Involvement of the S-aglycon in the conformational preferences of thioglucosides

Article abstract of DOI:10.1016/j.tetasy.2008.01.003

The conformational preferences of two series of alkyl β-d-thioglucopyranosides in solution were investigated by NMR and CD. The rotamer populations of the hydroxymethyl group were found to depend on the structural nature of the S-aglycon. The population of the gt rotamer increased and that of the gg rotamer decreased as the alkyl group attached to the S atom increased in size. These rotamer populations have a linear correlation with the Taft' steric parameters, the n_S s(-) σ_{C s(-) O}^* exo-anomeric interaction may express these rotational preferences. Comparative analysis of the hydroxymethyl populations between alkyl O- and S-glucosides revealed identical or slightly higher gt and smaller gg populations for the latter compounds.

Full text of DOI:10.1016/j.tetasy.2008.01.003

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 258–264
Involvement of the S-aglycon in the conformational
preferences of thioglucosides
*
´
Carlos A. Sanhueza, Rosa L. Dorta and Jesu´s T. Vazquez
Instituto Universitario de Bio-Orga´nica ‘Antonio Gonza´lez’, Departamento de Quı´mica Orga´nica,
Universidad de La Laguna, 38206 La Laguna, Tenerife, Spain
Received 4 December 2007; accepted 4 January 2008
Abstract—The conformational preferences of two series of alkyl b-D-thioglucopyranosides in solution were investigated by NMR and
CD. The rotamer populations of the hydroxymethyl group were found to depend on the structural nature of the S-aglycon. The pop-
ulation of the gt rotamer increased and that of the gg rotamer decreased as the alkyl group attached to the S atom increased in size. These
rotamer populations have a linear correlation with the Taft’ steric parameters, the nS–rÃC–O exo-anomeric interaction may express these
rotational preferences. Comparative analysis of the hydroxymethyl populations between alkyl O- and S-glucosides revealed identical or
slightly higher gt and smaller gg populations for the latter compounds.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results
Thiosugars possess unique physicochemical and bio-
To carry out our conformational studies with alkyl b-thio-
glucosides, by means of nuclear magnetic resonance and
circular dichroism, we have synthesized two series of model
compounds. The first thioglucoside series possesses four
acetyl groups, namely, alkyl 2,3,4,6-tetra-O-acetyl b-D-
thioglucosides. The second possesses two acetyl and two
chromophoric p-bromobenzoyl groups, namely, alkyl 2,3-
di-O-acetyl-4,6-di-(p-bromobenzoyl) b-D-thioglucosides.
logical properties, as
a consequence of geometric,
conformational, and electronic differences from their
oxygen analogs.1 Thioglycosides are the most abundant
family of naturally occurring thiosugars isolated from
many different plant species. Replacement of the exo-
cyclic oxygen atom with a sulfur atom increases their
stability toward chemical and enzymatic action.2 It also
confers a high degree of flexibility around the inter-
glycosidic linkage.2 These compounds are therefore
useful for a variety of purposes in bioorganic and
medicinal chemistry research.
The model compounds 1a, 3a–8a, and 3b–8b were
synthesized according to method A,8 namely, from penta-
O-acetyl-b-D-(+)-glucopyranose (Scheme 1) or from
Our previous reports were centered on the understanding
of the conformational preferences of the most important
monosaccharides in nature: gluco-,3 galacto-,4 and manno-
pyranosides,5 as well as disaccharides,6 and on the glycom-
imetic C-glucopyranosides.7 To extend the scope of our
studies, we focused on thioglycosides, a common and
attractive option for glycomimetic design.
R
1a, acetyl
2a, methyl
3a, ethyl
4a, propyl
6
O
OAc
OAc
O
S
AcO
AcO
AcO
AcO
R
1
5a, benzyl
OAc
3
6a, isopropyl
7a, cyclohexyl
8a, tert-butyl
OAc
OAc
Scheme 1. Synthesis of the model thioglucosides 1a–8a. Reagents and
conditions: Method A: R-SH, BF3ÁEt2O, CH2Cl2, rt; Method B: (i)
thiourea, BF3ÁEt2O, CH3CN, reflux, (ii) Et3N, CH3I or Ac2O.
*
Corresponding author. Tel.: +34 922 318581; fax: +34 922 318571;
e-mail: jtruvaz@ull.es
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.01.003

C. A. Sanhueza et al. / Tetrahedron: Asymmetry 19 (2008) 258–264
259
R
1b, acetyl
2b, methyl
3b, ethyl
4b, n-propyl
5b, benzyl
6b, iso-propyl
7b, cyclohexyl
8b, tert-butyl
O
OH
OH
O
OAc
OAc
O
OAc
OAc
O
S
HO
HO
O
R
c or d
b
a
Ph
O
OAc
OH
OAc
OAc
OAc
= p-BrBzO
Scheme 2. Synthesis of model b-thioglucosides 1b–8b. Reagents and conditions: (a) (i) PhCH(OCH3)2, p-TsOH, DMF, 50 °C, (ii) Ac2O, Py; (b) (i) AcOH/
H2O (8:2), 60 °C, (ii) p-BrBzCl/Py, DMAP, 60 °C; (c) Method A: R-SH, BF3ÁEt2O, CH2Cl2; (d) Method B: (i) (NH2)2CS, BF3ÁEt2O, CH3CN, 80 °C, (ii)
Et3N, CH3I or Ac2O, rt.
1,2,3-tris-O-acetyl-4,6-bis-O-(4-bromobenzoyl)-b-D-gluco-
pyranose9 (Scheme 2) by substitution of the anomeric acet-
yl group by a nucleophilic thiol. The S-acetyl derivative 1b
and methyl thioglucosides 2a and 2b were obtained by an
alternative methodology (method B).10 Thus, these com-
pounds were obtained from the glucosyl thiouronium salt
with acetic anhydride or methyl iodide, in accordance with
Tiwari’s procedure.10
of the series, the JH5,H6R coupling constants have higher
values than JH5,H6S. Thus, for thioglycosides belonging to
the acetyl series (1a–8a), d H6S chemical shifts are between
d 4.08 and 4.14 and for d H6R between d 4.19 and 4.25 (Ta-
ble 1), while for compounds 1b–8b, corresponding to the
dibenzoyl series, d H6S values are between d 4.48 and
4.53 and for d H6R between d 4.35 and 4.40 (Table 2). In
addition, the coupling constant values of JH5,H6R and
JH5,H6S followed the same behavior; thus for the acetyl ser-
ies, JH5, H6R showed values between 4.5 and 6.0 Hz, while
JH5, H6S was around 2.3 Hz; on the other hand, for the
dibenzoyl series, JH5,H6R values were between 4.7 and
6.6 Hz and JH5,H6S around 3.2 Hz.
The characterization of the b-thioglycosides was achieved
by means of mono- (1H and 13C) and bi-dimensional
(COSY-G, HMQC, and T-ROESY) NMR spectroscopy.
The b anomeric configuration was determined by analyzing
the JH1–H2 value (around 9.9 Hz), and confirming it in the
T-ROESY experiments by observing cross-peaks between
the anomeric proton H1 and H3, and between H1 and H5.
2.1. Conformational analysis
Rotation around the torsional angle x (O5–C5–C6–O6) led
to three staggered conformers: gauche–gauche (gg,
x = À60), gauche–trans (gt, x = 60), and trans–gauche
(tg, x = 180) (Fig. 1). The rotational behavior of the
hydroxymethyl group can be determined by analyzing the
JH5,H6 coupling constants. Thus, an increase in the JH5,H6R
constant around the C5–C6 bond (x) was observed as the
bulkiness of the S-aglycon increased. For the acetyl S-glu-
coside series, this coupling constant increased from 4.5 to
1
The H NMR signals of the prochiral protons H6S and
H6R were differentiated according to the data in the litera-
ture,11 on the basis of their chemical shifts and coupling
constants. In general, for D-glucopyranoside series, H6R
proton signals appear at higher field than H6S signals (d
H6S > d H6R), the reverse behavior being observed in ace-
tate series where H6S appears at higher field than H6R (d
H6R > d H6S). Furthermore, independently of the nature
Table 1. NMR data, and calculated rotamer populations (%) around the C5–C6 bond for the model thioglucoside derivatives (acetyl series)
Entry
R
d C1
d H1
d H6R
d H6S
JH5–H6R
JH5–H6S
Pgg
Pgt
Ptg
1a
2a
3a
4a
5a
6a
7a
8a
Acetyl
Methyl
Ethyl
n-Propyl
Benzyl
iso-Propyl
Cyclohexyl
tert-Butyl
80.1
82.7
83.5
83.7
81.7
83.4
83.2
82.3
5.24
4.38
4.48
4.47
4.30
4.58
4.59
4.63
4.25
4.23
4.24
4.23
4.25
4.23
4.22
4.19
4.08
4.13
4.13
4.12
4.14
4.12
4.12
4.10
4.5
4.8
4.9
5.0
5.1
5.2
5.3
6.0
2.1
2.2
2.2
2.2
2.2
2.3
2.4
2.3
64
61
60
59
58
56
55
48
36
39
40
41
42
44
45
52
0
0
0
0
0
0
0
0
Table 2. NMR data, and calculated rotamer populations (%) around the C5–C6 bond for the model thioglucoside derivatives (dibenzoyl series)
Entry
R
d C1
d H1
d H6R
d H6S
JH5–H6R
JH5–H6S
Pgg
Pgt
Ptg
1b
2b
3b
4b
5b
6b
7b
8b
Acetyl
Methyl
Ethyl
n-Propyl
Benzyl
iso-Propyl
Cyclohexyl
tert-Butyl
80.4
83.1
83.7
83.9
82.1
83.5
83.3
82.5
5.36
4.50
4.61
4.59
4.39
4.69
4.70
4.74
4.35
4.39
4.40
4.39
4.40
4.38
4.39
4.37
4.48
4.53
4.53
4.53
4.52
4.51
4.50
4.49
4.8
4.7
5.1
5.2
5.0
5.6
5.8
6.6
3.0
3.4
3.3
3.3
3.2
3.2
3.2
2.9
58
56
52
51
54
49
46
39
37
35
39
40
38
43
46
56
5
9
9
9
8
8
8
5

260
C. A. Sanhueza et al. / Tetrahedron: Asymmetry 19 (2008) 258–264
gg
Both series exhibited almost identical gt populations,
HR
HS
although slightly higher gg and nil tg populations were ob-
tained for the acetyl series than for the dibenzoyl series (Ta-
bles 1 and 2). The increases in the rotational population of
the tg rotamer in the latter series may be explained by a
favorable p–p interaction between the two aromatic rings
in this array.13
6
gt
tg
HR
HS
HS
5
HR
O
O
O
S
S
S
R
R
R
H
H
H
Figure 1. Hydroxymethyl rotamers in b-thioglucosides.
6.0 Hz, passing from compound 1a to 8a. Similarly, a grad-
ual increase of JH5,H6R from 4.7 to 6.6 Hz was observed
from 2b to 8b for the aliphatic alkyl S-glucosides (diben-
zoyl series). Namely, from 2b (4.7 Hz) to compounds with
a linear aglycon: 3b (5.1), and 4b (5.2), to compounds with
a branched aglycon: 6b (5.6), 7b (5.8), and 8b (6.6 Hz). On
the other hand, the JH5,H6S value remained more or less
constant (around 2.3 Hz for the acetyl series and around
3.2 Hz for the dibenzoyl series).
2.2. Circular dichroism analysis
Circular dichroism (CD) is a powerful technique that has
mainly been used for determining the absolute configura-
tion and conformation of a great number of compounds
of both natural and synthetic origins. The development
of the CD exciton chirality method14 has made this tech-
nique even more useful. Its high sensitivity and simple spec-
tral interpretation provide further conformational data.
The exciton-coupled p-bromobenzoyl chromophores pres-
ent in our model compounds 1b–8b (dibenzoyl series) per-
mit them to be analyzed by this method.
The rotamer populations of the hydroxymethyl group can
be calculated by applying the Serianni equations system,12
using the experimental JH5,H6R and JH5,H6S coupling con-
stants. Thus, the calculated populations for the acetyl
and dibenzoyl series are summarized in Tables 1 and 2.
They correlate with an increased gt population at the ex-
pense of the gg, the tg population remaining almost con-
stant or nil, as seen in Graphs 1 and 2 for the acetyl and
dibenzoyl thioglucoside series.
The CD spectra exhibited the exciton Cotton effects around
252 and 234 nm (Fig. 2). The amplitude of the split CD
curves (A value)15 gradually decreased from compound
1b (22.4), 2b (21.9), 3b (21.6), 4b (20.1), 6b (19.6), 7b
(15.8), to 8b (14.7).16 The CD spectral differences between
the model compounds arise from the pairwise interactions
involving the chromophore at position 6, since no ring dis-
tortion has been observed for our model compounds.
Therefore, these intensities are consistent with a gradually
reduced positive contribution from the pairwise interaction
between the chromophore at position 4 and that at position
6 in the gg spatial disposition and/or with a gradually high-
er negative contribution between these chromophores in
the gt spatial disposition (Fig. 3).14 These differences are
in agreement with the above NMR results. In addition,
while CD measurements were carried out in CH3CN,
NMR analyses were carried out in CDCl3, so this confor-
mational behavior is not solvent dependent.
70
60
50
40
30
20
10
0
1a
2a
3a
4a
5a
6a
7a
8a
17
1b
2b
Graph 1. Calculated rotameric populations (%) (Pgt: blue; Pgg: red) for
compounds 1a–8a (acetyl series).
3b
4b
6b
Δε
7b
70
60
50
40
30
20
10
0
8b
0
-8
1b
2b
3b
4b
5b
6b
7b
8b
200
350
λ (nm)
Graph 2. Calculated rotameric populations (%) (Pgt: blue; Pgg: red; Ptg:
green) for compounds 1b–8b (dibenzoyl series).
Figure 2. CD spectra of some model b-thioglucosides (CH3CN).

C. A. Sanhueza et al. / Tetrahedron: Asymmetry 19 (2008) 258–264
261
2 are also likely to exist,23 decreasing the non-exo rotamer
and reducing flexibility (Fig. 6).
nil
6
4
O
O
O
gg
gt
tg
Figure 3. 4/6 Pairwise interaction involving the chromophore at the 6
position in each of the three stable rotamers (gg, gt, and tg).
R
O
O
O
S
S
S
R
2
R
nS
σ*CO
nR
σ*CO
pro-R
O5
2.3. Origin of the conformational preferences of the
hydroxymethyl group
R
C2
C2
pro-R
O5
pro-S
C2
O5
S
S
S
R
R
pro-S
H1
H1
H1
The observed preferences cannot be due to non-bonded
interactions between the hydroxymethyl group and the
S-aglycon, since this would induce an increase in the gg
population as the size of the S-aglycon increases instead
of decreasing. However, a good correlation between the
hydroxymethyl rotational populations around the C5–C6
bond and Taft’s steric parameters (ES) was observed for
both series (Figs. 4 and 5).17,18 Furthermore, plots of the
populations versus corresponding ra values (polarizability
parameter) showed no good linear relationships
(R2 = 0.54).19
exo syn
−
exo−
anti
non−exo
Figure 6. Molecular orbitals involved in the exo-anomeric effect for the
three idealized staggered rotamers around the C1–S bond.
The higher antiperiplanar disposition population of the
pro-S electron pair against the endocyclic oxygen, as the
exo-syn rotamer population increases, should lead to a
stronger exo-anomeric effect.24,25 So, different values of this
effect should modify the bond lengths around the anomeric
carbon, as occurred in O-glycosides,26 and express in this
way the conformational preferences of the hydroxymethyl
group.
65
60
55
50
45
40
The participation of the exo-anomeric effect is supported
by the behavior of the chemical shift for the anomeric pro-
ton, since it is shielded along with the structural nature of
the aliphatic alkyl group attached to the sulfur atom. From
the methyl derivative 2a (4.38 ppm) to compounds with a
primary alkyl group, such as ethyl 3a and propyl 4a
(around 4.48 ppm), to those with a secondary alkyl group:
isopropyl 6a and cyclohexyl 7a (around 4.58), and to the
tert-butyl derivative 8a (4.63 ppm). The same behavior
occurred for H-1 in the dibenzoyl series, from 4.50 for 2b
to 4.74 ppm for 8b (Dd = 0.24 ppm).
Cy
i -Pr
t-Bu
Me
35
0.1
-0.1 -0.3 -0.5 -0.7 -0.9 -1.1 -1.3 -1.5 -1.7
Taft's steric parameters, Es
Figure 4. Rotational populations of gg/gt rotamers (red/blue) versus
corresponding ES values (acetyl series).20
So far, we have demonstrated the rotational population
dependence of the hydroxymethyl group in alkyl gluco-,3
galacto-,4 and mannopyranosides,5 C-glycosides,7 and
herein b-thioglucosides on the structural nature of the agly-
con, its absolute configuration and anomeric configuration.
This behavior is explained by the different values of the
exo-anomeric effect in O-glycosides,3–5 and herein with
S-glucosides too, and by the exo-deoxoanomeric effect in
60
55
50
45
40
35
t-Bu
i-Pr
Cy
Me
30
0.1
-0.1 -0.3 -0.5 -0.7 -0.9
-1.1 -1.3 -1.5 -1.7
Taft's steric parameters, Es
65
60
Figure 5. Rotational populations of gg/gt rotamers (red/blue) versus
corresponding ES values (dibenzoyl series).21
O
55
S
The ES values are composite terms, derived from both
potential energy steric effects (steric strains) and kinetic
energy steric effects (steric hindrances to motion). Accord-
ing to Taft,17 introduction of a straight-chain alkyl group
in place of the standard hydrogen substituent raises the
activation energy due to steric hindrance. Therefore, as
the substituent becomes bulkier, rotation around the S-glu-
cosidic bond decreases and the more stable rotamer, the
exo-syn, increases its population.22 Non-bonded interac-
tions between the S-aglycon and the substituent at position
50
S
45
O
40
t-Bu
i-Pr
Me
Cy
-0.7 -0.9 -1.1 -1.3 -1.5 -1.7
Taft's steric parameters, Es
35
0.1 -0.1
-0.3 -0.5
Figure 7. Rotational populations of gg/gt rotamers (j/N) for alkyl O-
(red) and S-glucosides (blue) versus corresponding ES values (acetyl
series).20,28

262
C. A. Sanhueza et al. / Tetrahedron: Asymmetry 19 (2008) 258–264
C-glycosides.7 Furthermore, as the size of the aglycon
increased, the population of the gt rotamer was observed
to increase in all cases. Comparing rotamer populations
of alkyl O-27 and S-glucosides revealed (Fig. 7) analogous
or slightly higher gt (blue triangle) and lower gg (blue
square) populations for the latter, both types of com-
pounds showing similar slopes and deviations. Therefore,
these data point to similar exo-anomeric effects for the S-
4.2. General procedures for the synthesis of b-D-
thioglucopyranosides
Method A:8 Boron trifluoride etherate (0.1 equiv) was
added dropwise to a stirred solution of the sugar donor
b-D-glucose pentaacetate or 1,2,3-tris-O-acetyl-4,6-bis-O-
(4-bromobenzoyl)-b-D-glucopyranose9 and the respective
thiol (2 equiv) in dry dichloromethane (5 mL/mmol) at
room temperature and under N2 atmosphere. The reaction
progress was followed by TLC. When the starting com-
pound was consumed it was quenched by addition of
Et3N and diluted with CH2Cl2. The organic layer was
washed with brine, dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The products were
purified by chromatography using silica gel and solutions
of n-hexane/ethyl acetate in various proportions as eluents.
3
˚
and O-glucosides. The C(sp )–S bond (1.81 A) being longer
3
˚
than C(sp )–O (1.41 A) does not favor a stereoelectronic
nS–rÃCO interaction, however, the similar electronegativity
between C and S, and the stronger nucleophilicity of the
lone electron pair of the sulfur atom compared to the
oxygen atom could counteract the greater bond length.
3. Conclusions
Method B:10 Boron trifluoride etherate (1.5 equiv) was
added dropwise to a stirred solution of the glycosyl donor
(1 equiv) and thiourea (2 equiv) in CH3CN (5 mL/mmol),
and the mixture refluxed at 80 °C. After full consumption
of the sugar, the reaction mixture was cooled to room tem-
perature and Et3N (3 equiv) and acetic anhydride
(1.5 equiv) or the corresponding alkyl halide (1.5 equiv)
were added. The mixture was stirred for 3 h and the solvent
removed under reduced pressure. The resultant syrup was
diluted with CH2Cl2 and washed with water, dried over
Na2SO4, and concentrated under reduced pressure. Purifi-
cation of the crude over silica gel and n-hexane/ethyl ace-
tate afforded the respective thioglycoside.
Two series of alkyl b-D-thioglucopyranosides were synthe-
sized and their conformational preferences in solution
investigated by NMR and CD. Analysis of the H NMR
1
coupling constant values and CD spectral data revealed
that the rotamer populations of the hydroxymethyl group
were dependent on the structural nature of the S-aglycon.
It was also observed that as the size of the alkyl group at-
tached to the S atom increased, the population of the gt
rotamer increased, at the expense of the gg rotamer. In
addition, a linear correlation was found between the Taft
steric parameters and the hydroxymethyl rotamer popula-
tions. A higher steric hindrance to motion as the substitu-
ent becomes bulkier is derived from Taft’s analysis; this
should lead to an increased population of the more stable
rotamer, the exo-syn. The stereoelectronic nS–rÃCO interac-
tion (the exo-anomeric effect) may express the rotational
preferences of the hydroxymethyl group.
4.3. 2,3-Di-O-Acetyl-1-S-acetyl-4,6-bis-O-(4-bromo-
benzoyl)-1-thio-b-D-glucopyranose 1b
TLC Rf = 0.35 (n-hexane/EtOAc 7:3); [a]D = +50.4 (c 0.6,
CHCl3); 1H NMR (CDCl3) d 7.85–7.76 (m, 4H), 7.57–7.52
(m, 4H), 5.49 (dd, J = 9.3 and 9.3 Hz, H-3), 5.41 (dd,
J = 9.7 and 9.7 Hz, H-4), 5.36 (d, J = 10.5 Hz, H-1), 5.21
(dd, J = 9.1 and 10.5 Hz, H-2), 4.48 (dd, J = 3.0 and
12.3 Hz, H-6S), 4.35 (dd, J = 4.8 and 12.3 Hz, H-6R),
4.11 (ddd, J = 3.0, 4.8 and 9.8 Hz, H-5), 2.39 (s, 3H),
2.04 (s, 3H), 1.92 (s, 3H); 13C NMR (CDCl3) d 191.9 (s),
169.9 (s), 169.4 (s), 165.3 (s), 164.4 (s), 132.0-127.4, 80.4
(d, C-1), 76.2 (d, C-5), 73.6 (d, C-3), 69.3 (d, C-4), 68.9
(d, C-2), 62.9 (t, C-6), 30.8 (q), 20.6 (q), 20.5 (q). UV
(CH3CN) kmax 244 nm; CD (CH3CN) kext nm (De) 251
(16.1), 233 (À6.3).
4. Experimental
4.1. General
1H NMR spectra were recorded at 400 MHz, and 13C
NMR at 100 MHz, VTU 300.0 K. Chemical shifts are re-
ported in ppm. The residual solvent peak (CDCl3) was used
as internal reference, 7.26 for proton and 77.0 for carbon
NMR. Optical rotations were measured on a digital spec-
tropolarimeter in a 1 dm cell. UV and CD spectra were
recorded in the range 350–200 nm using 10 mm cells. The
concentrations of the CD samples were ascertained from
the UV spectra, using the experimentally determined e val-
ues at 250 nm: di-(p-bromobenzoate) e 38,200.
4.4. Methyl 2,3-di-O-acetyl-4,6-bis-O-(4-bromobenzoyl)-1-
thio-b-D-glucopyranoside 2b
TLC Rf = 0.35 (n-hexane/EtOAc 3:1); [a]D = +6.0 (c 0.8,
CHCl3); HRMS (FAB): Calcd for C25H24O9 79Br2SCs
1
([M+Cs]+): 790.8562, found: 790.8583; H NMR (CDCl3)
For analytical thin-layer chromatography, silica gel ready-
foils were used and 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
d 7.83–7.77 (m, 4H), 7.56–7.51 (m, 4H), 5.45 (dd, J = 9.3
and 9.3 Hz, H-3), 5.39 (dd, J = 9.4 and 9.4 Hz, H-4), 5.15
(dd, J = 9.5 and 9.5 Hz, H-2), 4.53 (dd, J = 3.4 and
12.6 Hz, H-6S), 4.50 (d, J = 10.0 Hz, H-1), 4.40 (dd,
J = 4.8 and 12.6 Hz, H-6R), 4.00 (ddd, J = 3.4, 4.8 and
9.3 Hz, H-5), 2.17 (s, 3H), 2.08 (s, 3H), 1.90 (s, 3H); 13C
NMR (CDCl3) d 170.0 (s), 169.5 (s), 165.3 (s), 164.4 (s),
131.9-127.4, 83.0 (d, C-1), 75.7 (d, C-5), 73.4 (d, C-3),
˚
using 60 A silica gel. All reagents were obtained from com-
mercial sources and used without further purification. Sol-
vents were dried and distilled before use. All reactions were
performed under a dry nitrogen atmosphere.

C. A. Sanhueza et al. / Tetrahedron: Asymmetry 19 (2008) 258–264
263
69.6 (d, C-4), 69.0 (d, C-2). 63.2 (t, C-6), 20.7 (q), 20.5 (q),
11.3 (q); UV (CH3CN) kmax 245 nm; CD (CH3CN) kext nm
(De) 251 (15.1), 234 (À6.8).
C31H28Br2O9S: C, 50.56; H, 3.83; S, 4.35. Found: C,
50.54; H, 3.98; S, 4.34.
4.8. Isopropyl 2,3-di-O-acetyl-4,6-bis-O-(4-bromo-benzoyl)-
1-thio-b-D-glucopyranoside 6b
4.5. Ethyl 2,3-di-O-acetyl-4,6-bis-O-(4-bromobenzoyl)-
1-thio-b-D-glucopyranoside 3b
TLC Rf = 0.40 (n-hexane/EtOAc 3:1); [a]D = À6.3 (c 0.7,
CHCl3); HRMS (FAB): Calcd for C27H28O9NaSBr2
TLC Rf = 0.42 (n-hexane/EtOAc 3:1); [a]D = +1.7 (c 1.0,
1
([M+Na]+): 708.9718, found: 708.9684; H NMR (CDCl3)
CHCl3); HRMS (FAB): Calcd for C26H26O9 79Br2SCs
1
([M+Cs]+): 804.8719, found: 804.8711; H NMR (CDCl3)
d 7.82–7.77 (m, 4H), 7.56–7.50 (m, 4H), 5.45 (dd, J = 9.4
and 9.4 Hz, H-3), 5.37 (dd, J = 9.7 and 9.7 Hz, H-4), 5.08
(dd, J = 9.4 and 9.4 Hz, H-2), 4.69 (d, J = 10.1 Hz, H-1),
4.51 (dd, J = 3.2 and 12.1 Hz, H-6S), 4.38 (dd, J = 5.6
and 12.1 Hz, H-6R), 3.98 (ddd, J = 3.2, 5.6 and 9.3 Hz,
H-5), 3.17 (m, 1H), 2.07 (s, 3H), 1.90 (s, 3H), 1.29 (d,
J = 6.7 Hz, 3H), 1.27 (d, J = 6.7 Hz, 3H); 13C NMR
(CDCl3) d 170.1 (s), 169.4 (s), 165.3 (s), 164.4 (s), 132.0-
127.5, 83.5 (d, C-1), 75.6 (d, C-5), 73.5(d, C-3), 70.2 (d,
C-2), 69.9 (d, C-4), 63.5 (t, C-6), 35.7 (d), 24.0 (q), 23.8
(q), 20.7 (q), 20.5 (q); UV (CH3CN) kmax 245 nm; CD
(CH3CN) kext nm (De) 251 (13.1), 233 (À6.5); Anal. Calcd
for C27H28Br2O9S: C, 47.11; H, 4.10; S, 4.66. Found: C,
47.11; H, 4.18; S, 4.46.
d 7.82–7.77 (m, 4H), 7.55–7.51 (m, 4H), 5.44 (dd, J = 9.2
and 9.2 Hz, H-3), 5.39 (dd, J = 9.5 and 9.5 Hz, H-4), 5.12
(dd, J = 9.5 and 9.5 Hz, H-2), 4.61 (d, J = 10.0 Hz, H-1),
4.52 (dd, J = 3.3 and 12.2 Hz, H-6S), 4.39 (dd, J = 5.1
and 12.2 Hz, H-6R), 3.98 (ddd, J = 3.3, 5.1 and 8.9 Hz,
H-5), 2.78–2.63 (m, 2H), 2.07 (s, 3H), 1.90 (s, 3H), 1.26
(dd, J = 7.4 and 7.4 Hz, 3H); 13C NMR (CDCl3) d 170.1
(s), 169.4 (s), 165.3 (s), 164.4 (s), 131.1-127.5, 83.7 (d, C-
1), 75.7 (d, C-5), 73.5(d, C-3), 69.9 (d, C-2), 69.8 (d, C-4),
63.4 (t, C-6), 24.2 (t), 20.7 (q), 20.5 (q), 14.9 (q); UV
(CH3CN) kmax 245 nm; CD (CH3CN) kext nm (De) 251
(14.6), 234 (À7.0).
4.6. Propyl 2,3-di-O-acetyl-4,6-bis-O-(4-bromobenzoyl)-1-
thio-b-D-glucopyranoside 4b
4.9. Cyclohexyl 2,3-di-O-acetyl-4,6-bis-O-(4-bromobenzo-
yl)-1-thio-b-D-glucopyranoside 7b
TLC Rf = 0.47 (n-hexane/EtOAc 3:1); [a]D = +1.9 (c 0.1,
TLC Rf = 0.45 (n-hexane/EtOAc 3:1); [a]D = +3.9 (c 0.9,
CHCl3); HRMS (FAB): Calcd for C27H28O9NaS79Br81Br
CHCl3); HRMS (FAB): Calcd for C30H32O9NaS81Br2
1
([M+Na]+): 710.9698, found: 710.9704; H NMR (CDCl3)
1
([M+Na]+): 752.9991, found: 752.9957; H NMR (CDCl3)
d 7.82–7.77 (m, 4H), 7.56–7.51 (m, 4H), 5.44 (dd, J = 9.2
and 9.2 Hz, H-3), 5.38 (dd, J = 9.5 and 9.5 Hz, H-4), 5.11
(dd, J = 9.5 and 9.5 Hz, H-2), 4.59 (d, J = 10.0 Hz, H-1),
4.52 (dd, J = 3.2 and 12.2 Hz, H-6S), 4.39 (dd, J = 5.2
and 12.2 Hz, H-6R), 3.97 (ddd, J = 3.2, 5.2 and 9.0 Hz,
H-5), 2.75–2.57 (m, 2H), 2.07 (s, 3H), 1.90 (s, 3H), 1.67–
1.57 (m, 2H), 0.94 (dd, J = 7.3 and 7.3 Hz, 3H); 13C
NMR (CDCl3) d 170.1 (s), 169.4 (s), 165.3 (s), 164.4 (s),
131.9–127.5, 83.9 (d, C-1), 75.7 (d, C-5), 73.5(d, C-3),
69.9 (d, C-2), 69.8 (d, C-4), 63.3 (t, C-6), 32.2 (t), 23.2 (t),
20.7 (q), 20.5 (q), 13.4 (q); UV (CH3CN) kmax 245 nm;
CD (CH3CN) kext nm (De) 251 (13.8), 234 (À6.3); Anal.
Calcd for C27H28Br2O9S: C, 47.11; H, 4.10; S, 4.66. Found:
C, 47.42; H, 3.84; S, 4.32.
d 7.82–7.77 (m, 4H), 7.55–7.50 (m, 4H), 5.44 (dd, J = 9.4
and 9.4 Hz, H-3), 5.35 (dd, J = 9.7 and 9.7 Hz, H-4), 5.07
(dd, J = 9.5 and 9.5 Hz, H-2), 4.70 (d, J = 10.1 Hz, H-1),
4.50 (dd, J = 3.2 and 12.2 Hz, H-6S), 4.39 (dd, J = 5.8
and 12.2 Hz, H-6R), 3.98 (ddd, J = 3.2, 5.8 and 9.4 Hz,
H-5), 2.90 (m, 1H), 2.06 (s, 3H), 2.03–1.91 (m, 2H), 1.89
(s, 3H), 1.69–1.56 (m, 4H), 1.45–1.13 (m, 4H); 13C NMR
(CDCl3) d 170.0 (s), 169.3 (s), 165.2 (s), 164.4 (s), 131.9–
127.5, 83.3 (d, C-1), 75.6 (d, C-5), 73.5(d, C-3), 70.2 (d,
C-2), 69.9 (d, C-4), 63.5 (t, C-6), 43.9 (d), 34.1 (t), 33.9
(t), 26.0 (t), 25.9 (t), 25.5 (t), 20.7 (q), 20.5 (q); UV
(CH3CN) kmax 245 nm; CD (CH3CN) kext nm (De) 251
(11.0), 233 (À4.8); Anal. Calcd for C30H32Br2O9S: C,
49.46; H, 4.43; S, 4.40. Found: C, 49.44; H, 4.60; S, 4.43.
4.7. Benzyl 2,3-di-O-acetyl-4,6-bis-O-(4-bromobenzoyl)-1-
thio-b-D-glucopyranoside 5b
4.10. tert-Butyl 2,3-di-O-acetyl-4,6-bis-O-(4-bromo-benzo-
yl)-1-thio-b-D-glucopyranoside 8b
TLC Rf = 0.38 (n-hexane/EtOAc 3:1); [a]D = À49.8 (c 0.8,
CHCl3); HRMS (FAB): Calcd for C31H28O9NaSBr2
([M+Na]+): 756.9718, found: 756.9733.; 1H NMR (CDCl3)
d 7.86–7.76 (m, 4H), 7.56–7.52 (m, 4H), 7.52–7.26 (m, 5H),
5.38–5.35 (m, H-3 and H-4), 5.15 (dd, J = 9.6 and 9.6 Hz,
H-2), 4.52 (dd, J = 3.2 and 12.2 Hz, H-6S), 4.40 (dd,
J = 5.0 and 12.2 Hz, H-6R), 4.39 (d, J = 9.9 Hz, H-1),
3.93 (d, J = 13.0 Hz, 1H), 3.87 (m, H-5), 3.83 (d,
J = 13.0 Hz, 1H), 2.03 (s, 3H), 1.89 (s, 3H); 13C NMR
(CDCl3) d 170.0 (s), 169.4 (s), 165.3 (s), 164.4 (s), 136.7–
127.4, 82.1 (d, C-1), 75.7 (d, C-5), 73.4 (d, C-3), 69.8 (d,
C-4), 69.8 (d, C-2), 63.4 (t, C-6), 33.8 (t), 20.7 (q), 20.5
(q); UV (CH3CN) kmax 245 nm; CD (CH3CN) kext nm
(De) 252 (12.9), 234 (À8.5), 211 (À8.9); Anal. Calcd for
TLC Rf = 0.42 (n-hexane/EtOAc 3:1); [a]D = À13.7 (c 0.6,
CHCl3); HRMS (FAB): Calcd for C28H30O9NaSBr2
1
([M+Na]+): 722.9875, found: 722.9841; H NMR (CDCl3)
d 7.81–7.78 (m, 4H), 7.57–7.52 (m, 4H), 5.48 (dd, J = 9.4
and 9.4 Hz, H-3), 5.32 (dd, J = 9.5 and 9.5 Hz, H-4), 5.03
(dd, J = 9.7 and 9.7 Hz, H-2), 4.74 (d, J = 10.2 Hz, H-1),
4.49 (dd, J = 2.9 and 12.2 Hz, H-6S), 4.37 (dd, J = 6.6
and 12.2 Hz, H-6R), 4.01 (ddd, J = 2.9, 6.6 and 9.7 Hz,
H-5), 2.05 (s, 3H), 1.90 (s, 3H), 1.35 (s, 9H); 13C NMR
(CDCl3) d 170.1 (s), 169.3 (s), 165.3 (s), 164.5 (s), 132.0–
127.5, 82.5 (d, C-1), 75.6 (d, C-5), 73.6 (d, C-3), 70.2 (d,
C-2), 69.9 (d, C-4), 63.8 (t, C-6), 44.3 (s), 31.4 (q  3Cs),
20.8 (q), 20.5 (q); UV (CH3CN) kmax 245 nm; CD
(CH3CN) kext nm (De) 252 (9.2), 233 (À5.5); Anal. Calcd

264
C. A. Sanhueza et al. / Tetrahedron: Asymmetry 19 (2008) 258–264
14. For a monograph on exciton CD spectroscopy see: (a)
Harada, N.; Nakanishi, K. Circular Dichroic Spectroscopy
Exciton Coupling in Organic Stereochemistry; University
Science Books: CA, 1983; (b) Nakanishi, K.; Berova, N.
The Exciton Chirality Method in Circular Dichroism, Prin-
ciples and Applications. In Nakanishi, K., Berova, N.,
Woody, R. W., Eds.; VCH Publishers: NY, 1994.
for C28H30Br2O9S: C, 47.88; H, 4.30; S, 4.57. Found: C,
47.89; H, 4.62; S, 4.35.
Acknowledgments
15. The amplitude (A value) of split CD Cotton effects is defined
as A = De1 À De2 where De1 and De2 are intensities of the first
and second Cotton effects, respectively.
´
This work was supported by the Ministerio de Educacion y
Ciencia (Spain), through grant CTQ2007-67532-C02-02/
BQU. C.A.S. thanks the Consejerıa de Educacion, Cultura
´
´
16. The extra aromatic ring in 5b alters its CD amplitude (A value
+21.4), thus becoming unsuitable for comparative analysis.
17. (a) Taft, R. W., Jr. J. Am. Chem. Soc. 1952, 74, 2729–2732;
(b) Taft, R. W., Jr. J. Am. Chem. Soc. 1952, 74, 3120–3128;
(c) Taft, R. W., Jr. J. Am. Chem. Soc. 1953, 75, 4532–4537;
(d) Taft, R. W., Jr. J. Am. Chem. Soc. 1953, 75, 4538–4539.
18. Steric parameters (Es) for: Me (0.00), Et (À0.07); n-Pr
(À0.36); Bn (À0.38); i-Pr (À0.47); Cy (À0.79); t-Bu (À1.54).
From Ref. 15.
19. Taft, R. W.; Koppel, I. A.; Topsom, R. D.; Anvia, F. J. Am.
Chem. Soc. 1990, 112, 2047–2052.
20. Regression line equations for the thioglucopyranosides 1a–8a:
Pgg = 8.3051ES + 60.997; R2 = 0.9763; Pgt = À8.3051ES +
39.003; R2 = 0.9763.
y Deportes (Gobierno de Canarias) for a fellowship.
References
1. (a) Witczak, Z. J.; Culhane, J. M. Appl. Microbiol. Biotechnol.
2005, 69, 237–244; (b) Robina, I.; Vogel, P.; Witczak, Z. J.
Curr. Org. Chem. 2001, 5, 1177–1214.
´
2. (a) Montero, E.; Vallmitjana, M.; Perez-Pons, J. A.; Querol,
´
E.; Jimenez-Barbero, J.; Canada, F. J. FEBS Lett. 1998, 421,
˜
´
´
243–248; (b) Aguilera, B.; Jimenez-Barbero, J.; Fernandez-
Mayoralas, A. Carbohydr. Res. 1998, 308, 19–27; (c) Weimar,
T.; Kreis, U. C.; Andrews, J. S.; Pinto, B. M. Carbohydr. Res.
21. Regression line equations for the thioglucopyranosides 1b–8b:
´
1999, 315, 222–233; (d) Montero, E.; Garcıa-Herrero, A.;
P
gg = 10.407ES + 54.939; R2 = 0.9135; Pgt = À12.972ES +
´
Asenso, J. L.; Hirai, K.; Ogawa, S.; Santoyo-Gonzalez, F.;
35.739; R2 = 0.9489.
´
Canada, F. J.; Jimenez-Barbero, J. Eur. J. Org. Chem. 2000,
˜
22. Semiempirical SCF-MO calculations have confirmed that the
exo-anomeric effect in methyl S-glycosides deals with a p-
character interaction along the C1–S bond, the exo-syn and
exo-anti rotamers having the maximal p-bond order. Llano,
J.; Montero, L. A. J. Comput. Chem. 1996, 17, 1371–1384.
1945–1952.
´
´
3. (a) Morales, E. Q.; Padron, J. I.; Trujillo, M.; Vazquez, J. T.
´
J. Org. Chem. 1995, 60, 2537–2548; (b) Padron, J. I.;
´
´
Vazquez, J. T. Chirality 1997, 9, 626–637; (c) Padron, J. I.;
´
Vazquez, J. T. Tetrahedron: Asymmetry 1998, 9, 613–627.
´
23. Asensio, J. L.; Canada, F. J.; Garcıa-Herrero, A.; Murillo,
˜
´
´
4. Padron, J. I.; Morales, E. Q.; Vazquez, J. T. J. Org. Chem.
´
M. T.; Fernandez-Mayoralas, A.; Johns, B. A.; Kozak, J.;
1998, 63, 8247–8258.
´
Zhu, Z.; Johnson, C. R.; Jimenez-Barbero, J. J. Am. Chem.
´
´
5. (a) Nobrega, C.; Vazquez, J. T. Tetrahedron: Asymmetry
Soc. 1999, 121, 11318–11329.
´
2003, 14, 2793–2801; (b) Mayato, C.; Dorta, R.; Vazquez, J.
24. The stereoelectronic exo-anomeric effect consists of the
conformational preference of glycosides for the gauche
orientation, as a consequence of the stereoelectronic interac-
tion between the p orbital of the interannular oxygen and the
r* orbital of the pyranose C1–O5 bond.
T. Tetrahedron: Asymmetry 2004, 15, 2385.
´
´
6. Roe¨n, A.; Padron, J. I.; Vazquez, J. T. J. Org. Chem. 2003,
68, 4615–4630.
´
7. (a) Mayato, C.; Dorta, R. L.; Vazquez, J. T. Tetrahedron:
Asymmetry 2007, 18, 931–948; (b) Mayato, C.; Dorta, R. L.;
25. (a) Thatcher, G.R.J. Anomeric and Associated Stereoelec-
tronic Effects. Scope and Controversy. In The Anomeric Effect
and Associated Stereoelectronic Effects; Thatcher, G.R.J., Ed.;
ACS Symposium Series 539: Washington, DC, 1993; (b)
Juaristi, E.; Cuevas, G. The Anomeric Effect in New
Directions in Organic and Biological Chemistry. In Rees, C.
´
Vazquez, J. T. Tetrahedron: Asymmetry 2007, 18, 2803–2811.
8. Kartha, K. P. R.; Field, R. A. Synthesis and Activation of
Carbohydrate Donors: Thioglycosides and Sulfoxides. In
Carbohydrates; Osborn, H., Ed.; Elsevier Science Ltd:
Oxford, 2003; pp 121–145.
9. Padron, J. I.; Vazquez, J. T. Chirality 1997, 9, 626–637.
10. Tiwari, P.; Agnihotri, G.; Misra, A. K. J. Carbohydr. Chem.
2005, 24, 723–732.
11. (a) Nishida, Y.; Ohrui, H.; Meguro, H. Tetrahedron Lett.
1984, 25, 1575–1578; (b) Ohrui, H.; Nishida, Y.; Watanabe,
M.; Hori, H.; Meguro, H. Tetrahedron Lett. 1985, 26, 3251–
3254; (c) Ohrui, H.; Nishida, Y.; Higuchi, H.; Hori, H.;
Meguro, H. Can. J. Chem. 1987, 65, 1145–1153; (d) Nishida,
Y.; Hori, H.; Ohrui, H.; Meguro, H. J. Carbohydr. Chem.
1988, 7, 239–250.
12. Thibaudeau, C.; Stenutz, R.; Hertz, B.; Klepach, T.; Zhao, S.;
Wu, Q.; Carmichael, I.; Serianni, A. S. J. Am. Chem. Soc.
2004, 126, 15668–15685, 2.8 gg + 2.2 gt + 11.1 tg = JH1S,H2
0.9 gg + 10.8 gt + 4.7 tg = JH1R,H2; gg + gt + tg = 1.
13. Hunter, C. A.; Sanders, J. K. M. J. Am. Chem. Soc. 1990,
112, 5525–5534.
´
´
´
W., Ed.; CRC Press: Inc Boca Raton, Florida, 1995.
26. The exo-anomeric effect is responsible for the reduction and
extension of C1–O1 and C1–O5 bonds, respectively, as
observed in X-ray diffraction studies: Briggs, A. J.; Glenn,
R.; Jones, P. G.; Kirby, A. J.; Ramaswamy, P. J. Am. Chem.
Soc. 1984, 106, 6200–6206.
27. The alkyl 2,3,4,6-tetra-O-acetyl b-D-glucopyranosides were
prepared to measure their JH5,H6 coupling constants:
methyl (JH5,H6S = 2.5 Hz; JH5,H6R = 4.7 Hz); ethyl (JH5,H6S
2.5 Hz; JH5,H6R = 4.8 Hz); benzyl (JH5,H6S = 2.5 Hz; JH5,H6R
=
=
4.8 Hz), iso-propyl (JH5,H6S = 2.5 Hz; JH5,H6R = 5.1 Hz); tert-
butyl (JH5,H6S = 2.5 Hz; JH5,H6R = 5.8 Hz).
;
28. Regression line equations for the O-glucopyranosides:
P
gg = 7.4568ES + 61.669; R2 = 0.9677; Pgt = À7.4568ES +
38.331; R2 = 0.9677.