of selectivity was also
observed.9
The identity of 21–23 was established on the basis of the NMR
spectra and particularly the configurations of each C-4 were con-
firmed by comparison of the JH,H with those observed for the anal-
ogous thiodisaccharides obtained from per-O-benzoyl-Galf.9
Another approach for the S-galactofuranosylation would be the
SN2 type coupling-of 15 with an acceptor with a good leaving
group. We investigated conditions for the reaction of 15 with ben-
zylbromide under basic conditions (Scheme 6). Activation of 15
with NaH in DMF or Et3N in CH2Cl2, gave glycoside 24 in poor yield
(19% and 12%, respectively). The best results were obtained when
15 was treated with benzyl bromide in a biphasic system in the
presence of NaHCO3,31 furnishing 24 in 80% yield with good
O
OBn
(TMS) S (1,4 equiv)
2
TMSOTf (0,4 equiv)
OH
OBn
O
O
Bn
O
BnO
CH Cl , 50 ºC
2
2
OBn
OBn
88 %
SH
14 100 % α
13
SH
O
O
OTBS
(TMS) S , TMSOTf
2 X
OTBS
OTBS
OTBS
CH OH
TBSO
OTBS
b-stereoselectivity (b
In the framework of our project on glycobiology of Galf,39 com-
pounds 6 and 18 were evaluated against the exo b- -galactofura-
a 4:1).
O
H C
2
2
D
9
15β
nosidase from Penicillium fellutanum. Neither compound was
Scheme 4. 1-Glycosylthiols from 1,6-anhydrosugars.
found to be an inhibitor of this enzyme.

74
L. Baldoni, C. Marino / Carbohydrate Research 362 (2012) 70–78
I
(TMS) S
2
1,3 equiv.
O
OTBS
OTBS
TMSI, 4Å MS
O
OTBS
O
OTBS
O
OTBS
Ac O, py
2
SH
SAc
CH Cl 0 °C
2
2,
temp. amb.
OTBS
OTBS
OTBS
OTBS
CH OTBS
OTBS
OTBS
OTBS
OTBS
CH OTBS
2
CH OTBS
2
2
CH OTBS
2
16
2
1
15 66 %
TBAF, THF
O
OTBS
O
OH
O
OH
S
S
SH
OH
OTBS
OTBS
OH
OH
OH
CH OTBS
2
CH OH
2
CH OH
2
2
2
19
17
18 41 %
Scheme 5. Synthesis of 1-thio-D-Galf via the iodide 2.
H
OAc
O
OAc
O
H
H
S
OAc
O
OTBS
O
S
OTBS
O
O
O
H
H
O
O
20
OTBS
OTBS
OTBS
OTBS
CH OTBS
2
H
O
Et N
3
O
O
OTBS
CH OTBS
2
CH Cl
2
2
0 ºC
22 35 %
21 46 %
O
OAc
O
S
SH
OTBS
OTBS
OTBS
CH OTBS
2
H
H
H
OTBS
OTBS
O
O
CH OTBS
2
BnBr
base
23 14%
15
SBn
O
CH Cl
2
2
OTBS
0 ºC
OTBS
OTBS
base
yield
CH OTBS
2
24
NaH, DMF
Et3N, CH2Cl2
19 %
12 %
NaHCO3, H2O/EtOAc 80 % (β/α 4:1)
Scheme 6. Synthesis of 1-S-
D-Galf derivatives using 15 as donor.
2.3. Conclusions
could be further elaborated by a cross-metathesis reaction or be
functionalized by oxidation and conjugation with proteins or chro-
mophores, among other applications.
The construction of the S-Galf linkage was attempted by two
strategies. First, the thioglycosylation of glycosyl iodide 2 was per-
formed with 4-methylthiophenol, with a 6-thiosugar acceptor and
with (TMS)2S. In the last case the isolable 1-thiogalactofuranose 15,
was obtained. The other approach, the S-alkylation of 15 or the
Michael addition of 15 to the enone 20, showed the potential of
this thioaldose to generate S-interglycosidic linkages.
The use of persilylated derivative 1 for the synthesis of C- and
S-Galf derivatives has been investigated. The target compounds
were selected on the basis of their utility as glycomimetics or as
precursors of glycobiological tools.
The C-glycoside 8 was obtained in good yield and moderate
b-diastereoselectivity by conducting the glycosylation reaction
without promoters and in weakly acid medium, in contrast to
the O-glycosylations, that have been performed under basic condi-
tions.10 In this way, the 1,2-elimination which resulted in the for-
The advantage of the described methodologies relies on the pos-
sibility to introduce C- or S-Galf units under mild conditions, com-
patible with labile acceptors. Studies directed to the improvement
mation of glycal
intermediate for conjugation reactions. The terminal double bond
7 was avoided. Compound 8 is a useful

L. Baldoni, C. Marino / Carbohydrate Research 362 (2012) 70–78
75
of the stereoselectivity of the glycosylation via galactofuranosyl io-
dide 2 using bulky acceptors and the S-alkylation of 15 with carbo-
hydrate derivatives are currently in progress.
137.4 (C-2), 129.0 (C-1), 86.3 (C-4), 76.6 (C-3), 74.3 (C-5), 63.5
(C-6), 29.7, 25.9, 25.8, 25.7 (SiC(CH3)3), 18.25, 18.16, 18.11, 18.09
(SiC(CH3)3), ꢂ3.9, ꢂ4.0, ꢂ4.5, ꢂ4.8, ꢂ4.86, ꢂ4.88, ꢂ5.43, ꢂ5.45
(Si(CH3)2). HRMS (ESI) m/z calcd for C30H66NaO5Si4 [M+Na]+:
641.3880. Found: 641.3900.
3. Experimental
3.1. General synthetic methods
3.3.2. 3-C-(2,3,5,6-Tetra-O-tert-butyldimethylsilyl-a,b-D-
galactofuranosyl)prop-1-ene (8)
Analytical thin layer chromatography (TLC) was performed on
Silica Gel 60 F254 (Merck) aluminum supported plates (layer thick-
ness 0.2 mm) with solvent systems given in the text. Visualization
of the spots was effected by exposure to UV light and charring with
a solution of 10% (v/v) sulfuric acid in EtOH, containing 0.5% p-anis-
aldehyde. Column chromatography was carried out with Silica Gel
60 (230–400 mesh, Merck). Optical rotations were measured with
a Perkin–Elmer 343 digital polarimeter. Nuclear magnetic reso-
nance (NMR) spectra were recorded with a Bruker AMX 500 spec-
trometer. Assignments of 1H and 13C were assisted by 2D 1H-COSY
and HSQC experiments. High resolution mass spectra (HRMS ESI+)
were recorded in a Bruker micrOTOF-Q II spectrometer.
Compound 8 was obtained according to the general procedure
for glycosylation, using allylTMS (1.3 equiv, 0.053 mL, 0.34 mmol)
as acceptor, without EtN(iPr)2. After stirring at room temperature
during 16 h the solution was diluted with CH2Cl2, washed with
NaHCO3 (ss) and water, dried (Na2SO4), and concentrated. The syr-
up obtained was purified by column chromatography (99:0.5 hex-
ane/EtOAc) affording syrupy compound 8 (0.118 g, 69%) as an
inseparable b
hexane/EtOAc twice developed), [
a
mixture in a 3:1 ratio, which gave Rf = 0.52 (7:0.1
ꢂ15.3 (c 1, CHCl3). For
a]
D
the major product (b-anomer): 1H NMR (CDCl3, 500 MHz) d
5.92–5.80 (m, 1H, CH2CH@CH2), 5.14–5.02 (m, 2H, CH2CH@CH2),
4.19–4.16 (m, 1H, H-3), 3.95–3.90 (m, 1H, H-1), 3.89–3.87 (m,
1H, H-2), 3.87–3.81 (m, 2H, H-4, H-5), 3.69 (dd, J = 5.3, 10.2 Hz,
1H, H-6), 3.56 (dd, J = 5.2, 10.2 Hz, H-60), 2.48–2.25 (m, 2H,
CH2CH@CH2), 0.93–0.84 (m, 36H, SiC(CH3)3), 0.11–0.03 (m, 24H,
Si(CH3)2). 13C NMR (CDCl3, 125.8 MHz) d 135.4 (CH2CH@CH2),
116.6 (CH2CH@CH2), 86.5 (C-4), 84.5 (C-1), 83.2 (C-2), 80.8 (C-3),
74.2 (C-5), 65.4 (C-6), 37.5 (CH2CH@CH2), 29.7, 27.3, 26.16, 26.09,
26.08, 26.06, 26.03, 25.96, 25.89, 25.8, 25.6, 24.5 (SiC(CH3)3),
18.5, 17.8 (SiC(CH3)3), ꢂ4.1, ꢂ4.2, ꢂ4.3, ꢂ4.39, ꢂ4.45, ꢂ5.27,
ꢂ5.33 (Si(CH3)2). HRMS (ESI) m/z calcd for C33H73O5Si4 [M+H]+:
661.4530. Found: 661.4551.
3.2. General procedure for the glycosylation of 1 promoted by
TMSI
A
solution of 1 (0.20 g, 0.26 mmol) in anhydrous CH2Cl2
(10.0 mL) containing dry 4 Å powdered molecular sieves was
cooled to 0 °C and stirred during 10 min under Ar. Then, TMSI
(1.2 equiv, 0.042 mL, 0.32 mmol) was added and the solution was
stirred at 0 °C until TLC monitoring showed complete transforma-
tion of 1 into two lower moving products, the 1-iodo intermediate
2 (Rf = 0.70, 10:1 hexane/EtOAc) and some 2,3,5,6-tetra-O-TBS-a,b-
D
-galactofuranose (Rf = 0.54), formed as a result of the hydrolysis of
3.3.3. 3-C-(a,b-D-Galactofuranosyl)prop-1-ene (6)
2 on the silica gel plate.10 A solution of the acceptor (1.3 equiv,
0.34 mmol) in CH2Cl2 (5.0 mL) and EtN(iPr)2 (0.054 mL,
0.32 mmol), when indicated, were added by syringe, and the stir-
ring was continued until consumption of the components of
Rf = 0.70 and 0.54. The work up is indicated in each individual case.
Compound 6 was obtained from 8 (0.14 g, 0.2 mmol) according
to the general procedure for O-desilylation. After 30 min of stirring
the solvent was evaporated and the syrup was purified by column
chromatography (9:1 EtOAc/CH3OH) to afford syrupy compound 6
(0.04 g, 96%) as an inseparable anomeric mixture (b/
ꢂ44.0 (c 0.9, CH3OH); Rf = 0.70 (7:1:2 n-PrOH/NH3/H2O). For the
b-anomer: 1H NMR (D2O, 500 MHz)
5.95–5.84 (m, 1H,
a 4:1); [a]
D
3.3. General procedure for O-desilylation
d
CH2CH@CH2), 5.25–5.12 (m, 1H, CH2CH@CH2), 4.16 (t, J = 6.5 Hz,
1H, H-3), 3.94 (dd, J = 6.0, 7.0 Hz, 1H, H-2), 3.92–3.88 (m, 1H, H-
1), 3.82–3.78 (m, 2H, H-4, H-5), 3.68–3.60 (m, 2H, H-6, H-60),
2.43 (m, 2H, CH2CH=CH2). 13C NMR (D2O, 125.8 MHz) d 132.2
(CH2CH@CH2), 116.4 (CH2CH@CH2), 79.8 (C-4), 79.7 (C-1), 77.8
(C-2), 75.4 (C-3), 69.6 (C-5), 61.2 (C-6), 35.0 (CH2CH@CH2). For
To a solution of the silylated compound (0.1 mmol) in freshly
distilled THF (10.0 mL), cooled at 0 °C, TBAF (0.209 g, 0.8 mmol)
was added.10,24 The solution was stirred for 10 min at 0 °C and then
at room temperature until TLC monitoring showed consumption of
the starting material. The solution was partitioned with CH2Cl2/
H2O and the aqueous phase was evaporated and purified by col-
umn chromatography, as indicated in each case.
the minor product (a
-anomer), selected signals: 1H NMR (D2O,
500 MHz) d 4.13 (dd, J = 1.5, 4.0 Hz, 1H, H-3), 4.09–4.04 (m, 2H,
H-1, H-2). 13C NMR (D2O, 125.8 MHz) d 133.0 (CH2CH@CH2),
115.8 (CH2CH@CH2), 83.1 (C-4), 79.27 (C-1), 77.4 (C-3), 75.7
(C-2), 70.2 (C-5), 61.2 (C-6), 30.9 (CH2CH@CH2). HRMS (ESI/APCI)
calcd for C9H16NaO5 [M+Na]+: 227.0890. Found: 227.0896.
3.3.1. 1,4-Anhydro-2,3,5,6-tetra-O-tert-butyldimethylsilyl-
D-
lyxo-hex-1-enitol (7)
A
solution of 1 (0.14 g, 0.19 mmol) in anhydrous CH2Cl2
(10.0 mL) containing dry 4 Å powdered molecular sieves was
cooled to 0 °C and stirred during 10 min under Ar. Then, TMSI
(1.2 equiv, 0.030 mL, 0.23 mmol) was added and the solution was
stirred at 0 °C during 0.5 h. Once formed the galactofuranosyl io-
dide 2, EtN(iPr)2 (0.54 mL, 0.32 mmol) or DBU (0.11 mL,
0.38 mmol) was added. The reaction was allowed to reach room
temperature and the stirring was continued for 24 h. TLC monitor-
ing showed a single product, Rf = 0.79 (10:1 hexane/EtOAc) or
Rf = 0.39 (7:0.1 hexane/EtOAc twice developed) which was purified
by column chromatography (10:1 hexane/EtOAc) affording syrupy
3.3.4. 4-Methylphenyl 2,3,5,6-tetra-O-tert-butyldimethylsilyl-1-
thio-a,b-D-galactofuranoside (10)
Compound 10 was obtained according to the general procedure
for glycosylations of 1 promoted by TMSI, using 4-methylthiophe-
nol (1.3 equiv, 0.042 g, 0.34 mmol) as acceptor in the presence of
EtN(iPr)2 (0.054 mL, 0.32 mmol). When TLC showed total conver-
sion to a product of Rf = 0.50 (7:0.1 hexane/EtOAc, twice devel-
oped) the solution was diluted with CH2Cl2, washed with
NaHCO3 (ss) and water, dried (Na2SO4), and concentrated. The syr-
up was purified by column chromatography (0.5% EtOAc in hex-
ane) affording syrupy compound 10 (0.182 g, 94.5%) as an
compound 7 (0.106 g, 66%), [
a]
ꢂ62.1 (c 1.1, CHCl3). 1H NMR
D
(CDCl3, 500 MHz) d 6.06 (s, 1H, H-1), 4.72 (dd, J = 0.8, 3.4 Hz, 1H,
H-3), 4.22 (dd, J = 2.7, 3.4 Hz, 1H, H-4), 3.74–3.65 (m, 2H, H-5, H-
6), 3,50 (dd, J = 5.0, 9.5 Hz, H-60), 0.92–0.87 (m, 36H, SiC(CH3)3),
0.15–0.07 (m, 24H, Si(CH3)2). 13C NMR (CDCl3, 125.8 MHz) d
inseparable anomeric mixture (b/
1H NMR (CDCl3, 500 MHz)
J = 3.1 Hz, 0.5H, H-1 ), 5.24 (d, J = 3.5 Hz, 1H, H-1b), 4.21 (dd,
a
2:1), [
a
]
ꢂ38.4 (c 1.1, CHCl3).
D
d
7.44–7.06 (aromatic), 5.42 (d,
a

76
L. Baldoni, C. Marino / Carbohydrate Research 362 (2012) 70–78
J = 2.7, 4.7 Hz, 1H, H-3b), 4.18–4.15 (m, 1H, H-4b), 4.15–4.14 (m,
0.5H, H-3 ), 4.11 (dd, J = 2.8, 3.5 Hz, 1H, H-2b), 4.07 (dd, J = 1.5,
3.1 Hz, 0.5H, H-2 ), 3.93–3.89 (m, 0.5H, H-5 ), 3.86–3.81 (m,
1.5H, H-4 , H-5b), 3.74–3.67 (m, 1.5H, H-6 ,b), 3.63 (dd, J = 4.9,
10.6 Hz, 0.5H, H-60a), 3.60 (dd, J = 5.6, 10.1 Hz, 1H, H-60b), 2.32,
Si(CH3)2). 13C NMR (CDCl3, 125.8 MHz) d 89.6 (C-4b), 87.4 (C-2b),
a
87.2 (C-4
a
), 85.3 (C-1b), 81.6 (C-1
a
), 80.3 (C-2
a), 79.6 (C-3b),
a
a
77.7 (C-3
a
), 74.1 (C-5 ), 73.7 (C-5b), 66.4 (C-6b), 65.2 (C-6a
a
),
a
a
26.2, 26.1, 26.04, 26.0, 25.8, 25.7, 25.6 (SiC(CH3)3), 18.4, 18.31,
18.27, 17.9, 17.8, 17.7 (SiC(CH3)3), ꢂ3.9, ꢂ4.1, ꢂ4.2, ꢂ4.37, ꢂ4.42,
ꢂ4.47, ꢂ4.5, ꢂ4.67, ꢂ4.7, ꢂ5.1, ꢂ5.23, ꢂ5.25 (Si(CH3)2). HRMS
(ESI) m/z calcd for C30H68NaO5SSi4 [M+Na]+: 675.3757. Found:
675.3782.
2.31 (2s, 4.5H, CH3a,b), 0.91–0.85 (m, 54H, SiC(CH3)3), 0.22–0.06
(m, 36H, Si(CH3)2). 13C NMR (CDCl3, 125.8 MHz) d 136.6, 136.1,
133.3, 132.3, 131.5, 130.7, 129.8, 129.43, 129.40 (aromatic), 93.2
(C-1b), 91.5 (C-1
a
), 90.1 (C-4
), 79.8 (C-3b), 77.8 (C-3 ), 74.2 (C-5
), 64.8 (C-6b), 26.2, 26.1, 26.0, 25.97, 25.9, 25.8, 25.74, 25.71,
,b), 18.6, 18.4, 18.3,
a
), 85.1 (C-4b), 84.9 (C-2b), 80.8 (C-
2
6
a
a
a
a), 73.5 (C-5b), 66.6 (C-
3.3.7. S-Acetyl-2,3,5,6-tetra-O-tert-butyldimethylsilyl-1-thio-
a
,b-
D-galactofuranose (16)
25.66 (SiC(CH3)3), 21.04, 21.01 (2C, SPhCH3
a
To a stirred solution of 15 (0.013 g, 0.02 mmol) in dry pyridine
18.2, 17.9, 17.8 (SiC(CH3)3), ꢂ3.8, ꢂ4.0, ꢂ4.1, ꢂ4.19, ꢂ4.21, ꢂ4.3,
ꢂ4.4, ꢂ4.45, ꢂ4.5, ꢂ4.6, ꢂ4.7, ꢂ4.8, ꢂ5.1, ꢂ5.2, ꢂ5.3, ꢂ5.34, ꢂ5.4
(Si(CH3)2). HRMS (ESI) m/z calcd for C37H74NaO5Si4 [M+Na]+:
765.4225. Found: 765.4247.
(1 mL) at 0 °C, acetic anhydride (0.050 mL) was added. After 2 h at
room temperature the reaction mixture was coevaporated under
vacuum with methanol and toluene, affording syrupy compound
16 (11.8 mg, 99%), Rf = 0.63 (10:1 hexaneEtOAc); [
0.7, CHCl3). 1H NMR (500 MHz, CDCl3) d 5.93 (d, J = 3.5 Hz, 0.5H,
H-1 ), 5.85 (d, J = 1.5 Hz, 1H, H-1b), 4.16–4.14 (m, 1H, H-3b),
4.14–4.11 (m, 1.5H, H-3 , H-2b), 4.07 (dd, J = 2.5, 3.5 Hz, 0.5H, H-
), 3.95 (dd, J = 2.3, 6.8 Hz, 1H, H-4b), 3.85–3.77 (m, 2H, H-4
H-5b, H-5 ), 3.66 (dd, J = 5.0, 10.5 Hz, 1H, H-6b), 3.65 (dd, J = 5.0,
10.5 Hz, 0.5H, H-6
), 3.57 (dd, J = 5.0, 10.5 Hz, 1.5H, H-60a,b),
a]
ꢂ32.0 (c
D
3.3.5. 1,2:3,4-Di-O-isopropylidene-6-S-(2,3,5,6-tetra-O-tert-
a
butyldimethylsilyl–
D
-galactofuranosyl)-6-thio-
a
-D
-
a
galactopyranose (12)
2a
a,
Compound 12 was obtained according to the general procedure
for glycosylations of 1 promoted by TMSI, using 1,2:3,4-di-O-isopro-
a
a
pylidene-6-thio-
a-
D
-galactopyranose (11)27 as acceptor (1.3 equiv,
2.34, 2.33 (2 s, 4.5 H, SCOCH3), 0.93–0.87 (m, 54H, SiC(CH3)3),
0.094 g, 0.34 mmol), in the presence of EtN(iPr)2 (0.054 mL,
0.32 mmol). When TLC showed total conversion to a product of
Rf = 0.36 (10:1 hexane/EtOAc), the solution was diluted with CH2Cl2,
washed with NaHCO3 (ss) and water, dried (Na2SO4), and concen-
trated. After purification by column chromatography (98:2 ? 95:5
0.12–0.03 (m, 36H, Si(CH3)2). 13C NMR (CDCl3, 125.8 MHz) d
194.73, 194.69 (SCOCH3
85.7 (C-1 ), 84.6 (C-2b), 79.5 (C-2
73.53, 73.48 (C-5 ,b), 66.0, 65.7 (C-6
CH3 ,b), 26.1, 26.09, 26.06, 26.0, 25.84, 25.78, 25.67, 25.66
a
,b), 89.9 (C-4b), 88.7 (C-4
), 78.3 (C-3b), 77.7 (C-3
,b), 30.97; 30.93 (SCO-
a
), 87.8 (C-1b),
a
a
a),
a
a
a
hexane/EtOAc) syrupy compound 12 (0.151 g, 65%), [
a
]
ꢂ9.6 (c
(SiC(CH3)3), 18.49, 18.45, 18.3, 18.1, 18.0, 17.81, 17.77 (SiC(CH3)3),
ꢂ4.1, ꢂ4.31, ꢂ4.33, ꢂ4.35, ꢂ4.39, ꢂ4.4, ꢂ4.53, ꢂ4.55, ꢂ4.6, ꢂ5.0,
ꢂ5.21, ꢂ5.23, ꢂ5.28, ꢂ5.31 (Si(CH3)2). HRMS (ESI) m/z calcd for
D
1.2, CHCl3). 1H NMR (CDCl3, 500 MHz) d 5.51 (d, J = 5.1 Hz, 1H, H-
1), 5.15 (d, J = 3.1 Hz, 1H, H-10), 4.60 (dd, J = 2.3, 7.9 Hz, 1H, H-3),
4.51 (dd, J = 1.7, 7.9 Hz, 1H, H-4), 4.29 (dd, J = 2.3, 5.0 Hz, 1H, H-2),
4.07 (apparent t, J = 1.6 Hz, 1H, H-30), 4.00 (ddd, J = 1.7, 5.5, 9.4, Hz,
1H, H-5), 3.94 (dd, J = 1.6, 3.1 Hz, 1H, H-20), 3.85–3.80 (m, 1H, H-
50), 3.71 (dd, J = 3.7, 10.7 Hz, 1H, H-60a), 3.67 (dd, J = 5.4, 10.7 Hz,
1H, H-60b), 2.93 (dd, J = 9.4, 13.7 Hz, 1H, H-6a), 2.79 (dd, J = 5.5,
13.7 Hz, 1H, H-6b), 1.52 (s, 3H, C(CH3)), 1.44 (s, 3H, C(CH3)), 1.34
(s, 3H, C(CH3)), 1.31 (s, 3H, C(CH3)), 0.94–0.84 (m, 36H, SiC(CH3)3),
0.16–0.03 (m, 24H, Si(CH3)2). 13C NMR (125.8 MHz) d 109.0, 108.7
(C(CH3)2), 96.7 (C-1), 90.0 (C-10), 89.5 (C-40), 80.7 (C-20), 78.0 (C-30),
74.3 (C-50), 70.9 (C-3), 70.75 (C-2), 70.71 (C-4), 67.3 (C-5), 66.4 (C-
60), 32.0 (C-6), 26.16, 26.14, 26.11, 26.04, 26.0, 25.94, 25.89, 25.79,
25.78, 25.72, 25.68, 25.66, 25.6, 25.1, 24.4 (SiC(CH3)3, C(CH3)2),
18.5, 18.3, 18.2, 17.7 (SiC(CH3)3), ꢂ4.0, ꢂ4.31, ꢂ4.35, ꢂ4.5, ꢂ4.6,
ꢂ4.7, ꢂ5.1, ꢂ5.2 (Si(CH3)2). HRMS (ESI) m/z calcd for C42H86NaO10S-
Si4 [M+Na]+: 917.4911. Found: 917.4908.Fractions of Rf = 0.73 (10:1
hexane/EtOAc) afforded compound 7 (0.048 g, 30%).
C
32H70NaO6SSi4 [M+Na]+: 717.3862. Found: 717.3889.
3.3.8. 1-Thio-b-D-galactofuranosyl-1-thio-b-D-galactofuranoside
(18)
Compound 18 was obtained according to the general procedure
for O-desilylation with TBAF/THF. After 1 h of stirring at 0 °C the
solvent was evaporated and the syrup obtained was purified by
column chromatography (4:1 AcOEt/CH3OH). Fractions of
Rf = 0.40 (7:1:2 nPrOH/NH3/H2O) afforded 18 (0.016 g; 41%) as
main component. 1H NMR (D2O, 500 MHz) selected signals: d
5.09 (d, J = 5.6 Hz, 1H, H-1), 4,33 (apparent t, J = 5.8 Hz, 1H, H-2),
4.19 (dd, J = 6.3, 7.7 Hz, 1H, H-3), 4.02 (dd, J = 3.4, 7.7 Hz, 1H, H-
4). 13C NMR (D2O, 125.8 MHz) selected signals: d 93.2 (C-1), 83.0
(C-4), 80.0 (C-2), 75.9 (C-3), 70.97 (C-5), 63.3 (C-6). HRMS (ESI)
m/z calcd for C12H22NaO10S2 [M+Na]+: 413.0547. Found: 413.0558.
3.3.9. 2-Propyl 6-O-acetyl-3-deoxy-4-S-(2,3,5,6-tetra-O-tert-
3.3.6. 2,3,5,6-Tetra-O-tert-butyldimethylsilyl-1-thio-
galactofuranose (15)
a
,b-
D
-
butyldimethylsilyl-b-
pyranosid-2-ulose (21), 2-propyl 6-O-acetyl-3-deoxy-4-R-(2,3,
5,6-tetra-O-tert-butyldimethylsilyl-b- -galactofuranosyl)-4-
thio- -threo-hexopyranosid-2-ulose (22) and 2-propyl
6-O-acetyl-3-deoxy-4-R-(2,3,5,6-tetra-O-tert-butyldimethyl-
silyl- -galactofuranosyl)-4-thio- -threo-hexopyranosid-2-
ulose (23)
To a solution of 2,3,5,6-tetra-O-tert-butyldimethylsilyl-1-thio-
,b- -galactofuranose (15, 0.062 g, 0.095 mmol) and 2-propyl
6-O-acetyl-2,3-dideoxy-
-glycero-hex-3-enopyranosid-2-ulose34
(20, 0.021 g, 0.092 mmol) in anhyd CH2Cl2 (1 mL) cooled at 0 °C, a
solution of Et3N 10% in CH2Cl2 (0.22 mL) was added. The mixture
was stirred at 0 °C for 3 h, when TLC (10:1 hexane/EtOAc) showed
two main products of Rf = 0.35 and 0.14, and a minor product
of Rf = 0.27. The solution was concentrated and purified by
column chromatography (95:5 ? 92:8 hexane/EtOAc). Fractions
D-galactofuranosyl)-4-tio-a-D-threo-hexo-
Compound 15 was obtained according to the general procedure
for glycosylations of 1 promoted by TMSI. Once formed the galac-
tofuranosyl iodide 2, (TMS)2S (1.3 equiv, 0.07 mL, 0.34 mmol) was
added and the reaction was stirred during 17 h at room tempera-
ture. Then, anhyd Et3N (0.02 mL) was added and the molecular
sieves powder was filtered off. The solvent was evaporated and
the excess of Et3N was co-evaporated with toluene. The purifica-
tion of the crude mixture by column chromatography (99.5:0.5
hexane/EtOAc) yielded syrupy compound 15 (0.11 g, 66%) as an
D
a
-D
a-
D
a-D
a
D
a-D
anomeric mixture (b/
a 2:1), Rf = 0.42 (7:0.1 hexane/EtOAc, twice
developed), [
a
]
D
ꢂ39.5 (c 1.1, CHCl3). 1H NMR (CDCl3, 500 MHz) d
5.28 (dd, J = 3.0, 10.0 Hz, 1H, H-1a), 5.11 (dd, J = 1.6, 9.2 Hz, 1H,
H-1b), 4.15–4.09 (m, 4H, H-2b, H-3
H-2 , H-5 ,b), 3.73–3.65 (m, 3H, H-4b, H-6
2H, H-60a,b), 2.59 (dd, J = 9.2 Hz, 1H, SHb), 2.25 (d, J = 10.0 Hz,
1H, SH ), 0.95–0.86 (m, 72H, SiC(CH3)3), 0.17–0.05 (m, 48H,
a
,b, H-4
a
), 3.85–3.78 (m, 3H,
a
a
a,b), 3.61–3.54 (m,
of Rf = 0.35 afforded syrupy compound 22 (0.028 g, 35%), [a]
D
a
ꢂ38.9 (c 1.1, CHCl3). 1H NMR (CDCl3, 500 MHz)
d 5.04 (d,

L. Baldoni, C. Marino / Carbohydrate Research 362 (2012) 70–78
77
J = 2.5 Hz, 1H, H-10), 4.78–4.73 (m, 2H, H-5, H-1), 4.31 (dd, J = 7.6,
12.0 Hz, 1H, H-6a), 4.27 (dd, J = 4.0, 12.0 Hz, 1H, H-6b), 4.15 (dd,
J = 2.1, 4.8 Hz, 1H, H-30), 4.03–3.97 (m, 2H, CH(CH3)2, H-40), 3.96
(apparent t, J = 2.4 Hz, 1H, H-20), 3.79 (m, 1H, H-50), 3.64 (dd,
J = 5.9, 10.3 Hz, 1H, H-60a), 3.62–3.59 (m, 1H, H-4), 3.57 (dd,
J = 5.9, 10.3 Hz, 1H, H-60b), 3.12 (dd, J = 4.6, 15.1 Hz, 1H, H-3ax),
2.70 (ddd, J = 1.0, 2.8, 14.9 Hz, 1H, H-3ec), 2.06 (s, 3H, COCH3),
1.26 (d, J = 6.0 Hz, 3H, CH3CH), 1.17 (d, J = 6.0 Hz, 3H, CH3CH),
0.91–0.86 (m, 36H, SiC(CH3)3), 0.10–0.04 (m, 24H, Si(CH3)2). 13C
NMR (CDCl3, 125.8 MHz) d 199.3 (C-2), 170.5 (COCH3), 98.0 (C-1),
88.0 (C-10), 85.7 (C-40), 85.1 (C-20), 80.0 (C-30), 73.5 (C-50), 71.5
(CH(CH3)2), 68.9 (C-5), 65.2, 65.1 (C-6,60), 44.7 (C-4), 42.5 (C-3),
26.0, 25.8, 25.7 (SiC(CH3)3), 23.3, 21.8 (CH(CH3)2), 20.8 (COCH3),
18.4, 18.3, 17.84, 17.8 (SiC(CH3)3), ꢂ3.8, ꢂ4.1, ꢂ4.2, ꢂ4.3, ꢂ4.6,
ꢂ4.8, ꢂ4.3, ꢂ4.6, ꢂ4.8, ꢂ5.26, ꢂ5.3 Si(CH3)2). HRMS (ESI) m/z calcd
for C41H84NaO10SSi4 [M+Na]+: 903.4754. Found: 903.4765.
to give a crude product that was purified by column chromatogra-
phy (10:0.1 EtOAc /hexane) to afford 24 as a colorless oil. Com-
pound 24 (0.041 g, 80%) was obtained as an inseparable
anomeric mixture (b/
a 3.7:1), Rf = 0.79 (10:1 hexane/EtOAc), [a]
D
ꢂ85.5 (c 0.9, CHCl3). 1H NMR (CDCl3, 500 MHz) d 7.29–7.11 (m,
6.3H, aromatic), 5.02 (d, J = 3.2 Hz, 0.27H, H-1
a), 4.81 (d,
J = 3.2 Hz, 1H, H-1 b), 4.07 (dd, J = 2.4, 4.8 Hz, 1H, H-3 b), 4.05–
4.04 (m, 0.27H, H-3 ), 4.00 (t, J = 4.3 Hz, 1H, H-4 b), 3.88 (t,
J = 2.7 Hz, 1H, H-2 b), 3.81–3.78 (m, 1H, H-2 , H-5 , CH2 ),
3.78–3.73 (m, 2H, H-5 b, CHaH b), 3.71–3.67 (m, 1.3H, H-4 , CHHb
b), 3.65–3.59 (m, 1.3H, H-6 , b),
, b), 3.56–3.50 (m, 1.3H, H-60
a
a
a
a
a
a
a
0.88–0.72 (m, 45.7H, SiC(CH3)3), 0.14- (-0.19) (m, 30.5H, Si(CH3)2).
13C NMR (125.8 MHz) d 138.6, 138.4, 129.1, 129.09, 128.34, 128.30,
126.8, 126.7 (C-aromatic), 89.0 ꢃ 2 (C-1 b, C-4
(C-4 b), 85.1 (C-2 b), 80.3 (C-2 ), 80.0 (C-3 b), 77.9 (C-3
(C-5 ), 73.6 (C-5 b), 66.4 (C-6 ), 65.0 (C-6 b), 35.5 (CH2S
a
), 87.0 (C-1
a
a
), 85.2
), 73.9
),
a
a
a
a
Fractions of Rf = 0.27 (10:1 hexane/EtOAc) gave 0.011 g (14%) of
35.3 (CH2S b), 26.2, 26.1, 26.05, 26.02, 25.9, 25.7, 25.6 (SiC(CH3)3),
18.6, 18.41, 18.38, 18.35, 18.2, 17.83, 17.82, 17.7 (SiC(CH3)3), ꢂ3.8,
ꢂ4.0, ꢂ4.2, ꢂ4.3, ꢂ4.36, ꢂ4.4, ꢂ4.47, ꢂ4.49, ꢂ4.6, ꢂ4.8, ꢂ4.9, ꢂ5.1,
ꢂ5.2, -5.3 (Si(CH3)2). HRMS (ESI) m/z calcd for C37H74NaO5SSi4
[M+Na]+: 765.4226. Found: 765.4250.
syrupy compound 23, [a]
+14.2 (c 0.4, CHCl3). 1H NMR (CDCl3,
D
500 MHz) d 5.13 (d, J = 3.0 Hz, 1H, H-10), 4.73–4.69 (m, 2H, H-1,
H-5), 4.33 (dd, J = 5.0, 11.5 Hz, 1H, H-6a), 4.28 (dd, J = 7.0,
11.5 Hz, 1H, H-6b), 4,10 (t, J = 1.5 Hz,1H, H-30), 4.02–3.95 (m, 1H,
CH(CH3)2), 3.90 (dd, J = 1.5, 3.0 Hz, 1H, H-20), 3.85–3.79 (m, 1H,
H-50), 3.75 (dd, J = 1.5, 8.5 Hz, 1H, H-40), 3.68 (dd, J = 4.5, 11.0 Hz,
1H, H-60a), 3.62–3.55 (m, 2H, H-60b, H-4), 3.14 (dd, J = 5.5,
15.5 Hz, 1H, H-3ax), 2.98 (ddd, J = 1.0, 2.5, 15.5 Hz, 1H, H-3ec),
2.07 (s, 3H, COCH3), 1.26 (d, J = 6.0 Hz, 3H, CH3CH), 1.17 (d,
J = 6.0 Hz, 3H, CH3CH), 0.93–0.85 (m, 36H, SiC(CH3)3), 0.16–0.04
(m, 24H, Si(CH3)2). 13C NMR (CDCl3, 125.8 MHz) d 199.2 (C-2),
170.6 (COCH3), 97.9 (C-1), 90.7 (C-10), 90.5 (C-40), 80.8 (C-20), 77.6
(C-30), 73.9 (C-50), 71.5 (CH(CH3)2), 68.4 (C-5), 66.5 (C-60), 64.8
(C-6), 48.0 (C-4), 44.5 (C-3), 27.7, 26.2, 26.1, 25.9, 25.7 (SiC(CH3)3),
23.3, 21.8 (CH(CH3)2), 20.8 (COCH3), 18.3, 18.2 (SiC(CH3)3), ꢂ4.2,
ꢂ4.4, ꢂ4.5, ꢂ4.6, ꢂ4.8, ꢂ5.1, ꢂ5.2, ꢂ6.3 (Si(CH3)2). HRMS (ESI)
Acknowledgements
The authors are indebted to the University of Buenos Aires,
Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT)
and the National Research Council of Argentina (CONICET). C.M. is
Research Members of CONICET, and L.B. was supported by a fellow-
ship from CONICET.
Supplementary data
Supplementary data (1H and 13C NMR spectra for compounds)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.carres.2012.08.021.
m/z calcd for
C
41H84NaO10SSi4 [M+Na]+: 903.4754. Found:
903.4767.
From fractions of Rf = 0.14 (10:1 hexane/EtOAc) compound 21
was obtained (0.037 g, 46%), [
a]
ꢂ7.5 (c 0.8, CHCl3). 1H NMR
D
References
(CDCl3, 500 MHz) d 5.14 (d, J = 4.0 Hz, 1H, H-10), 4.77 (s, 1H, H-1),
4.50–4.47 (m, 2H, H-6a, H-6b), 4.38–4.34 (m, 1H, H-5), 4.21–4.18
(m, 1H, H-30), 4.06 (dd, J = 2.9, 5.0 Hz, 1H, H-40), 4.00–3.96 (m,
1H, CH(CH3)2), 3.95 (dd, J = 2.9, 4.0 Hz, 1H, H-20), 3.82–3.78 (m,
1H, H-50), 3.65 (dd, J = 6.8, 10.0 Hz, 1H, H-60a), 3.58 (dd, J = 5.6,
10.0 Hz, 1H, H-60b), 3.27 (ddd, J = 4.7, 10.9, 12.9 Hz, 1H, H-4),
2.98 (dd, J = 12.9, 14.3 Hz, 1H, H-3ax), 2.77 (ddd, J = 1.0, 4.4,
14.5 Hz, 1H, H-3ec), 2.07 (s, 3H, COCH3), 1.27 (d, J = 6.0 Hz, 3H,
CH3CH), 1.17 (d, J = 6.0 Hz, 3H, CH3CH), 0.91–0.86 (m, 36H,
SiC(CH3)3), 0.12–0.04 (m, 24H, Si(CH3)2). 13C NMR (CDCl3,
125.8 MHz) d 199.9 (C-2), 170.6 (COCH3), 98.0 (C-1), 88.7 (C-10),
85.2 (C-20), 84.3 (C-40), 79.8 (C-30), 73.3 (C-50), 71.7 (CH(CH3)2),
70.3 (C-5), 64.5 (C-60), 63.8 (C-6), 43.0 (C-4, C-3), 25.9, 25.7
(SiC(CH3)3), 23.3, 21.8 (CH(CH3)2), 20.8 (COCH3), 18.3, 18.2, 17.8
(SiC(CH3)3), ꢂ3.7, ꢂ4.1, ꢂ4.2, ꢂ4.3, ꢂ4.5, ꢂ4.7, ꢂ5.32, ꢂ5.34
(Si(CH3)2). HRMS (ESI) m/z calcd for C41H84NaO10SSi4 [M+Na]+:
903.4754. Found: 903.4766.
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