Conformational properties of glucosyl-thioglucosides and their S-oxides in solution

Article abstract of DOI:10.1016/j.tetasy.2013.03.020

A stereochemical study of a series of alkyl glucosyl-β-(1→6)- thioglucosides and their S-oxides by means of nuclear magnetic resonance and circular dichroism revealed that the populations around the thioglucosidic bond (ring I) as well as those of the interglycosidic linkage ω depend on the aglycone, the solvent and, in the S-oxides, on the absolute configuration of the sulfur atom. The results for the thio-disaccharides showed the strong influence of the solvent polarity on the conformational preferences of the interglycosidic bond. In polar solvents, the magnitudes of the rotamer populations, P_gg and P_gt, remained practically constant through the series, while in non-polar solvents a clear predominance of gt conformation was observed as well as the influence of the aglycone on the conformational equilibrium. The results for both (S_S)- and (R _S)-alkyl thiogentiobiosyl S-oxide series showed a clear predominance of the gt rotamer, P_gt always having a higher magnitude in the latter series than in the former. Both series exhibited linear correlations between interglycosidic P_gg and P_gt and Taft's steric parameter (E_S) for the alkyl group attached to the sulfinyl group, especially in non-polar solvents. The stereochemical study around the C1-S bond established that the flexibility around this linkage depends on aglycone size, solvent polarity, and the absolute configuration of the sulfur, derivatives of the S_S series showing higher flexibility in both polar and non-polar media. The conformational properties of these compounds in solution are explained in terms of stereoelectronic, steric, and solvent effects.

Full text of DOI:10.1016/j.tetasy.2013.03.020

Tetrahedron: Asymmetry 24 (2013) 582–593
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Conformational properties of glucosyl-thioglucosides and their S-oxides
in solution
⇑
Carlos A. Sanhueza, Rosa L. Dorta, Jesús T. Vázquez
Instituto Universitario de Bio-Orgánica ‘Antonio González’, Departamento de Química Orgánica, Universidad de La Laguna, 38206 La Laguna, Tenerife, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 March 2013
Accepted 20 March 2013
A stereochemical study of a series of alkyl glucosyl-b-(1?6)-thioglucosides and their S-oxides by means
of nuclear magnetic resonance and circular dichroism revealed that the populations around the thioglu-
cosidic bond (ring I) as well as those of the interglycosidic linkage
x depend on the aglycone, the solvent
and, in the S-oxides, on the absolute configuration of the sulfur atom. The results for the thio-disaccha-
rides showed the strong influence of the solvent polarity on the conformational preferences of the inter-
glycosidic bond. In polar solvents, the magnitudes of the rotamer populations, Pgg and Pgt, remained
practically constant through the series, while in non-polar solvents a clear predominance of gt conforma-
tion was observed as well as the influence of the aglycone on the conformational equilibrium. The results
for both (SS)- and (RS)-alkyl thiogentiobiosyl S-oxide series showed a clear predominance of the gt rot-
amer, Pgt always having a higher magnitude in the latter series than in the former. Both series exhibited
linear correlations between interglycosidic Pgg and Pgt and Taft’s steric parameter (ES) for the alkyl group
attached to the sulfinyl group, especially in non-polar solvents. The stereochemical study around the
C1–S bond established that the flexibility around this linkage depends on aglycone size, solvent polarity,
and the absolute configuration of the sulfur, derivatives of the SS series showing higher flexibility in both
polar and non-polar media. The conformational properties of these compounds in solution are explained
in terms of stereoelectronic, steric, and solvent effects.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
Ring I
OH
6'
'
ω
φ
Carbohydrates play important roles in biological systems.
Protein/glycan recognition phenomena can be found in several
events involved in cell–cell communication and system regulation
such as: homeostasis,1 immune response,2 inflammation,3 tumor
metastasis,4 bacterial colonization, and infection.5 The success of
protein/carbohydrate recognition in its early stage is highly sensi-
tive to conformational requirements, where the glycan should dis-
HO
O
O
ω
HO
HO
O
ψ
OH
OH
6
1'
HO
1
OH
Ring II
OGlcp
C4
H6S
H6R
O5
O5
H6R
C4
O5
C4
H6
play
a
suitable disposition. Therefore, the study of the
ω =
conformational properties of carbohydrates is of key importance
for a better understanding of these interactions.6 The conforma-
tional flexibility of saccharides is described through torsion angles
H6S
H6
OGlcp
GlcpO
R
S
H5
H5
H5
gt
w
(C10–O6–C6–C5), / (O50–C10–O6–C6), and
x (O5–C5–C6–O6). In
gg
tg
particular, the flexibility around the C5–C6 bond is of key impor-
tance in oligosaccharides, which possess (1?6) glycosidic bonds
in their structure. This type of linkage, particularly b-(1?6), con-
fers a high degree of conformational freedom on the saccharide,
thus these molecules present a higher entropy compared to
saccharides with other glycosidic bond configurations.7 The torsion
Figure 1. Rotamers around the interglycosidic C5–C6 bond in (1?6)-glucosyl-
glucosides: gauche–trans (gt), gauche–gauche (gg), and trans–gauche (tg).8
practice we distinguish three staggered rotamers namely gauche–
gauche (gg,
(tg, = 180) as described in Figure 1.
Studies of the hydroxymethyl conformation in glycosides, free
or connected to another sugar ring (torsion angle ), have revealed
x
= ꢀ60), gauche–trans (gt,
x = 60), and trans–gauche
angle
x can adopt any value between 0° and 360°. However, in
x
⇑
Corresponding author. Tel.: +34 922318581; fax: +34 922318571.
E-mail address: jtruvaz@ull.es (J.T. Vázquez).
x
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.03.020

C. A. Sanhueza et al. / Tetrahedron: Asymmetry 24 (2013) 582–593
583
OAc
O
OAc
O
AcO
O
AcO
AcO
AcO
AcO
AcO
a
b
O
O
OAc
OAc
OAc
O
OAc
OAc
OAc
OAc
O
S
1, R = Methyl
R
S
2, R = Ethyl
3, R = iso-Propyl
4, R = Cyclohexyl
5, R = tert-Butyl
OAc
O
OAc
O
AcO
O
AcO
O
AcO
AcO
AcO
AcO
+
OAc
OAc
O
OAc
OAc
OAc
OAc
O
R
R
S
6R,
6S,
R = Methyl
7R, R = Ethyl
8R, R = iso-Propyl
9 ,
R = Methyl
7S, R = Ethyl
O
8S, R = iso-Propyl
9 ,
R R = tert-Butyl
S R = tert-Butyl
Scheme 1. Synthesis of glucosyl thioglucosides 1–5 and their S-oxides 6R–9R and 6S–9S. Reagents and conditions: (a) compound 1: (NH2)2CS, BF3ꢁEt2O, MeCN, reflux, then
Et3N, CH3I; compounds 2–5: R–SH, BF3ꢁEt2O, DCM, rt; (b) H2O2, Ac2O, silica gel, DCM, rt.
that the populations of this group depend on the structure of the
aglycone and its absolute configuration, the anomeric configura-
tion, the glycosidic linkage type, and the nature of the solvent.9
Furthermore, a conformational domino effect has been observed
in alkyl disaccharides, where all the above factors present in glyco-
sides were detected.9h,i
due to the high volatility of methanethiol, but used in its place was
that based on the S-alkylation of glycosyl thiouronium salts devel-
oped by Ibatullin.18
The anomeric configuration of thiogentiobiosides 1–5 was
3
established by measuring the JH1,H2 coupling constants (ꢂ9.8 Hz)
and analysis of spatial couplings between H1, H3, and H5 from
T-ROESY experiments. The anomeric configuration of the intergly-
Stereoelectronic10 and steric effects have been proposed to
explain all these factors affecting the populations of the hydroxy-
methyl group in solution. Recently, a conformational study with al-
kyl glycosyl sulfoxides has allowed the stereoelectronic
requirements involved in these populations to be studied.11
0
0
cosidic bond was corroborated in the same way (JH1 ,H2 ꢂ8.0 Hz),
and cross peaks between H10, H30, and H50).
The pro-chiral protons H6R and H6S for both rings were identi-
fied and assigned as described in the literature.19 Protons H6R and
H6S on ring I are vicinal to the interglycosidic acetal function while
H6R0 and H6S0 on ring II are vicinal to the ester. According to the
data, the chemical shift relationship for protons on ring I is
dH6S > dH6R, while for protons on ring II the opposite was estab-
lished (dH6R0 > dH6S0). The coupling constant relationships with
H5 were found to be JH5,H6R > JH5H6S, which was consistent with
the previous chemical shift analysis.
Conformational analysis of b-D-glucopyranosyl-(1?6)-D-glu-
cose (gentiobiose) in aqueous solution12 shows that rotamers gg
and gt are the two main contributors to the conformational equi-
librium around the interglycosidic bond, with populations of 34%
and 66%, respectively. In contrast to monosaccharides, where the
gg rotamer is the most populated, the hydroxymethyl group con-
necting the two sugar rings exhibits a preference for the gt popula-
tion. Furthermore, it has been determined that the rotation around
torsion angle / is restricted due to the exo-anomeric effect,10 while
The sulfur atom of the alkyl thiogentiobiosides was oxidized
using the H2O2/Ac2O/SiO2 system,20 which affords an epimeric
mixture of (RS)- and (SS)-sulfinyl gentiobiosides 6–9 (Scheme 1).
Due to the asymmetric induction of the sugar moiety, sulfoxides
of (SS)-configuration were the major product expected by oxidation
of thiogentiobiosides.21,22 Although the epimeric ratio (SS) > (RS)
was observed in all the model compounds synthesized, we noticed
that this relationship tends to remain similar as the bulk of the
angle
w
has higher flexibility.13
Glycosyl sulfoxides have become important intermediates for
the synthesis of bioactive molecules14,15 and several of them show
biological activity themselves, including antitumoral, anti-infec-
tive, and antidiabetic action.14 Furthermore, the stereoelectronic
interactions that cause the exo-anomeric effect have been proven
to be involved in alkyl glycosyl sulfoxides, with the absolute con-
figuration at the sulfur atom being of primary importance. Herein,
we focus on the conformational properties around the glycosidic
C1–S and interglycosidic C5–C6 bonds of a series of alkyl thiogen-
tiobiosides and their corresponding sulfoxide series in solution,
along with how the molecular characteristics of the (SS)- and
(RS)-sulfoxide series affect these properties in various media.
3
aglyconic alkyl group increases. Analysis of JH1,H2 coupling con-
stants and H1, H3, and H5 cross peaks in T-ROESY experiments
provided evidence for retention of the anomeric configuration in
both sugar residues after sulfur oxidation. Both (SS)- and (RS)-epi-
mers can be isolated by normal phase chromatography on silica
gel using ethyl acetate/hexane(s) systems as eluents. After separat-
ing the epimers, the spectroscopic characterization and assignment
of the absolute sulfinyl configuration was crucial for the success of
the present study. The absolute configuration of the sulfur was as-
signed by NMR and CD analyses according to the method devel-
oped in our group (Fig. 2).23
2. Results and discussion
2.1. Synthesis and characterization
Alkyl b-thiogentiobiosides 2–5 were synthesized by treatment
of b-Gentiobiose octaacetate with BF3ꢁEt2O and the corresponding
thiol (Scheme 1). This method is straightforward and economical,
and achieves a high yield of thioglycosides.16 The neighboring
group participation of the acetyl group at C2 led to the stereoselec-
tive formation of b-thiodisaccharides. Nevertheless, long exposure
2.2. Conformational analysis of the hydroxymethyl groups in
alkyl 1-thiogentiobiosides
The coupling constants JH5,H6R and JH5,H6S for both sugar units
were obtained by first order analysis. The assignment and coupling
constant measurements were carried out without difficulty due to
the good separation of the chemical shifts for the H6 protons and
their total correlation with the described spectroscopic character-
of these to a Lewis acid may result in anomerization to an a-thio-
glycoside17 and control of the reaction time is crucial for improved
yield. This procedure was not employed in preparing compound 1,

584
C. A. Sanhueza et al. / Tetrahedron: Asymmetry 24 (2013) 582–593
5
of
Dd = 1 ppm (ring I) or Dd = 0.5 ppm (ring II) from compound 1
223
(R = methyl) to compound 5 (R = tert-butyl).
Noteworthy results were obtained from the coupling constants
JH5,H6 on the saccharide ring bearing the S-alkyl moiety. As the de-
gree of substitution of the S-aglycone increased, the JH5,H6R value
increased. For methyl derivative 1, the lowest JH5,H6R of 6.8 Hz
was observed, whereas for compound 5, which possesses the bulk-
iest aglycone, this value rose to 7.5 Hz. A similar but reduced ten-
Δε
6S
0
0
0
dency was also noted for JH5 ,H6R on the second ring, with a
d = 0.3 ppm between 1 and 5 compared to d = 0.7 ppm observed
6R
D
D
for JH5,H6R. In contrast, JH5,H6S showed a decrease in magnitude from
methyl derivative 1 (JH5,H6S = 2.2 Hz) to tert-butyl thiogentiobioside
218
0
0
5
(JH5,H6S = 1.7 Hz) while JH5 ,H6S remains practically constant
12
−
190
250
300
350 nm
through the series.
The rotamer populations for the interglycosidic (ring I) and free
(ring II) hydroxymethyl groups were calculated from the JH5,H6
Figure 2. CD spectra of compounds 6S and 6R in CH3CN.
3
coupling constants, using the equation system proposed by Serian-
ni.24 These provide the most accurate representation for rotameric
populations in solution among the different types of Karplus equa-
tions25 and do not lead to negative values for the tg rotamer. Table 2
shows the calculated rotamer populations for compounds 1–5 in
different solvents.
Table 1
Chemical shifts for H1, C1, H6R and H6S, and JH5,H6R and JH5,H6S coupling constants for
rings I and II of alkyl 1-thio-b-gentiobiosides 1–5 (CDCl3)
Ring I
No.
R
dH1
dC1
dH6R
dH6S
JH5,H6R
JH5,H6S
The collected data show the strong influence of solvent polarity
on the conformational preferences of the interglycosidic bond. In
the polar solvents methanol-d4 and acetonitrile-d3, rotamers gg
and gt made a similar contribution to the conformational equilib-
rium. However, a slight preference for the gt conformation was ob-
served in acetone-d6. For the three polar solvents studied,
magnitudes of Pgg and Pgt remained practically constant through
the series; the full set of model compounds showed practically
identical conformational preferences in the interglycosidic linkage
for each polar solvent.
1
2
3
4
5
Me
Et
i-Pr
Cy
4.37
4.47
4.53
4.55
4.61
82.9
83.2
82.9
82.9
82.0
3.57
3.60
3.66
3.65
3.66
3.88
3.87
3.80
3.83
3.79
6.8
7.2
7.2
7.2
7.5
2.2
2.0
1.7
1.7
1.7
t-Bu
Ring II
dH10
dC10
dH6R0
dH6S0
JH5 ,H6R
JH5 ,H6S
0
0
0
0
No.
R
1
2
3
4
5
Me
Et
i-Pr
Cy
4.57
4.58
4.56
4.60
4.58
100.9
100.7
100.5
100.6
100.3
4.27
4.28
4.24
4.27
4.26
4.12
4.13
4.13
4.13
4.11
4.7
4.8
4.9
4.9
5.0
2.3
2.3
2.4
2.4
2.3
Different conformational behavior was observed for the inter-
glycosidic bond in non-polar solvents (benzene-d6 and chloro-
t-Bu
form-d), where there was
a clear predominance of the gt
conformation with an average Pgt value of 62%. Furthermore, in
these solvents the influence of the aglycone over the conforma-
tional equilibrium was also observed as reflected in the Pgg and
Pgt values along the series. An increase in the degree of substitution
Table 2
Calculated rotational populations Pgg and Pgt in different solvents for alkyl
1-thiogentiobiosides 1–5
of the aglyconic alkyl group led to Pgt rising at the cost of Pgg
.
No.
C6D6
Pgg
CDCl3
(CD3)2CO
CD3OD
CD3CN
Pgt
Pgg
Pgt
Pgg
Pgt
Pgg
Pgt
Pgg
Pgt
Ring I
70
1
2
3
4
5
43
40
38
39
33
57
60
62
61
67
40
38
37
37
34
60
62
63
63
66
42
44
44
44
43
58
56
56
56
57
53
51
49
51
49
47
49
51
49
51
51
52
52
52
52
49
48
48
48
48
P
gt
60
50
Ring II
40
30
P
gg
1
2
3
4
5
64
62
62
61
60
36
38
38
39
40
61
60
59
59
59
39
40
41
41
41
57
57
56
55
55
43
43
44
45
45
61
60
59
58
57
39
40
41
42
43
59
58
58
58
57
41
42
42
42
43
70
60
50
40
30
P
gt
istics.19 Selected NMR data for compounds 1–5 are presented in
Table 1.
Analysis of the NMR data established that major changes occur
in ring I, which holds the S-aglycone. The chemical shift for the
anomeric proton on this ring showed a displacement to a low field
P
gg
Me
Et
t-Bu
i-Pr
− 0.4
Cy
with a difference of
Dd = 0.24 ppm from compound 1 (R = methyl)
0
− 0.8
ES
− 1.2
− 1.6
to compound 5 (R = tert-butyl), establishing a trend that depends
on the degree of substitution of the S-aglycone. The chemical shifts
for H10 on ring II remained approximately constant through the
series with a value of 4.59 ppm, while the shift for the anomeric
carbon showed a small displacement to high field with a difference
Figure 3. Rotamer populations Pgg and Pgt of the interglycosidic linkage (ring I)
obtained in chloroform-d (above) and benzene-d6 (below) versus ES for thiogen-
tiobiosides 1–5.28

C. A. Sanhueza et al. / Tetrahedron: Asymmetry 24 (2013) 582–593
585
Methyl derivative 1 exhibited a Pgt of 57% for benzene-d6, while Pgt
increased to 67% for tert-butyl derivative 5. For chloroform-d these
values were 60% and 66%, respectively.
As previously determined by our group for both b-thioglyco-
sides26 and b-glycosyl sulfoxides,11 good correlations between
C5–C6 rotamer populations and Taft’s steric parameters (ES)27
were also observed for thiogentiobiosides 1–5 in the different
solvents used herein. Rotamer populations Pgg and Pgt obtained in
non-polar solvents are represented as a function of ES in Figure 3.
S-aglycone increases, instead of decreasing. According to Taft,27
as the substituent becomes bulkier, the rotation around the S-glu-
cosidic bond decreases, meaning that the population of the more
stable rotamer exo-syn increases. Non-bonded interactions
between the S-aglycone and the substituent at the 2-position are
also likely, decreasing the non-exo rotamer and reducing the
flexibility (Fig. 5).
A higher steric hindrance to motion as the substituent becomes
bulkier leads to an increase in the more stable exo-syn, and there-
fore in the exo-anomeric effect. The participation of this effect is
supported by the behavior of the chemical shift for the anomeric
proton, since it is shielded along with the structural nature of the
aliphatic alkyl group attached to the sulfur atom (Table 1). The
shift runs from the methyl derivative 1 (4.37 ppm) to a primary
alkyl group, such as ethyl 2 (4.48), to those with a secondary alkyl
group: isopropyl 3 (4.56) and cyclohexyl 4 (4.56), and to the
tert-butyl derivative 5 (4.62 ppm). As a result, the different values
of the stereoelectronic LPS ! rCꢃO interaction (the exo-anomeric ef-
fect) may express the rotational preferences of the hydroxymethyl
group.
For both benzene-d6 and chloroform-d,
a linear relationship
between rotamer populations for gg/gt and ES was established,
the Pgt and Pgg values increased and decreased, respectively, as
the absolute value of ES increased.
The rotamer populations Pgg and Pgt obtained in polar solvents
versus the corresponding Taft steric parameters are shown in
Figure 4. In contrast to the flexibility observed in non-polar sys-
tems, the conformation around the C5–C6 bond through the series
was confined, while the structure of the alkyl group did not seem
to influence the interglycosidic conformation. However, different
rotamer contributions were found, depending on the nature of
the solvent. In acetonitrile, the gg rotamer was predominant at
equilibrium, whereas in acetone it was gt. For these solvents, the
Pgg and Pgt were practically identical for each compound through-
out the series. In methanol, there was a slight trend in Pgg and Pgt
values toward an increase in the absolute value of ES, leading to
an increase in the gt rotamer contribution. This behavior is similar
but not as pronounced as that observed in non-polar solvents.
As occurred with thioglucosides,26 the observed preferences
around the hydroxymethyl group cannot be due to non-bonded
interactions between this group and the S-aglycone, since this
would induce an increase in the gg population as the size of the
2.3. Conformational analysis of the hydroxymethyl groups in
alkyl 1-thiogentiobioside S-oxides
As with thiogentiobiosides, the spin–spin coupling constants
JH5,H6R and JH5,H6S for both rings were obtained by first-order anal-
ysis. For derivatives 6S–9S, signals of interest were well isolated in
the 1H NMR spectrum and the assignations were made following
the data as described in the literature.17 However, it was not pos-
sible to obtain the JH5,H6 values for RS sulfoxides in CDCl3 due to the
overlap of the H6R and H6S signals with H5 and H50. However,
chemical shifts for H6R0 and H6S0 appear well isolated in the 1H
NMR spectrum. Selected NMR data for the (SS)- and (RS)-sulfoxide
series in CDCl3 are presented in Tables 3 and 4 respectively.
Regarding the chemical shifts for the anomeric carbon bonded
to a sulfinyl functionality, the dC1 in (RS)-sulfoxides appeared at
a higher field compared to its (SS)-epimer. For instance, dC1 in
methyl derivative 6R was 87.4 ppm while in its (SS)-epimer 6S
C1 appeared deshielded at 90.5 ppm. This relationship was
observed in the four epimeric pairs. Comparison of dC1 along each
epimeric series revealed a progressive displacement to higher
fields as the degree of substitution of the alkyl group increases, that
is, for the (SS)-series, dC1 from methyl to tert-butyl derivative
moved from 90.5 to 86.4 ppm while for the (RS)-series, these values
were 87.4–84.9 ppm, respectively.
70
60
P
gg
50
P
gt
40
30
70
60
P
P
The chemical shifts for C10 showed practically no variations be-
tween the epimers and along the series, with an average chemical
shift of 100.5 ppm. On the other hand, dH1 showed different
behaviors depending on the epimeric series. In (RS)-sulfoxides, it
was possible to establish a trend where dH1 moves to a lower field
as the degree of substitution of the aglycone increases (dH1
6R = 4.08 ppm; dH1 9R = 4.32 ppm). For the (SS)-series, a similar
trend was seen for derivatives 6S, 7S, and 8S but moving to higher
fields, (dH1 6S = 4.37; dH1 8S = 4.19 ppm); however, tert-butyl
derivative 9S escaped from this tendency (dH1 9S = 4.30 ppm).
A progressive rise in magnitude of JH5,H6R in the (SS)-sulfoxides
was observed as the degree of substitution of the aglycone in-
creases (6S (Me) = 5.3 Hz; 9S (tert-Bu) = 7.3 Hz), with a similar
gt
50
40
30
gg
70
60
50
40
30
P
gt
P
gg
0
0
trend for JH5 ,H6R on the second ring, but much less marked
(6S = 4.8 Hz; 9S = 5.1 Hz). From the analysis of (RS)-sulfoxides in
Me
0
Cy
t-Bu
i-Pr
− 0.4
Et
0
0
CDCl3, there is only
a slight trend of JH5 ,H6R (6R = 5.0 Hz;
− 0.8
ES
− 1.2
− 1.6
9R = 5.4 Hz) through the series.
Hydroxymethyl rotamer populations for sulfoxides 6S–9S and
6R–9R were calculated from JH5,H6R and JH5,H6S values determined
in different solvents using the Karplus-type set of equations pro-
posed by Serianni.24 Data obtained for the conformational proper-
Figure 4. Rotamer populations gg/gt of the interglycosidic linkage (ring I) for
compounds 1–5 versus Taft0s parameter (ES) in polar solvents: acetonitrile-d3
(above), methanol-d4 (center), and acetone-d6 (below).29

586
C. A. Sanhueza et al. / Tetrahedron: Asymmetry 24 (2013) 582–593
Glcp
Glcp
R
Glcp
ω
O
O
O
S
S
S
R
σ*C1
σ*C1
O5
−
LPS
LPS
O5
−
R
exo-syn
g
exo-anti
g
+
or
−
or
Equilibria: R structure, and solvent dependence
Figure 5. Molecular orbitals involved in the exo-anomeric effect for the three idealized staggered rotamers around the C1–S bond.30
non-exo or anti
Table 3
80
60
40
P
Chemical shifts for H1, C1, H6R and H6S, and JH5,H6R and JH5,H6S coupling constants for
rings I and II of alkyl thiogentiobioside S-oxides 6S–9S (CDCl3)
gt
Ring I
No.
R
dC1
dH1
dH6R
dH6S
JH5,H6R
JH5,H6S
6S
7S
8S
9S
Me
Et
i-Pr
t-Bu
90.5
89.6
88.2
86.4
4.37
4.30
4.19
4.30
3.62
3.57
3.56
3.62
4.03
3.94
3.86
3.77
5.3
5.9
6.6
7.3
2.3
2.2
2.1
2.2
P
Me
0
gg
Et
i-Pr
− 0.4
Ring II
− 0.8
ES
− 1.2
− 1.6
dC10
dH10
dH6R0
dH6S0
JH5,H6R
JH5,H6S
0
0
No.
R
6S
7S
8S
9S
Me
Et
i-Pr
t-Bu
100.5
100.5
100.6
100.6
4.56
4.51
4.49
4.51
4.28
4.25
4.24
4.25
4.15
4.11
4.11
4.12
4.8
4.8
4.9
5.1
2.3
2.2
2.2
2.3
Figure 6. Rotational populations Pgg and Pgt of the interglycosidic linkage (ring I)
obtained in dichloromethane-d2 versus ES for sulfoxides 6R–8R.31
ties around the C5–C6 bond (interglycosidic linkage) are displayed
in Tables 5 and 6 for (SS)- and (RS)-series, respectively.
Table 4
For the (SS)-series, rotamer gt was predominant in the C5–C6
conformation, except for methyl derivative 6S, which showed a
greater gg contribution in some solvents. The presence of rotamer
tg was not detected, although a dependence of the Pgg and Pgt val-
ues on the nature of the aglycone was clear. As the degree of sub-
stitution of the alkyl group increased, Pgt rises and subsequently Pgg
diminishes. This trend was found in the majority of the solvents
studied; however in acetonitrile, the aglycone structure did not
appear to influence the interglycosidic conformation and the ratio
Pgg/Pgt ꢄ50:50% remained constant throughout the series.
The predominance of the gt rotamer was found in (RS)-sulfox-
ides, which in most cases showed Pgt values higher than 60%
(except for acetonitrile: Pgt ꢂ54%). In addition, the (R)-sulfoxides
presented higher gt contributions compared to their respective
(S)-epimers.
Chemical shifts for H1, C1, H6R and H6S, and JH5,H6R and JH5,H6S coupling constants for
rings I and II of alkyl thiogentiobioside S-oxides 6R–9R (CDCl3)
Ring I
a
a
No.
R
dC1
dH1
dH6R
dH6S
JH5,H6R
JH5,H6S
6R
7R
8R
9R
Me
Et
i-Pr
t-Bu
87.4
86.3
85.2
84.9
4.08
4.14
4.28
4.32
3.74
3.76
3.80
3.79
3.86
3.85
3.80
3.79
—
—
—
—
—
—
—
—
Ring II
0
0
No.
R
dC10
dH10
dH6R0
dH6S0
JH5,H6R
JH5,H6S
6R
7R
8R
9R
Me
Et
i-Pr
t-Bu
100.5
100.5
100.4
100.4
4.56
4.56
4.53
4.55
4.27
4.28
4.26
4.26
4.14
4.14
4.12
4.11
5.0
5.1
5.1
5.4
2.1
2.3
2.2
2.2
a
Values unobtainable due to signal overlap.
80
Table 5
P
Rotamer populations for the interglycosidic C5–C6 bond in different solvents for
sulfoxides 6S–9S
gt
60
40
No.
CD2Cl2
CDCl3
(CD3)2CO
CD3OD
CD3CN
P
Pgg
Pgt
Pgg
Pgt
Pgg
Pgt
Pgg
Pgt
Pgg
Pgt
gg
6S
7S
8S
9S
51
47
44
41
49
53
56
59
55
50
44
37
45
50
56
63
45
44
41
39
55
56
59
61
61
58
53
46
39
42
47
54
50
49
49
48
50
51
51
52
80
P
gt
60
Table 6
Rotamer populations for the interglycosidic C5–C6 bond in different solvents for
sulfoxides 6R–9R
P
gg
40
Me
Et
i-Pr
− 0.4
t-Bu
No.
CD2Cl2
Pgg
(CD3)2CO
CD3OD
Pgg
CD3CN
Pgg
0
− 0.8
− 1.2
− 1.6
Pgt
Pgg
Pgt
Pgt
Pgt
ES
6R
7R
8R
9R
36
34
29
—
64
66
71
—
36
35
34
35
64
65
66
65
39
37
36
35
61
63
64
65
46
43
48
47
54
57
52
53
Figure 7. Rotational populations Pgg and Pgt of the interglycosidic linkage (ring I)
obtained in dichloromethane-d2 (above) and chloroform-d (below) versus ES for
sulfoxides 6S–9S.32

C. A. Sanhueza et al. / Tetrahedron: Asymmetry 24 (2013) 582–593
587
80
80
60
40
60
P
P
gt
gt
P
gg
40
P
gg
80
80
60
40
P
gt
P
60
40
gt
P
gg
P
gg
80
80
60
40
P
gt
P
60
40
gt
P
gg
P
Me
0
gg
Et
i-Pr
− 0.4
t-Bu
− 0.8
ES
− 1.2
− 1.6
Me
0
Et
i-Pr
− 0.4
t-Bu
− 1.6
− 0.8
ES
− 1.2
Figure 9. Rotational populations Pgg and Pgt of the interglycosidic linkage (ring I)
obtained in acetonitrile-d3 (above), methanol-d3 (center), and acetone-d6 (below)
versus ES for sulfoxides 6S–9S.34
Figure 8. Rotational populations Pgg and Pgt of the interglycosidic linkage (ring I)
obtained in acetonitrile-d3 (above) methanol-d3 (center), and acetone-d6 (below)
versus ES for sulfoxides 6R–9R.33
A correlation between Pgg and Pgt versus ES for derivatives 6S–9S
in polar solvents is presented in Figure 9.
The influence of the nature of the aglycone on C5–C6 conforma-
tion was also observed throughout the RS series. In methanol and
dichloromethane, the populations for gg and gt tended to decrease
and increase, respectively, as the degree of substitution of the alkyl
group increased; this trend was prominent in dichloromethane.
Conversely, in acetone and acetonitrile, Pgg and Pgt tended to
remain constant throughout the series.
In this case, linear correlations between rotamer populations
and ES were also found. However, the (SS)-series showed a different
behavior depending on the solvent. Conformational equilibrium in
acetonitrile was practically constant throughout the series and no
dependence on ES values could be established. The results obtained
for acetone showed a slight dependence of the populations on ES,
where an increase in its absolute value led to an increased Pgt pop-
ulation and consequent drop in Pgg. This last trend was also ob-
served, but more markedly, in methanol, where the contribution
of Pgt gradually increased along the series, with it being the pre-
dominant conformer in sulfoxide 9S, which had the highest ES
value.
As in thioglycosides,26 good correlations were observed
between the rotamer populations in the different solvents and
Taft’s steric parameter (ES).27 For a better analysis and discussion
of results, the data are presented according to solvent polarity.
Figure 6 shows gg/gt rotamer populations for sulfoxides 6R–8R
obtained in dichloromethane versus the ES parameter correspond-
ing to the aglyconic alkyl group. A good linear dependence on the
rotamer populations and ES was established, that is, as the absolute
value of ES increased, gt and gg contributions increased and
decreased, respectively.
2.4. Conformational analysis around the C1–S linkage in alkyl 1-
thiogentiobiosyl S-oxides
For sulfoxides 6S–9S, the calculated values for Pgg and Pgt in
CD2Cl2 and CDCl3 versus ES are shown in Figure 7. In both solvents,
there is a linear correlation between Pgg and Pgt values with ES. The
contributions of gg and gt rotamers decrease and increase, respec-
tively, as the absolute value of Taft’s parameter increases, with this
tendency being more pronounced in CDCl3.
In non-polar solvents, both (SS)- and (RS)-sulfoxides presented a
linear correlation between gg/gt rotamer populations and Taft’s
parameter for the alkyl group of the aglycone. However, this
dependence was more pronounced in the case of (RS)-sulfoxides.
Figure 8 shows the relationship between gg and gt populations
with ES for sulfoxides 6R–9R in polar solvents. The rotamer popu-
lations remain practically constant throughout the series for all po-
lar solvents, and the gt rotamer is the most populated in all cases.
For a better analysis of the rotamers involved in this linkage, we
decided to use a convenient nomenclature based on the orientation
between the R alkyl group of the aglycone and the endocyclic oxy-
gen atom O5 (Fig. 10). According to this, for the glycosidic bond we
distinguish three staggered rotamers called gauche plus (g+),
gauche minus (gꢀ), and anti.
The stereoelectronic interactions between the lone pair of elec-
trons in sulfur and the sigma antibonding orbital of the C1–O5
bond gave rise to the exo-anomeric effect in the glycosyl sulfoxides.
Due to the presence of only one lone pair in glycosyl sulfoxides, the
LPS ! rꢃC1ꢀO5 hyperconjugation is determined by the absolute con-
figuration of sulfur as well as the conformational preferences
around the glycosidic bond. Therefore, both epimeric series present
distinct intrinsic requirements for the exo-anomeric effect. For (SS)-

588
C. A. Sanhueza et al. / Tetrahedron: Asymmetry 24 (2013) 582–593
g+
R
C2
O5
R
C2
O5
C2
O5
S
S
S
g−
anti
R
H1
H1
H1
Glcp
Glcp
Glcp
-
O
R
ω
(SS)
O
O
O
+
+
+
S
S
-
S
R
O
-
σ
*
LPS
R
O
C1 O5
−
Glcp
Glcp
Glcp
-
O
R
ω
O
O
O
(
)
RS
+
+
+
S
S
S
-
R
O
-
R
σ*C1
LPS
O5
−
O
g−
g+
anti
Figure 10. Rotamers around the C1–S linkage in alkyl b-gentiobiosyl sulfoxides and nomenclature used herein (upper line). SS sulfoxides (center line, blue color). RS sulfoxides
(bottom line, red color).30
equilibrium, with the gꢀ conformer being more favored by steric
NOE
effects. Moreover, for (RS)-sulfoxides the gꢀ conformer is stabilized
Glcp
Glcp
H2
O
by the stereoelectronic interaction LPS ! rꢃC1ꢀO5, corresponding to
the exo-anomeric effect. On the other hand, the presence of the
g+ conformer on methyl derivative 6R can be explained by the
C1–O5 and S–O dipoles on the g+ conformer being in the anti dis-
position, generating a null resultant dipole, which is favored in low
polarity solvents (Fig. 12). NOE experiments did not show the pres-
ence of the anti conformer.
O
S
O
S
O
H1
NOE
g
+
g
−
The irradiation of the aglyconic methyl group of sulfoxide 6S
showed an NOE with H1 and a second even more intense NOE with
H2, indicating the presence of gꢀ and g+ rotamers in the equilib-
rium, pointing to g+ as the most favored conformer. For tert-butyl
derivative 9S, NOE was only observed with H1, revealing a confor-
mation confined to gꢀ. In the case of (SS)-sulfoxides, the g+ confor-
mation fulfills the requirements for the exo-anomeric effect. The
high contribution of this rotamer to 6S, as implied by NOE experi-
ments, could be explained by the stereoelectronic stabilization of
g+ in addition to the low steric hindrance of the methyl group.
Figure 13 summarizes these conformational properties.
Figure 11. NOE for gꢀ and g+ conformations in glycosyl sulfoxides.
sulfoxides, the conformer g+ fulfills the geometric and conforma-
tional requirements for the exo-anomeric effect, while in the
(RS)-series the gꢀ rotamer satisfies the conditions.
In order to study the conformational properties around the
C1–S bond, NOE experiments were carried out on methyl deriva-
tives 6R and 6S and tert-butyl derivatives 9R and 9S. NOE analysis
is presented according to solvent polarity (Fig. 11).
2.4.1. Non-polar solvent (CD2Cl2)
2.4.2. Polar solvents
Irradiation of the aglyconic methyl group on 6R showed two
NOE effects with H1 and H2, that with H2 being of lesser intensity.
For tert-butyl derivative 9R, irradiation of the methyl groups
showed an NOE effect only with H1. For the sulfoxide of the smal-
ler aglycone, these results provide evidence that g+ and gꢀ con-
The NOE experiment for derivative 6R in acetonitrile presented
an intense effect between the methyl group and H1 and a small
effect with H2, providing evidence of a conformational equilibrium
where the gꢀ rotamer predominates. For tert-butyl derivative 9R,
an NOE was observed only with H1, supporting a conformation
anchored in gꢀ. NOE data in polar solvents indicated that rotamer
gꢀ is the main contributor to the glycosidic conformational
equilibrium; this is valid even for methyl derivative 6R, which
possesses the smallest aglycone. The restricted flexibility around
C1–S of 6R in polar media results from the stabilization of gꢀ by
both the stereoelectronic interaction LPS ! rꢃC1ꢀO5 and the result-
ing net dipole formed between S–O and C1–O5 bonds, an align-
ment favored in polar systems (Fig. 14). The same stabilization
occurs in tert-butyl derivative 9R in addition to the steric
hindrance between the bulky tert-butyl group and H2, which
destabilizes the g+ conformation.
formers are present in the equilibrium, with
a
greater
contribution of gꢀ. Meanwhile, for the sulfoxide of the bulkiest
aglycone the observed NOE effect points to a conformation at
C1–S anchored in gꢀ. These results are supported by steric and
stereoelectronic effects; the steric hindrance between H2 and
voluminous aglycone disfavors the contribution of g+ to the
Glcp
δ−
O5
R
R
O
C2
δ−
+
S
S
H
The 1D-NOE experiment for methyl sulfoxide 6S in acetonitrile
revealed effects with H1 and H2 of similar intensities, indicating a
conformational equilibrium between gꢀ and g+. For 9S, only an
NOE with H1 was observed, hence the conformation was anchored
in the gꢀ rotamer.
O
-
O
g+
Figure 12. Alignment of C1–O5 and S–O dipoles for RS sulfoxides on g+
conformation.

C. A. Sanhueza et al. / Tetrahedron: Asymmetry 24 (2013) 582–593
589
Glcp
Glcp
Glcp
-
O
S
R
O
O
O
RS
+
+
+
S
S
-
R
O
-
R
σ
*
LPS
C1 O5
−
O
all aglycons
Glcp
Glcp
Glcp
-
O
S
R
SS
O
O
O
+
+
+
S
S
-
R
O
-
σ*C1
O
LPS
R
O5
−
equilibrium R dependent
bulky aglycons: g− > g+ (apolar and polar)
small aglycons: g+ > g− (apolar) or g+ = g− (polar)
g−
g+
anti
Figure 13. Conformations around the thioglucosidic linkage for RS and SS sulfoxides in solution.
δ−
former. Both S-oxides exhibited linear correlations between the
interglycosidic Pgg and Pgt and the corresponding Taft’s steric
parameters (ES) of the alkyl group attached to the sulfinyl group,
particularly in non-polar solvents, where increased gt and
decreased gg populations were observed as the absolute value of
ES increased. Sulfoxides with an (RS)-configuration exhibited
better-defined correlations than the (SS)-sulfoxides.
Glcp
-
O
O
O5
O
C2
+
S
S
H
R
R
σ*C1
LPS
O5
−
g
−
The results of the stereochemical studies on the C1–S revealed
that in gentiobiosyl sulfoxides the LPS ! rꢃC1ꢀO5 hyperconjugation
is determined by the absolute configuration of the sulfur, in addi-
tion to the aglycone size and the nature of the solvent, with deriv-
atives of the (SS)-series showing a higher flexibility than their (RS)-
epimers. NOE analysis of the methyl and tert-butyl derivatives of
both series in different media revealed that the conformational
properties of gentiobiosyl sulfoxides in solution can be explained
for each series on the basis of stereoelectronic and steric effects,
as well as those of the solvent.
Considering these conformational results for the thioglycosidic
linkage along with others obtained for the interglycosidic hydroxy-
methyl group, we established that for (RS)-sulfoxides in non-polar
media there is a correlation between the conformational properties
of the interglycosidic C5–C6 bond and the exo-anomeric effect.
Figure 14. Alignment of C1–O5 and S–O dipoles for (RS)-sulfoxides in the
gꢀ conformation.
Closer examination of the C1–S bond conformational equilib-
rium established that flexibility around this linkage depends on
the aglycone size, the solvent polarity, and the absolute configura-
tion of the sulfur. The methyl derivative of the (SS)-series had a
higher flexibility in both polar and non-polar media compared to
its (RS)-epimer. The rigidity of the methyl sulfoxide 6R in both
polar and non-polar media can be explained by the exo-anomeric
effect, whereby the stereoelectronic interaction LPS ! rCꢃ1ꢀO5
would restrict free rotation around the thioglycosidic bond. For
tert-butyl derivatives 9S and 9R, the conformation is mainly direc-
ted by the steric hindrance between the tert-butyl group and H2.
This interaction confines the glycosidic conformation to the gꢀ rot-
amer (Fig. 13).
4. Experimental
4.1. General
3. Conclusion
The alkyl b-thiogentiobiosides 1–5 and their corresponding
(RS)- and (SS)-sulfinyl gentiobiosides, 6R–9R and 6S–9S, respec-
tively, were synthesized and characterized, and their conforma-
tional properties studied. Analysis of the hydroxymethyl groups
in alkyl 1-thiogentiobiosides revealed that although both depend
on the structural nature of the S-aglycone, the one connecting
the two sugar rings is the more affected. The results showed the
strong influence of the solvent polarity on the conformational pref-
erences of the interglycosidic bond. While in polar solvents, the
magnitudes of the rotamer populations, Pgg and Pgt, remained prac-
tically constant throughout the series; in non-polar solvents differ-
ent conformational behavior was observed, with the gt rotamer
being the most stable. Linear correlations between the increasing
Pgt and the decreasing Pgg as well as the corresponding Taft’s steric
parameter (ES) of the S-aglyconic alkyl group were observed in
non-polar solvents.
1H NMR spectra were recorded at 400 or 500 MHz, and 13C NMR
at 75 MHz, VTU (variable temperature unit) 300.0 K. Chemical
shifts are reported in parts per million. The residual solvent peak
was used as an internal reference: for CDCl3, 7.26 for proton and
77.0 ppm for the central peak of carbon NMR. Optical rotations
were measured on a digital polarimeter in a 1 dm cell at 25 °C.
UV and CD spectra were recorded in the range of 400–200 nm
using 10 mm cells. For analytical thin-layer chromatography, silica
gel ready-foils were used, developed with 254 nm UV light and/or
spraying with AcOH/H2O/H2SO4 (80:16:4) and heating at 150 °C.
Flash column chromatography was performed using silica gel
(60 Å). All reagents were from commercial sources (b-Gentiobiose
were purchased from Sigma–Aldrich), and used without further
purification. Solvents were dried and distilled before use. All reac-
tions were performed under a dry nitrogen atmosphere. The com-
pounds prepared were characterized on the basis of their one- (1H
and 13C) and two-dimensional (COSY, HMQC, and T-ROESY) NMR
spectra and HRMS, as well as by UV and CD spectroscopy for the
case of sulfinyl derivatives.
The study performed with (SS)- and (RS)-alkyl thiogentiobiosyl
S-oxides revealed the dominance of the gt rotamer, with Pgt always
having a higher magnitude in the latter S-oxides than in the

590
C. A. Sanhueza et al. / Tetrahedron: Asymmetry 24 (2013) 582–593
4.2. General procedure for the synthesis of alkyl
thiogentiobiosides
(q). Anal. Calcd for C27H38O17S: C, 48.64; H, 5.75; S, 4.81. Found:
C, 48.18; H, 5.30; S, 4.64.
4.2.1. Method A16
4.5. Ethyl 2,3,4-tri-O-acetyl-6-O-(2,3,4,6-tetra-O-acetyl-b-
glucopyranosyl)-1-thio-b- -glucopyranoside 2
D-
Boron trifluoride etherate (0.1 equiv) was added via syringe to a
D
stirred solution of b-D-gentiobiose octaacetate and the respective
thiol (2.0 equiv) in dry dichloromethane (5.0 mL/mmol) at room
temperature and under a nitrogen atmosphere. When TLC showed
complete consumption of the starting material, the system was
quenched by the addition of triethylamine and then diluted with
dichloromethane. The organic fraction was washed with water
and the aqueous layer re-extracted twice with a similar volume
of dichloromethane. The organic layers were combined, dried over
sodium sulfate and concentrated for purification by flash chroma-
tography using silica gel and ethyl acetate/n-hexane systems as
eluents.
Following the general procedure A, for b-thioglycosides synthe-
sis, 268 mg (0.40 mmol) of gentiobiose octaacetate with 0.88 L of
l
ethylmercaptan gave 231 mg (0.34 mmol, 85%) of gentiobiose thio-
glycoside 2.36TLC Rf = 0.40 (n-hex/EtOAc 2:3); mp = 200 °C;
[
a
]
D = ꢀ20.0 (c 0.6, CHCl3); HRMS calcd for C28H40O17NaS
703.1884 ([M+Na]+), found 703.1885; 1H NMR (d, CDCl3): 5.21
(dd, J = 9.5, 9.5 Hz, H-30), 5.19 (dd, J = 9.2, 9.2 Hz, H-3), 5.08 (dd,
J = 9.7, 9.7 Hz, H-4), 4.99 (dd, J = 9.5, 9.5 Hz, H-2), 4.98 (dd, J = 9.7,
9.7 Hz, H-20), 4.90 (dd, J = 9.8, 9.8 Hz, H-40), 4.58 (d, J = 8.0 Hz,
H-10), 4.47 (d, J = 10.0 Hz, H-1), 4.28 (dd, J = 4.8, 12.3 Hz, H-6R0),
4.13 (dd, J = 2.3, 12.3 Hz, H-6S0), 3.87 (dd, J = 2.0, 10.9 Hz, H-6S),
3.69 (m, H5, H50), 3.60 (dd, J = 7.2, 10.9 Hz, H-6R), 2.71 (m, 2H),
2.10 (s, 3H), 2.07 (s, 3H), 2.06 (s, 3H), 2.04 (s, 3H), 2.03 (s, 3H),
2.00 (s, 3H), 2.00 (s, 3H), 1.28 (dd, J = 7.5, 7.5 Hz, 3H); 13C NMR
(d, CDCl3) 170.5 (s), 170.2 (s), 170.1 (s), 169.6 (s), 169.4 (s), 169.4
(s), 169.3 (s), 100.7 (d, C-10), 83.2 (d, C-1), 77.3 (d, C-5), 78.8
(d, C-30), 72.8 (d, C-3), 71.9 (d, C-50), 71.2 (d, C-20), 69.9 (d, C-2),
69.2 (d, C-40), 68.5 (t, C-6), 68.3 (d, C-4), 61.8 (t, C-60), 24.1 (t),
20.7 (q), 20.7 (q), 20.7 (q), 20.6 (q), 20.6 (q), 20.6 (q), 20.6 (q),
14.9 (q). Anal. Calcd for C28H40O17S: C, 49.41; H, 5.92; S, 4.71.
Found: C, 49.90; H, 5.72; S, 4.42.
4.2.2. Method B18
Boron trifluoride etherate (1.5 equiv) was added dropwise to a
stirred solution of b-D-gentiobiose octaacetate and thiourea
(2.0 equiv) in acetonitrile (5.0 mL/mmol) and the mixture refluxed
at 80 °C. After total consumption of the starting material (as shown
by TLC), the mixture was cooled to room temperature, after which
triethylamine (3.0 equiv) and the respective alkyl halide (1.5 equiv)
were added. The system was stirred for 3 h and the solvent was
removed under reduced pressure. The crude was dissolved in
dichloromethane and washed with water, dried over sodium sul-
fate, and concentrated for purification by flash chromatography
over silica gel and ethyl acetate/n-hexane systems as eluents.
4.6. iso-Propyl 2,3,4-tri-O-acetyl-6-O-(2,3,4,6-tetra-O-acetyl-b-
glucopyranosyl)-1-thio-b- -glucopyranoside 3
D-
D
4.3. General procedure for the synthesis of alkyl
thiogentiobiosyl S-oxides
Following the general procedure A, 633 mg (0.93 mmol) of gen-
tiobiose octaacetate and 170 L of iso-propyl mercaptan gave
497 mg (0.72 mmol, 77%) of gentiobiose thioglycoside 3. TLC
Rf = 0.42 (n-hex/EtOAc 2:3); mp = 204 °C; D = ꢀ20.5 (c 0.4,
l
To a suspension of the alkyl thiogentiobioside, acetic anhydride
(1.3 equiv), and silica gel (200 mg/mmol) in dichloromethane,
hydrogen peroxide (1.2 equiv from a 34% solution) was added
dropwise. The reaction was vigorously stirred until total consump-
tion of the starting material was evident from TLC. The solution
was then diluted with dichloromethane and filtered to remove sil-
ica gel, washed with a saturated aqueous sodium bicarbonate solu-
tion and dried over magnesium sulfate. The solvent was removed
under reduced pressure and the epimeric mixture purified by flash
chromatography over silica gel with ethyl acetate/n-hexane sys-
tems as eluents.
[a]
CHCl3); HRMS calcd for C29H42O17NaS 717.2040 ([M+Na]+), found
717.2042; 1H NMR (d, CDCl3) 5.19 (dd, J = 9.3, 9.3 Hz, H-3), 5.14
(dd, J = 9.3, 9.3 Hz, H-30), 5.04 (dd, J = 9.6, 9.6 Hz, H-40), 4.95 (dd,
J = 9.3, 9.3 Hz, H-20), 4.93 (dd, J = 9.4, 9.4 Hz, H-2), 4.86 (dd,
J = 9.6, 9.6 Hz, H-4), 4.56 (d, J = 8.0 Hz, H-10), 4.53 (d, J = 10.1 Hz,
H-1), 4.24 (dd, J = 4.9, 12.4 Hz, H-6R0), 4.09 (dd, J = 2.4, 12.4 Hz,
H-6S0), 3.80 (dd, J = 1.7, 11.0 Hz, H-6S), 3.67 (m, H-5, H-50), 3.66
(dd, J = 7.2, 11.0 Hz, H-6R), 3.15 (m, 1H), 2.07 (s, 3H), 2.03 (s, 3H),
2.02 (s, 3H), 2.01 (s, 3H), 2.00 (s, 3H), 1.97 (s, 3H), 1.97 (s, 3H),
1.29 (d, J = 7.0 Hz, 3H), 1.27 (d, J = 7.0 Hz, 3H). 13C NMR (d, CDCl3)
170.7 (s), 170.3 (s), 169.7 (s), 169.4 (s), 169.4 (s), 169.4 (s), 169.3
(s), 100.5 (d, C-10), 82.9 (d, C-1), 77.2 (d, C-5), 73.7 (d, C-3), 72.7
(d, C-30), 71.8 (d, C-50), 71.0 (d, C-20), 70.1 (d, C-2), 68.9 (d, C-4),
68.3 (t, C-6), 68.0 (d, C-40), 61.7 (t, C-60), 35.3 (d), 24.2 (q), 23.7
(q), 20.8 (q), 20.8 (q), 20.7 (q), 20.7 (q), 20.7 (q), 20.6 (q), 20.6
(q). Anal. Calcd for C29H42O17S: C, 50.14; H, 6.09; S, 4.62. Found:
C, 49.98; H, 5.75; S, 4.35.
4.4. Methyl 2,3,4-tri-O-acetyl-6-O-(2,3,4,6-tetra-O-acetyl-b-
glucopyranosyl)-1-thio-b- -glucopyranoside 1
D-
D
Following the general procedure B, 300 mg (0.44 mmol) of gen-
tiobiose octaacetate, 67 mg of thiourea, and 40 L of CH3I gave
202 mg (0.27 mmol, 62%) of gentiobiose thioglycoside 1.35 TLC
Rf = 0.38 (n-hex/EtOAc 2:3); mp = 164 °C; [ D = ꢀ7.9 (c 0.6, CHCl3);
HRMS calcd for
27H38O17NaS 689.1727 ([M+Na]+), found:
l
a]
C
689.1725; 1H NMR (d, CDCl3) 5.20 (dd, J = 9.5, 9.5 Hz, H-3), 5.19
(dd, J = 9.5, 9.5 Hz, H-30), 5.07 (dd, J = 9.8, 9.8 Hz, H-40), 4.99 (dd,
J = 9.5, 9.5 Hz, H-2), 4.97 (dd, J = 8.0, 9.8 Hz, H-20), 4.89 (dd,
J = 9.8, 9.8 Hz, H-4), 4.57 (d, J = 8.0 Hz, H-10), 4.37 (d, J = 9.8 Hz,
H-1), 4.27 (dd, J = 4.7, 12.4 Hz, H-6R0), 4.12 (dd, J = 2.3, 12.4 Hz,
H-6S0), 3.88 (dd, J = 2.2, 11.2 Hz, H-6S), 3.69 (m, H-5, H-50), 3.57
(dd, J = 6.8, 11.2 Hz, H-6R), 2.17 (s, 3H), 2.09 (s, 3H), 2.07 (s, 3H),
2.05 (s, 3H), 2.02 (s, 3H), 2.01 (s, 3H), 1.99 (s, 3H), 1.99 (s, 3H);
13C NMR (d, CDCl3) 170.7 (s), 170.2 (s), 170.1 (s), 169.6 (s), 169.5
(s), 169.5 (s), 169.4 (s), 100.9 (d, C-10), 82.9 (d, C-1), 77.2 (d, C-5),
73.7 (d, C-3), 72.7 (d, C-30), 71.9 (d, C-50), 71.1 (d, C-20), 69.2 (d,
C-2), 68.9 (d, C-4), 68.4 (t, C-6), 68.3 (d, C-40), 61.8 (t, C-60), 20.7
(q), 20.7 (q), 20.7 (q), 20.6 (q), 20.6 (q), 20.6 (q), 20.5 (q), 11.5
4.7. Cyclohexyl 2,3,4-tri-O-acetyl-6-O-(2,3,4,6-tetra-O-acetyl-b-
D-glucopyranosyl)-1-thio-b-D-glucopyranoside 4
Following the general procedure A, 527 mg (0.78 mmol) of gen-
tiobiose octaacetate and 200 L of cyclohexyl mercaptan gave
459 mg (0.63 mmol, 81%) of gentiobiose thioglycoside 4. TLC
l
Rf = 0.45 (n-hex/EtOAc 2:3); mp = 194 °C;
[
a
]
D = ꢀ21.4 (c 0.6,
CHCl3); HRMS calcd for C32H46O17NaS 757.2353 ([M+Na]+), found
757.2353; 1H NMR (d, CDCl3) 5.21 (dd, J = 9.2, 9.2 Hz, H-3), 5.19
(dd, J = 9.2, 9.2 Hz, H-30), 5.07 (dd, J = 9.7, 9.7 Hz, H-4), 4.97 (dd,
J = 8.3, 9.4 Hz, H-20), 4.95 (dd, J = 9.6, 9.6 Hz, H-2), 4.89 (dd,
J = 9.6, 9.6 Hz, H-40), 4.60 (d, J = 8.0 Hz, H-10), 4.55 (d, J = 9.9 Hz,
H-1), 4.27 (dd, J = 4.9, 12.4 Hz, H-6R0), 4.13 (dd, J = 2.4, 12.4 Hz,

C. A. Sanhueza et al. / Tetrahedron: Asymmetry 24 (2013) 582–593
591
H-6S0), 3.83 (dd, J = 1.7, 10.9 Hz, H-6S), 3.67 (m, H-5, H-50), 3.65
4.10. (RS)-Methyl 2,3,4-tri-O-acetyl-6-O-(2,3,4,6-tetra-O-acetyl-
b- -glucopyranosyl)-1-thio-b- -glucopyranoside S-oxide 6R
(dd, J = 7.2, 10.9 Hz, H-6R), 2.94 (m, 1H), 2.11 (s, 3H), 2.07 (s, 3H),
2.05 (s, 3H), 2.04 (s, 3H), 2.03 (s, 3H), 2.00 (s, 3H), 2.00 (s, 3H),
1.95 (m, 1H), 1.77 (m, 2H), 1.63 (m, 2H), 1.35 (m, 6H); 13C NMR
(d, CDCl3) 170.6 (s), 170.2 (s), 170.2 (s), 169.6 (s), 169.4 (s), 169.4
(s), 169.3 (s), 100.6 (d, C-10), 82.9 (d, C-1), 77.4 (d, C-5), 73.9 (d,
C-3), 72.8 (d, C-30), 71.9 (d, C-50), 71.1 (d, C-20), 70.3 (d, C-2), 69.1
(d, C-40), 68.4 (t, C-6), 68.3 (d, C-4), 61.8 (t, C-60), 43.5 (d), 34.3
(t) 33.8 (t), 25.8 (t), 25.6 (t), 25.6 (t), 20.6 (q), 20.7 (q), 20.7 (q),
20.6 (q), 20.6 (q), 20.5 (q), 20.5 (q). Anal. Calcd for C32H46O17S: C,
52.31; H, 6.31; S, 4.36. Found: C, 52.45; H, 6.05; S, 4.13.
D
D
TLC Rf = 0.35 (MeOH/CH2Cl2 1:19); mp = 230 °C; [
a
]D = ꢀ50.8
(c 0.4, CHCl3); HRMS calcd for C27H38O18NaS 705.1677 ([M+Na]+),
found 705.1685; 1H NMR (d, CDCl3) 5.39 (dd, J = 9.4, 9.4 Hz, H-2),
5.35 (dd, J = 9.1, 9.1 Hz, H-3), 5.19 (dd, J = 9.5, 9.5 Hz, H-30), 5.07
(dd, J = 9.7, 9.7 Hz, H-40), 4.98 (dd, J = 8.1, 9.6 Hz, H-20), 4.97 (dd,
J = 9.7, 9.7 Hz, H-4), 4.56 (d, J = 8.1 Hz, H-10), 4.27 (dd, J = 5.0,
12.3 Hz, H-6R0), 4.14 (dd, J = 2.1, 12.3 Hz, H-6S0), 4.08 (d,
J = 9.6 Hz, H-1), 3.86 (m, H-6S, H-5), 3.74 (dd, J = 7.5, 11.0 Hz,
H-6R), 3.70 (ddd, J = 2.1, 5.0, 10.0 Hz, H-50), 2.68 (s, 3H), 2.10
(s, 3H), 2.07 (s, 3H), 2.06 (s, 3H), 2.04 (s, 3H), 2.03 (s, 3H), 2.03 (s,
3H), 2.01 (s, 3H); 13C NMR (d, CDCl3) 170.5 (s), 170.1 (s), 169.4
(s), 169.4 (s), 169.4 (s), 169.2 (s), 168.9 (s), 100.5 (d, C-10), 87.4
(d, C-1), 78.1 (d, C-5), 73.6 (d, C-3), 72.7 (d, C-30), 72.0 (d, C-50),
71.2 (d, C-20), 68.4 (d, C-4), 68.2 (d, C-40), 68.1 (t, C-6), 66.9 (d, C-
2), 61.7 (t, C-60), 33.3 (q), 20.7 (q), 20.5 (q), 20.5 (q), 20.5 (q),
4.8. tert-Butyl 2,3,4-tri-O-acetyl-6-O-(2,3,4,6-tetra-O-acetyl-b-
glucopyranosyl)-1-thio-b- -glucopyranoside 5
D-
D
Following the general procedure A, 554 mg (0.82 mmol) of gen-
tiobiose octaacetate and 220 L of tert-butyl mercaptan gave
402 mg (0.57 mmol, 69%) of gentiobiose thioglycoside 5. TLC
Rf = 0.44 (n-hex/EtOAc 2:3); mp = 215 °C; D = ꢀ12.8 (c 0.5,
l
20.5 (q), 20.5 (q), 20.5 (q); UV (CH3CN) kmax
(CH3CN) kext
) 218 (ꢀ8.6), 194 nm (4.4). Anal. Calcd for
27H38O18S: C, 47.50; H, 5.61; S, 4.70. Found: C, 47.13; H, 5.28;
S, 4.24.
(e) 210 nm 3500; CD
[a]
(De
CHCl3); HRMS calcd for C30H44O17NaS 731.2197 ([M+Na]+), found
731.2197; 1H NMR (d, CDCl3) 5.23 (dd, J = 9.4, 9.4 Hz, H-3), 5.15
(dd, J = 9.4, 9.4 Hz, H-30), 5.05 (dd, J = 9.7, 9.7 Hz, H-40), 4.96
(dd, J = 8.0, 9.5 Hz, H-20), 4.93 (dd, J = 9.7, 9.7 Hz, H-2), 4.86 (dd,
J = 9.7, 9.7 Hz, H-4), 4.61 (d, J = 10.1 Hz, H-1), 4.58 (d, J = 8.0 Hz,
H-10), 4.26 (dd, J = 5.0, 12.3 Hz, H-6R0), 4.11 (dd, J = 2.3, 12.3 Hz,
H-6S0), 3.79 (dd, J = 1.7, 10.8 Hz, H-6S), 3.69 (m, H-5, H-50), 3.66
(dd, J = 7.5, 10.8 Hz, H-6R), 2.16 (s, 3H), 2.09 (s, 3H), 2.03 (s, 3H),
2.02 (s, 3H), 2.02 (s, 3H), 2.02 (s, 3H), 1.99 (s, 3H), 1.36 (s, 9H).
13C NMR (d, CDCl3) 170.6 (s), 170.2 (s), 170.2 (s), 169.6 (s), 169.4
(s), 169.3 (s), 169.2 (s), 100.3 (d, C-10), 82.0 (d, C-1), 77.2 (d, C-5),
73.9 (d, C-3), 72.9 (d, C-30), 71.9 (d, C-50), 71.1 (d, C-20), 70.2 (d,
C-2), 69.0 (d, C-4), 68.3 (d, C-40), 68.2 (d, C-6), 61.8 (t, C-60), 44.2
(s), 31.5 (q, x 3), 20.8 (q), 20.7 (q), 20.7 (q), 20.6 (q), 20.6 (q),
20.5 (q), 20.5 (q). Anal. Calcd for C30H44O17S: C, 50.84; H, 6.26; S,
4.52. Found: C, 51.03; H, 5.77; S, 4.28.
C
4.10.1. Sulfoxides 7S and 7R
Following the general procedure for the synthesis of glucosyl
thioglucoside S-oxides, 155 mg (0.23 mmol) of thioglycoside 2
gave 131 mg (0.19 mmol, 83%) of the corresponding sulfoxide epi-
mers (SS/RS = 2:1).
4.11. (SS)-Ethyl 2,3,4-tri-O-acetyl-6-O-(2,3,4,6-tetra-O-acetyl-b-
D
-glucopyranosyl)-1-thio-b-
D
-glucopyranoside S-oxide 7S
TLC Rf = 0.40 (MeOH/CH2Cl2 1:19); mp = 178 °C; [
a
]D = ꢀ25.0
(c 0.7, CHCl3); HRMS calcd for C28H40O18NaS 719.1833 ([M+Na]+),
found 719.1841; 1H NMR (d, CDCl3) 5.27 (dd, J = 9.1, 9.1 Hz, H-3),
5.21 (dd, J = 9.5, 9.5 Hz, H-2), 5.18 (dd, J = 9.5, 9.5 Hz, H-30), 5.06
(dd, J = 9.7, 9.7 Hz, H-40), 4.96 (dd, J = 7.9, 9.4 Hz, H-20), 4.96
(dd, J = 9.5, 9.5 Hz, H-4), 4.51 (d, J = 7.9 Hz, H-10), 4.30 (d, J = 9.6 Hz,
H-1), 4.25 (dd, J = 4.8, 12.3 Hz, H-6R0), 4.11 (dd, J = 2.2, 12.3 Hz, H-
6S0), 3.94 (dd, J = 2.2, 11.1 Hz, H-6S), 3.77 (ddd, J = 2.2, 5.9, 9.9 Hz,
H-5), 3.69 (ddd, J = 2.2, 4.8, 9.9 Hz, H-50), 3.57 (dd, J = 5.9,
11.1 Hz, H-6R), 2.89 (m, 2H), 2.09 (s, 3H), 2.06 (s, 3H), 2.05 (s,
3H), 2.04 (s, 3H), 2.01 (s, 3H), 2.00 (s, 3H), 1.99 (s, 3H), 1.37 (dd,
J = 7.5, 7.5 Hz, 3H); 13C NMR (d, CDCl3) 170.5 (s), 170.1 (s), 169.9
(s), 169.6 (s), 169.4 (s), 169.3 (s), 169.3 (s), 100.5 (d, C-10), 89.6
(d, C-1), 77.6 (d, C-5), 73.2 (d, C-3), 72.7 (d, C-30), 71.9 (d, C-50),
70.9 (d, C-20), 68.4 (d, C-2), 68.3 (d, C-40), 68.2 (d, C-4), 67.4
(t, C-6), 61.8 (t, C-60), 41.6 (t), 20.7 (q), 20.6 (q), 20.6 (q), 20.6 (q),
4.8.1. Sulfoxides 6S and 6R
Following the general method for the synthesis of glucosyl thi-
oglucoside S-oxides, 156 mg (0.23 mmol) of thioglycoside 1 led to
144 mg (0.21 mmol, 91%) of the corresponding sulfoxide epimers
(SS/RS = 2.5:1).
4.9. (SS)-Methyl 2,3,4-tri-O-acetyl-6-O-(2,3,4,6-tetra-O-acetyl-b-
D
-glucopyranosyl)-1-thio-b-
D
-glucopyranoside S-oxide 6S
TLC Rf = 0.37 (MeOH/CH2Cl2 1:19); mp = 177 °C; [
a
]D = ꢀ7.1
(c 0.3, CHCl3); HRMS calcd for C27H38O18NaS 705.1677 ([M+Na]+),
found 705.1682; 1H NMR (d, CDCl3) 5.31 (dd, J = 9.2, 9.2 Hz, H-3),
5.22 (dd, J = 9.5, 9.5 Hz, H-30), 5.09 (dd, J = 9.7, 9.7 Hz, H-40), 5.06
(dd, J = 9.7, 9.7 Hz, H-2), 5.03 (dd, J = 9.6, 9.6 Hz, H-4), 4.99
(dd, J = 7.8, 9.5 Hz, H-20), 4.56 (d, J = 7.8 Hz, H-10), 4.37 (d,
J = 10.1 Hz, H-1), 4.28 (dd, J = 4.8, 12.3 Hz, H-6R0), 4.15 (dd, J = 2.3,
12.3 Hz, H-6S0), 4.03 (dd, J = 2.3, 11.2 Hz, H-6S), 3.81 (ddd, J = 2.3,
5.3, 9.9 Hz, H-5), 3.72 (ddd, J = 2.3, 4.8, 10.0 Hz, H-50), 3.62 (dd,
J = 5.3, 11.2 Hz, H-6R), 2.70 (s, 3H), 2.12 (s, 3H), 2.09 (s, 3H), 2.08
(s, 3H), 2.07 (s, 3H), 2.04 (s, 3H), 2.03 (s, 3H), 2.02 (s, 3H); 13C
NMR (d, CDCl3) 170.6 (s), 170.2 (s), 170.0 (s), 169.7 (s), 169.5 (s),
169.4 (s), 169.3 (s), 100.5 (d, C-10), 90.5 (d, C-1), 77.6 (d, C-5),
73.2 (d, C-3), 72.7 (d, C-30), 71.9 (d, C-50), 71.1 (d, C-20), 68.3
(d, C-40), 68.3 (d, C-2), 68.2 (d, C-4), 67.2 (t, C-6), 61.8 (t, C-60),
33.1 (q), 20.7 (q), 20.7 (q), 20.6 (q), 20.6 (q), 20.6 (q), 20.5 (q),
20.5 (q), 20.5 (q), 20.5 (q), 6.5 (q); UV (CH3CN) kmax
(3500); CD (CH3CN) kext
for C28H40O18S: C, 48.27; H, 5.59; S, 4.60. Found: C, 48.53; H, 5.59;
(e) 210 nm
) 227 (8.4), 201 nm (ꢀ17.9). Anal. Calcd
(D
e
S, 4.31.
4.12. (RS)-Ethyl 2,3,4-tri-O-acetyl-6-O-(2,3,4,6-tetra-O-acetyl-b-
D
-glucopyranosyl)-1-thio-b-
D
-glucopyranoside S-oxide 7R
TLC Rf = 0.38 (MeOH/CH2Cl2 1:19); mp = 221 °C; [
a
]
D = ꢀ46.1 (c
0.2, CHCl3); HRMS calcd for C28H40O18NaS 719.1833 ([M+Na]+),
found 719.1836; 1H NMR (d, CDCl3) 5.43 (dd, J = 9.5, 9.5 Hz, H-2),
5.36 (dd, J = 9.2, 9.2 Hz, H-3), 5.20 (dd, J = 9.5, 9.5 Hz, H-30), 5.07
(dd, J = 9.7, 9.7 Hz, H-40), 4.99 (dd, J = 8.0, 9.6 Hz, H-20), 4.97 (dd,
J = 9.5, 9.5 Hz, H-4), 4.56 (d, J = 8.0 Hz, H-10), 4.28 (dd, J = 5.1,
12.3 Hz, H-6R0), 4.14 (dd, J = 2.3, 12.3 Hz, H-6S0), 4.14
(d, J = 9.8 Hz, H-1), 3.85 (m, H-5, H6S), 3.76 (dd, J = 8.6, 11.2 Hz,
H-6R), 3.71 (ddd, J = 2.3, 5.1, 9.9 Hz, H-50), 3.12 (m, 1H), 2.80 (m,
1H), 2.11 (s, 3H), 2.08 (s, 3H), 2.07 (s, 3H), 2.06 (s, 3H), 2.05 (s,
20.5 (q); UV (CH3CN) kmax
) 223 (4.4), 200 nm (ꢀ11.9). Anal. Calcd for C27H38O18S: C,
47.50; H, 5.61; S, 4.70. Found: C, 47.16; H, 5.32; S, 4.26.
(e) 210 nm (3500; CD (CH3CN) kext
(De

592
C. A. Sanhueza et al. / Tetrahedron: Asymmetry 24 (2013) 582–593
3H), 2.04 (s, 3H), 2.01 (s, 3H), 1.36 (s, 3H); 13C NMR (d, CDCl3) 170.5
(s), 170.3 (s), 170.1 (s), 169.4 (s), 169.4 (s), 169.2 (s), 168.8 (s),
100.5 (d, C-10), 86.3 (d, C-1), 78.3 (d, C-5), 73.7 (d, C-3), 72.7 (d,
C-30) 72.0 (d, C-5), 71.1 (d, C-20), 68.4 (d, C-4), 68.2 (d, C-40), 68.2
(t, C-6), 66.9 (d, C-2), 61.8 (t, C-60), 41.3 (t), 20.7 (s), 20.6 (s), 20.5
4.14.1. Sulfoxides 9S and 9R
Following the general procedure for the synthesis of glucosyl
thioglucoside S-oxides, 309 mg (0.44 mmol) of thioglycoside 5
led to 264 mg (0.37 mmol, 84%) of the corresponding sulfoxide epi-
mers (SS/RS = 1.4:1).
(s), 20.5 (s), 20.5 (s), 20.5 (s), 20.5 (s), 7.4 (s); UV (CH3CN) kmax
210 nm (3500 ; CD (CH3CN) kext
Anal. Calcd for C28H40O18S: C, 48.27; H, 5.59; S, 4.60. Found: C,
48.37; H, 5.64; S, 4.24.
(e
(D
e
) 220 (ꢀ10.8), 196 nm (3.2).
4.15. (SS)-tert-Butyl 2,3,4-tri-O-acetyl-6-O-(2,3,4,6-tetra-O-
acetyl-b-
9S
D-glucopyranosyl)-1-thio-b-D-glucopyranoside S-oxide
TLC Rf = 0.48 (MeOH/CH2Cl2 1:19); mp = 197 °C; [a]D = +8.3
4.12.1. Sulfoxides 8S and 8R
(c 0.6, CHCl3); HRMS calcd for C30H44O18NaS 747.2146 ([M+Na]+),
found 747.2158; 1H NMR (d, CDCl3) 5.51 (dd, J = 9.3, 9.3 Hz, H-2),
5.24 (dd, J = 9.1, 9.1 Hz, H-3), 5.16 (dd, J = 9.5, 9.5 Hz, H-30), 5.03
(dd, J = 9.7, 9.7 Hz, H-40), 4.94 (dd, J = 8.0, 9.4 Hz, H-20), 4.91
(dd, J = 9.9, 9.9 Hz, H-4), 4.51 (d, J = 8.0 Hz, H-10), 4.30 (d, J = 9.6 Hz,
H-1), 4.25 (dd, J = 5.1, 13.3 Hz, H-6R0), 4.12 (dd, J = 2.2, 13.3 Hz, H-
6S0), 3.77 (m, H-5, H-6S), 3.68 (ddd, J = 2.2, 5.1, 10.0 Hz, H-50), 3.62
(dd, J = 7.3, 12.0 Hz, H-6R), 2.10 (s, 3H), 2.04 (s, 3H), 2.03 (s, 3H),
2.02 (s, 3H), 2.02 (s, 3H), 2.01 (s, 3H), 1.99 (s, 3H), 1.31 (s, 9H);
13C NMR (d, CDCl3) 170.5 (s), 170.2 (s), 170.1 (s), 169.4 (s), 169.4
(s), 169.3 (s), 169.1 (s), 100.6 (d, C-10), 86.4 (d, C-1), 77.6 (d, C-5),
73.7 (d, C-3), 72.8 (d, C-30), 72.1 (d, C-5), 71.0 (d, C-20), 68.8 (d, C-
2), 68.3 (d, C-4), 68.2 (d, C-40), 68.1 (t, C-6), 61.8 (t,
C-60), 55.7 (s), 23.1 (q, x 3C), 20.7 (q), 20.7 (q), 20.7 (q), 20.6 (q),
Following the general procedure for the synthesis of glucosyl
thioglucoside S-oxides, 398 mg (0.57 mmol) of thioglycoside 3
led to 372 mg (0.52 mmol, 91%) of the corresponding sulfoxide
epimers (SS/RS = 1.6:1).
4.13. (SS)-Isopropyl 2,3,4-tri-O-acetyl-6-O-(2,3,4,6-tetra-O-
acetyl-b-D-glucopyranosyl)-1-thio-b-D-glucopyranoside S-oxide
8S
TLC Rf = 0.41 (MeOH/CH2Cl2 1:19); mp = 139 °C; [
a
]
D = ꢀ1.7
(c 1.1, CHCl3); HRMS calcd for C29H42O18NaS 733.1990 ([M+Na]+),
found 733.1990; 1H NMR (d, CDCl3) 5.40 (dd, J = 9.5, 9.5 Hz, H-2),
5.26 (dd, J = 9.2, 9.2 Hz, H-3), 5.17 (dd, J = 9.5, 9.5 Hz, H-30), 5.03
(dd, J = 9.6, 9.6 Hz, H-40), 4.94 (dd, J = 8.0, 9.5 Hz, H-20), 4.92 (dd, J
= 9.7, 9.7 Hz, H-4), 4.49 (d, J = 8.0 Hz, H-10), 4.24 (dd, J = 4.9,
12.3 Hz, H-6R0), 4.19 (d, J = 9.7 Hz, H-1), 4.11 (dd, J = 2.2, 12.3 Hz,
H-6S0), 3.86 (dd, J = 2.1, 11.2 Hz, H-6S), 3.76 (ddd, J = 2.1, 6.6,
9.3 Hz, H-5), 3.67 (ddd, J = 2.2, 4.9, 10.0 Hz, H-50), 3.56 (dd, J = 6.6,
11.2 Hz, H-6R), 3.09 (m, 1H), 2.07 (s, 3H), 2.04 (s, 3H), 2.03 (s,
3H), 2.02 (s, 3H), 2.01 (s, 3H), 1.99 (s, 3H), 1.98 (s, 3H), 1.32
(d, J = 7.1 Hz, 3H), 1.28 (d, J = 7.1 Hz, 3H). 13C NMR (d, CDCl3)
170.5 (s), 170.1 (s), 170.0 (s), 169.5 (s), 169.4 (s), 169.4 (s), 169.2
(s), 100.6 (d, C-10), 88.2 (d, C-1), 77.8 (d, C-5), 73.3 (d, C-3), 72.7
(d, C-30), 72.0 (d, C-50), 70.9 (d, C-20), 68.8 (d, C-2), 68.3 d, C-4,
68.2 (d, C-40), 67.7 (t, C-6), 61.8 (t, C-60), 47.7 (d), 20.7 (q), 20.7
(q), 20.6 (q), 20.6 (q), 20.6 (q), 20.5 (q), 20.5 (q), 16.9 (q), 13.1
20.6 (q), 20.5 (q), 20.5 (q); UV (CH3CN) kmax
(CH3CN) kext
) 230 (7.9), 203 nm (ꢀ6.8). Anal. Calcd for
30H44O18S: C, 49.72; H, 6.12; S, 4.42. Found: C, 49.76; H, 6.10; S,
3.97.
(e 210 nm (3500; CD
(De
C
4.16. (RS)-tert-Butyl 2,3,4-tri-O-acetyl-6-O-(2,3,4,6-tetra-O-
acetyl-b-
9R
D-glucopyranosyl)-1-thio-b-D-glucopyranoside S-oxide
TLC Rf = 0.47 (MeOH/CH2Cl2 1:19); mp = 190 °C; [
a
]D = ꢀ51.1 (c
0.4, CHCl3); HRMS calcd for C30H44O18NaS 747.2146 ([M+Na]+),
found 747.2150; 1H NMR (d, CDCl3) 5.40 (dd, J = 9.1, 9.1 Hz, H-2),
5.30 (dd, J = 9.3, 9.3 Hz, H-3), 5.16 (dd, J = 9.4, 9.4 Hz, H-30), 5.03
(dd, J = 9.7, 9.7 Hz, H-40), 4.94 (dd, J = 8.0, 9.3 Hz, H-20), 4.92 (dd,
J = 9.5, 9.5 Hz, H-4), 4.55 (d, J = 8.0 Hz, H-10), 4.32 (d, J = 10.0 Hz,
H-1), 4.26 (dd, J = 5.4, 12.3 Hz, H-6R0), 4.11 (dd, J = 2.2, 12.3 Hz,
H-6S0), 3.79 (m, H-5, H-6R, H-6S), 3.69 (ddd, J = 2.2, 5.4, 10.0 Hz,
H-50), 2.10 (s, 3H), 2.05 (s, 3H), 2.04 (s, 3H), 2.03 (s, 3H), 2.02 (s,
3H), 2.01 (s, 3H), 1.99 (s, 3H), 1.33 (s, 9H); 13C NMR (d, CDCl3)
170.5 (s), 170.4 (s), 170.3 (s), 170.1 (s), 169.4 (s), 169.2 (s), 168.7
(s), 100.4 (d, C-10), 84.9 (d, C-1), 78.2 (d, C-5), 73.7 (d, C-3), 72.9
(d, C-30), 72.0 (d, C-5), 71.2 (d, C-20), 68.4 (d, C-4), 68.2 (t, C-6),
68.2 (d, C-40), 67.4 (d, C-2), 61.8 (t, C-60), 55.9 (s), 24.1 (q x 3C),
20.7 (q), 20.6 (q), 20.5 (q), 20.5 (q), 20.5 (q), 20.5 (q), 20.5 (q);
(q); UV (CH3CN) kmax (e 210 nm (3500; CD (CH3CN) kext (De) 229
(7.6), 203 nm (ꢀ6.4). Anal. Calcd for C29H42O18S: C, 49.01; H,
5.96; S, 4.51. Found: C, 49.21; H, 5.72; S, 4.08.
4.14. (RS)-Isopropyl 2,3,4-tri-O-acetyl-6-O-(2,3,4,6-tetra-O-
acetyl-b-glucopyranosyl)-1-thio-b-glucopyranoside S-oxide 8R
TLC Rf = 0.40 (MeOH/CH2Cl2 1:19); mp = 221 °C; [
a]
D = ꢀ50.0 (c
0.5, CHCl3); HRMS calcd for C29H42O18NaS 733.1990 ([M+Na]+),
found 733.2001; 1H NMR (d, CDCl3) 5.42 (dd, J = 9.6, 9.6 Hz, H-2),
5.36 (dd, J = 9.3, 9.3 Hz, H-3), 5.18 (dd, J = 9.6, 9.6 Hz, H-30), 5.05
(dd, J = 9.7, 9.7 Hz, H-40), 4.98 (dd, J = 8.0, 9.6 Hz, H-20), 4.94 (dd,
J = 9.5, 9.5 Hz, H-4), 4.53 (d, J = 8.1 Hz, H-10), 4.28 (d, J = 9.8 Hz, H-
1), 4.26 (dd, J = 5.1, 12.1 Hz, H-6R0), 4.12 (dd, J = 2.2, 12.1 Hz,
H-6S0), 3.80 (m, H-6R, H-6S and H-5), 3.69 (ddd, J = 2.2, 5.1,
10.0 Hz, H-50), 3.36 (m, 1H), 2.10 (s, 3H), 2.06 (s, 3H), 2.05 (s,
3H), 2.03 (s, 3H), 2.03 (s, 3H), 2.03 (s, 3H), 2.00 (s, 3H), 1.43 (d,
J = 7.0 Hz, 3H), 1.16 (d, J = 7.0 Hz, 3H); 13C NMR (d, CDCl3) 170.5
(s), 170.4 (s), 170.1 (s), 169.5 (s), 169.5 (s), 169.4 (s), 169.1 (s),
100.4 (d, C-10), 85.2 (d, C-1), 78.4 (d, C-5), 73.8 (d, C-3), 72.8 (d,
C-30), 72.0 (d, C-50), 71.3 (d, C-20), 68.5 (d, C-4), 68.2 (d, C-40),
68.2 (t, C-6), 67.0 (t, C-2), 61.8 (t, C-60), 47.2 (d), 20.7 (q), 20.7
(q), 20.6 (q), 20.6 (q), 20.5 (q), 20.5 (q), 20.5 (q), 16.7 (q), 15.5
UV (CH3CN) kmax (e 210 nm (3500; CD (CH3CN) kext (De) 224
(ꢀ8.2), 204 nm (8.4). Anal. Calcd for C30H44O18S: C, 49.72; H,
6.12; S, 4.42. Found: C, 49.31; H, 5.72; S, 3.87.
Acknowledgements
This research was supported by the Ministerio de Ciencia e
Innovación (MICINN, Spain), through grant CTQ2007-67532-C02-
02/BQU, and by the Universidad de La Laguna. C.A.S. thanks the
Consejería de Educación, Cultura y Deportes (Gobierno de Cana-
rias) for a fellowship.
References
(q); UV (CH3CN) kmax (e 210 nm (3500; CD (CH3CN) kext (De) 222
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5.96; S, 4.51. Found: C, 49.27; H, 5.38; S, 4.02.

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the endocyclic oxygen O5 was used, as shown in Figure 10. In addition, we
herein differentiate (SS)- and (RS)-sulfoxides with blue and red colors,
respectively.
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Pgt = ꢀ14.1 ES + 64.5 (R2 = 0.98).
32. Regression line equations for compounds 6S–9S: Dichloromethane: Pgg = 10.3 ES
+
51.8 (R2 = 0.88); Pgt = ꢀ10.3 ES + 48.2 (R2 = 0.88); Chloroform: Pgg = 5.3 ES + 48.5
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33. Regression line equations for compounds 6R–9R: Acetonitrile: Pgg = ꢀ1.5 + 45.2
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(R2 = 0.69); Pgt = ꢀ2.0 ES + 62.2 (R2 = 0.69); Acetone Pgg = 0.3 ES + 35.2
(R2 = 0.07); Pgt = ꢀ0.3 ES + 64.8 (R2 = 0.07).
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34. Regression line equations for compounds 6S–9S: Acetonitrile: Pgg = 1.0 ES + 49.5
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