Synthesis and conformational analysis of disaccharide analogues containing disulfide and selenosulfide functionalities in the interglycosidic linkages

Article abstract of DOI:10.1139/v05-107

The synthesis of novel disaccharides containing disulfide (methyl-4-S-(β-D-galactopyranosyl-1′-thio)-4-thio-α-D- glucopyranoside (1)) and selenosulfide (methyl-4-Se-(β-D-galactopyranosyl- 1′-thio)-4-seleno-α-D-glucopyranoside (2)) functionalities in the i

Full text of DOI:10.1139/v05-107

929
Synthesis and conformational analysis of
disaccharide analogues containing disulfide and
selenosulfide functionalities in the interglycosidic
linkages1
Nagasree Chakka, Blair D. Johnston, and B. Mario Pinto
Abstract: The synthesis of novel disaccharides containing disulfide (methyl-4-S-(β-D-galactopyranosyl-1′-thio)-4-thio-
α-D-glucopyranoside (1)) and selenosulfide (methyl-4-Se-(β-D-galactopyranosyl-1′-thio)-4-seleno-α-D-glucopyranoside
(2)) functionalities in the interglycosidic linkages is described. The synthetic strategy relied on the reaction of a β-
glycosylthiosulfonate with a carbohydrate thiol or selenol nucleophile. The resulting protected β-dihetero-linked
disaccharides were deprotected to give the target compounds. The conformational preferences of these dihetero ana-
logues were inferred from NOESY experiments and line-broadening effects in variable-temperature NMR spectra, and
are rationalized in terms of molecular orbital theory. Low-energy conformations of these compounds can populate re-
gions of conformational space not usually occupied by β-linked disaccharides, and offer the possibility for presentation
of novel ligand topographies.
Key words: disaccharides, disulfides, selenosulfides, interglycosidic linkages, conformations, MO explanation.
Résumé : On décrit la synthèse de nouveaux disaccharides comportant des fonctionnalités disulfure (4-S-(β-D-galacto-
pyranosyl-1′-thio)-4-thio-α-D-glucopyranoside de méthyle (1)) et sélénosulfure (4-Se-(β-D-galactopyranosyl-1′-thio)-4-
séléno-α-D-glucopyranoside de méthyle (2)) dans les liaisons interglycosidiques. La stratégie de synthèse se base sur la
réaction d’un β-glycosylthiosulfonate avec un carbohydrate comportant un nucléophile thiol ou sélénol. Les disacchari-
des protégés à liaison β-dihétéro ont été déprotégés pour fournit les composés cibles. Les préférences conformationnel-
les de ces analogues dihétéro ont été déduites d’expériences « NEOSY » et d’effets d’élargissement de bande dans les
spectres de RMN à température variable et elles sont rationalisées en fonction de la théorie des orbitales moléculaires.
Les conformations de basse énergie de ces composés occuper des régions de l’espace conformationnel qui ne sont gé-
néralement pas occupés par des disaccharides à liaisons β et elles offrent la possibilité de présenter de nouvelles topo-
graphies pour les ligands.
Mots clés : disaccharides, disulfures, sélénosulfures, liaisons interglycosidiques, conformations, explication d’orbitales
moléculaires.
[Traduit par la Rédaction] Chakka et al. 936
Introduction
provide access to an alternative selection of ligand
topographies that might have advantages in drug design.
In general, the conformational preferences about glyco-
sidic linkages in oligosaccharides can be described by the φ
and ψ torsional angles, as shown in Fig. 1. Excursions about
the ψ torsional angles in α- and β-glycosides are pro-
nounced, and are dictated by the exact steric requirements
about a particular glycosidic linkage (8). However, the pref-
erences about the φ torsional angle are much more restricted
by the endo- (9) and exo- (10) anomeric effect. Thus, the
preferences in α-glycosides are largely restricted to a φH
gauche+ conformation, whereas those in β-glycosides are re-
Carbohydrates and carbohydrate mimetics are essential
tools for the investigation of a variety of biological functions
that are mediated by carbohydrate recognition events (1, 2).
Furthermore, some of these compounds are known to be
therapeutic agents (3–7). It is therefore of interest to exam-
ine novel types of carbohydrate derivatives or mimetics to
expand the collection of potential drug candidates. The next
level of carbohydrate mimetic design should include the po-
tential for presentation of different conformational families
on the potential energy surface. Such an approach should
Received 4 October 2004. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on 10 August 2005.
Dedicated to Howard Alper for his contributions to chemistry.
N. Chakka, B.D. Johnston, and B.M. Pinto.2 Department of Chemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada.
1This article is part of a Special Issue dedicated to Professor Howard Alper.
2Corresponding author (e-mail: bpinto@sfu.ca).
Can. J. Chem. 83: 929–936 (2005)
doi: 10.1139/V05-107
© 2005 NRC Canada

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Can. J. Chem. Vol. 83, 2005
Fig. 1. Stabilizing orbital interactions associated with (a) the endo-anomeric effect and (b), (c), (d) the exo-anomeric effect.
R
(a)
(b)
(c)
(d)
X
X
X
X
Y
Y
R
R
R
Y
Y
stricted to the φH gauche– conformation, dictated by the exo-
anomeric effect (see structures b and c in Fig. 1), other con-
formations about the exocyclic C–O linkage being mini-
mally populated (11).
Fig. 2. Interconversion between preferred ground-state conforma-
tions.
X
X
R
X
R
(syn)
Thus far, carbohydrate heteroanalogues have been used to
advantage to gain access to alternative conformational pref-
erences. For example, disaccharides containing 5-thio sug-
ars, i.e., a sulfur atom in the ring, with different heteroatoms
in the interglycosidic linkage, show population of conforma-
tions with different φ torsional angles (12), and thiooligo-
saccharides, i.e., those containing a sulfur atom in the
interglycosidic linkage, e.g., thiocellobiose, show variations
in both φ and ψ angles (13). Similarly, the pseudodisac-
charide moiety in the tetrasaccharide dihydroglucoacarbose,
containing a nitrogen atom in an α-glycosidic linkage, also
displays variations in the ψ angle when free in solution (14).
However, examples of β-glycosides containing φ angles that
differ from the gauche conformation shown, e.g., a φH anti
conformation (structure d in Fig. 1), have been elusive (15).
It is worthy of note that the φH anti conformation will still
permit operation of the exo-anomeric effect, i.e., the nY →
σ*C–X stabilizing orbital interaction.
We were intrigued by the reported conformational prefer-
ences of oligosaccharides containing dihetero functionalities
in the interglycosidic linkage, for example, those about the
N–O glycosidic linkage in the naturally occurring caliche-
amycins (16), a family of enediyne antitumor antibiotics.
These newly discovered compounds with unusual molecular
structure have striking biological activity. This unusual N–O
linkage has attracted the attention of several groups, and
disaccharide mimics wherein two monosaccharide units are
linked by a N—O bond have recently been reported (17–19).
We propose here to investigate the corresponding com-
pounds containing the S–S and S–Se functionalities in the
glycosidic linkages.
X
R
- g
R
R
X
X
R
X
(anti)
+ g
X
R
R
Scheme 1.
OH
O
OH
X
S
HO
OH
OH
O
OCH3
HO
OH
PO
OP
OP
O
O
HX
PO
SSO2CH3
PO
OP
OP
OCH3
B
A
X = S for disulfide 1
P = protecting group
X = Se for selenosulfide 2
Fraser et al. (20) have reported a variable-temperature
NMR study of the effects of substitution on the barriers to
rotation about the sulfur–sulfur bond in acyclic disulfides,
and proposed that interconversion between the preferred
ground-state enantiomeric +g and –g conformations pro-
ceeds by way of either syn or anti transition states (Fig. 2).
A study of the influence of structure on the height of the
interconversion barrier for a series of different R groups
showed that the syn transition state, previously assumed to
be less stable, was actually of lower energy than the anti
transition state. The barrier to rotation about the S—S bond
was found to increase from Ea = 7.0 to Ea = 9.4 kcal/mol
with an increase in substituent size. The apparent steric rate
retardation was explained in terms of a strong preference for
the syn over the anti transition state. However, Jorgensen
and Snyder (21) concluded on the basis of molecular me-
chanics calculations on dialkyl disulfides that rotation pro-
ceeds by way of an anti transition state. Although syn/anti
barriers for simple, uncongested disulfides (e.g., HSSH and
CH3SSCH3) have been computed at various levels of sophis-
tication (22), the anti energy maximum was always lower
than the syn energy maximum. Our own previous study of
restricted rotation in hindered dichalcogenides showed that
diselenides and ditellurides exhibit similar conformational
preferences to disulfides (23).
We chose to examine in detail the conformational prefer-
ences in β-linked disaccharides containing disulfide and
selenosulfide moieties in the interglycosidic linkage and re-
port herein that these compounds take up the nomal φH
gauche+ conformation about the C-1′—S bond but exhibit
restricted rotation about the S—X bond and preferentially
populate either the (+g) or the (–g) conformation about this
linkage. Szilágyi et al. (24) and Davis et al. (25) have sepa-
rately reported the syntheses of symmetric, nonreducing di-
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Chakka et al.
931
Scheme 2.
OAc
OAc
OAc
OAc
O
S
CH3CN
O
O
H3C
S Na
AcO
SSO2CH3
AcO
O
OAc
5 (88%)
AcO
50-60 °C, 3 h
Br
4
3
saccharides containing interglycosidic (1→1′) disulfide
linkages; these compounds also display unusual conforma-
tional preferences. In addition, the syntheses of monosac-
charides containing sulfenamide aglycons have been
described recently (26).
Scheme 3.
OAc
OAc
OBz
O
O
HS
+
AcO
SSO2CH3
BzO
OAc
OBz
Results and discussion
OCH3
5
6
Bu4NHSO4
aq. NaHCO3
EtOAc, RT
Synthesis
Retrosynthetic analysis of the target compounds showed
that they could be synthesized by the coupling reaction of
monosaccharide A (a glycosylthio donor) with a mono-
saccharide B containing an appropriate nucleophile at C-4
(Scheme 1).
OBz
O
The synthesis of the glycosyl donor 5 was first attempted
by the reaction of acetobromogalactopyranose 3 with sodium
thiomesylate 4 (27, 28) in ethanol, as described for the cor-
responding glucose derivative (29). No desired product was
observed even after refluxing. A similar result was obtained
when DMF was used as the solvent. However, the displace-
ment reaction proceeded smoothly in acetonitrile at room
temperature, to give thiomesylate 5 (Scheme 2).
The coupling reaction of thiomesylate 5 with thiol 6 (30)
in the presence of a phase-transfer catalyst (tetrabutylam-
monium hydrogensulfate) and saturated aqueous sodium bi-
carbonate in EtOAc at room temperature gave the (1′→4)
disulfide 7 in excellent yield (Scheme 3). Methanolysis then
afforded the target disulfide 1.
Analogously, the coupling reaction of thiomesylate 5 with
selenol 8 (31) gave selenosulfide 9, (4→4′) diselenide 10
being formed as an oxidative by-product. The target seleno-
sulfide 2 was obtained by deprotection of compound 9 by
methanolysis. Similarly, diselenide 11 was obtained by
deprotection of (4→4′) diselenide 10 under Zemplén condi-
tions (Scheme 4).
OAc
OAc
O
S
S
BzO
OBz
AcO
OCH3
OAc
7 (88%)
NaOMe/MeOH
OH
O
OH
OH
S
HO
O
OH
HO
S
OCH3
OH
1 (82%)
ranted for the purposes of this study. Inspection of molecular
models suggested that the observed NOEs would be consis-
tent with a conformation in which the C1′SXC4 (X = S, Se)
torsion angle is about –60° (Fig. 3). Our assignment of
conformational preferences is consistent with those reported
by Szilágyi et al. (24) for 1→1′-linked disaccharides con-
taining a disulfide moiety in the interglycosidic linkage.
The 1H NMR spectra for compounds 7 and 9 in deuterated
toluene showed broad resonances for H-1′, H-5′, H-6A′, and
H-6B′ in ring A, suggesting that there is exchange on the
NMR timescale between conformations in the intermediate
exchange regime at room temperature. Heating the samples
to about 350 K led to sharp NMR signals, as indicated in
Fig. 4 for the case of 7. As the temperature was lowered be-
low room temperature, the spectra showed coalescence
behaviour and eventually, below 200 K, resolution into reso-
nances for two separate conformers at the slow-exchange
limit. The ratio of the major conformer to the minor con-
former was 3:1 based on integrations of the separate H-4
Conformational analysis
The conformational preferences of compounds 7 and 9
may be defined in terms of the ϕ, ψ, and ω angles shown in
Fig. 3. These preferences were probed by means of 1H NMR
spectroscopy. The NOESY spectrum for each compound
showed cross peaks for H-3/H-1′, H-3/H-5′, and OCH3/H-
5′, in addition to the cross peaks generally expected for the
two monosaccharide units. COSY-type cross peaks for
strongly coupled resonances could be distinguished from
true NOESY correlations by their anti-phase character. The
specific NOESY cross peaks suggest that the disaccharides
have a preferred –gauche (–g) conformation about the ψ an-
gle, although the ω angle could not be defined explicitly
with the limited number of observed NOE cross peaks
(Fig. 3). A more rigorous analysis by computational meth-
ods in the absence of experimental data did not seem war-
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Can. J. Chem. Vol. 83, 2005
Scheme 4.
OAc
OAc
OBz
O
O
HSe
BzO
AcO
SSO2CH3
+
OAc
OBz
OCH3
5
8
Bu4NHSO4
aq. NaHCO3
EtOAc, RT
OBz
O
OBz
OAc
OAc
Se
BzO
O
Se
BzO
O
OBz
AcO
S
OCH3
OBz
OAc
OCH3
2
10 (19%)
9 (52%)
NaOMe/MeOH
NaOMe/MeOH
OH
O
OH
O
Se
OH
OH
HO
Se
HO
O
OH
S
OCH3
HO
OH
OCH3
OH
2
2 (82%)
11 (98%)
Fig. 3. Preferred conformations of compounds 7 and 9.
resonances at δ 2.95 and δ 2.45 in the spectrum recorded at
193 K (Fig. 4). Based on these variable-temperature NMR
results, we conclude that a second conformation, namely the
+gauche (+g) conformation (Fig. 3) is also populated.
Broadening of the H-1′ and H-5′ signals can then be ac-
counted for by the proximity of ring B to ring A, in the (–g)
conformation, where ring B is under ring A, and broadening
of the H-6′ signal by the proximity of the two rings in the
(+g) conformation, where ring B is above ring A (Fig. 3).
The observations of weak OCH3/H-6′ correlations in the
NOESY spectra lend additional support to the importance of
the (+g) conformation about the S—X bond in these com-
pounds.
The NOESY spectra for target compounds 1 and 2
showed cross peaks for OCH3 with the H-5′/H-6′ multiplet.
However, the high degree of spectral overlap did not permit
unambiguous assignment of the other signals. It seems rea-
sonable that compounds 1 and 2 will have similar
© 2005 NRC Canada

Chakka et al.
933
1
Fig. 4. Variable-temperature H NMR spectra of compound 7 in toluene-d8.
H - 6a, H - 6b
H - 1'
H - 6'a, H - 6'b
H - 2'
H - 4'
H- 4
H - 1
H - 3'
H - 3
H - 2
H - 5
H - 5'
Temp. = 353 K
Temp. = 313 K
Temp. = 298 K
Temp. = 243 K
Temp. = 213 K
Temp. = 193 K
H- 4 major
H- 4 minor
2.50
6.50
6.00
5.50
5.00
4.50
4.00
3.50
3.00
ppm (t1)
Fig. 5. Fragment molecular orbital interactions in compounds 1 and 2 (X = S, Se).
(c)
(b)
(a)
OCH
3
O
OH
CH O
3
OH
O
OH
OH
X
HO
O
O
HO
S
X
OH
S
HO
OH
HO
OH
HO
OH
OCH
HO
3
O
X
O
HO
OH
HO
S
HO
OH
OH
HO
*
conformational preferences as their protected precursors.
However, in these cases, no significant line-broadening ef-
fects were observed at room temperature, indicating that the
barrier to rotation about the S—X (X = S, Se) bond is less
than in the corresponding protected compounds.
mit expression of the nS → σC1−O5Gal exo-anomeric interac-
tion (Fig. 6). These two conformations are therefore stabi-
lized by both the exo-anomeric effect and the
hyperconjugative interactions associated with the RS–SR′
and RS––SeR′ linkages (Fig. 6). Importantly, the (+g) con-
formation (Fig. 6b) places the glucose ring above the
galactose ring in a manner similar to the elusive φH anti con-
formation in β-linked disaccharides while the (–g) confor-
mation places the two sugar rings in a similar orientation to
that observed for ordinary disaccharides.
The gauche conformational preferences about the S—S
and S—Se bonds are consistent with arguments based on
perturbational molecular orbital theory. Thus, an anti or syn
preference is disfavored based on a 4e repulsive interaction
between the 3p orbitals on the sulfur atom with either the S
(3p) or Se (4p) orbital on the adjacent atom (Figs. 5b, 5c)
(32). In contrast, the gauche conformations (e.g., Fig. 5a)
Conclusions
*
permit a 2e stabilizing nS → σX−C hyperconjugative interac-
tion.
Disaccharide analogues in which the interglycosidic link-
age is either a disulfide or selenosulfide moiety have been
Interestingly, both (+g) and (–g) conformations also per-
© 2005 NRC Canada

934
Can. J. Chem. Vol. 83, 2005
*
*
Fig. 6. Combined exo-anomeric nS → σ C-1−Ο-5 and nS → σ X−R
2.84 mmol) in acetonitrile (25 mL) at room temperature un-
der nitrogen. The temperature was then slowly raised to 50–
60 °C and the reaction mixture was stirred for 3 h until TLC
showed completion of the reaction. The suspension was
cooled and the solvent was removed. The residue was puri-
fied by chromatography on silica gel, (EtOAc–hexane, 7:12)
to give the title compound as a white solid (0.95 g, 88%);
mp 124–126 °C. [α]2D3 +3 (c 1.9, CHCl3). 1H NMR
interactions (X = S, Se).
1
2
R
OAc
OAc
AcO
AcO
X
S
AcO
AcO
O
O
S
X
(400 MHz, acetone-d6) δ: 5.50 (1H, dd, J3,4 = 3.5 Hz, J4,5
=
AcO
AcO
1.0 Hz, H-4), 5.47 (1H, d, J1,2 = 10.4 Hz, H-1), 5.39 (1H,
dd, J2,3 = 9.9 Hz, H-3), 5.19 (1H, dd, H-2), 4.44 (1H, ddd,
H-5), 4.22 (1H, dd, J5,6a = 4.4 Hz, J6a,6b = 11.6 Hz, H-6a),
4.13 (1H, dd, J5,6b = 8.0 Hz, H-6b), 3.56 (3H, s, SSO2CH3),
2.15–1.92 (12H, 4s, 4 × OAc). 13C NMR (400 MHz, CDCl3)
δ: 170.17–169.69 (CO, 4 × OAc), 86.98 (C-1), 75.37 (C-5),
71.33 (C-3), 67.07 (C-4), 65.79 (C-2), 61.86 (C-6), 52.76
(SSO2CH3), 20.62–20.47 (Me, 4 × OAc). Anal. calcd. for
C15H22O11S2: C 40.72, H 5.01; found: C 41.01, H 5.05.
R
-g
+g
synthesized. The compounds display interesting conforma-
tional preferences, as determined by NOE spectroscopy and
line-broadening effects. These preferences are consistent
with the operation of the destabilizing and stabilizing orbital
interactions associated with the RS–SR′ and RS–SeR′ link-
ages as well as with the stabilizing nS → σ*C-1 ′–O-5 ′ exo-
anomeric orbital interaction. The conformational preferences
suggest a means of expanding the repertoire of carbohydrate
topographies for use as biological probes.
Methyl 2,3,6-tri-O-benzoyl-4-S-(2′,3′,4′,6′-tetra-O-acetyl-
␤-D-galactopyranosyl-1′-thio)-4-thio-␣-D-glucopyranoside
(7)
To a mixture of thiosulfonate 5 (2.14 g, 4.8 mmol) and
thiol 6 (2.75 g, 5.1 mmol) in EtOAc (58 mL) was added
phase-transfer catalyst, tetrabutylammonium hydrogensulfate
(2.16 g, 6.4 mmol), and saturated aqueous sodium hydro-
gencarbonate (13 mL). The reaction mixture was stirred at
room temperature under nitrogen for 18 h and then diluted
with EtOAc (100 mL). The organic layer was then washed
with saturated sodium chloride solution (2 × 30 mL) fol-
lowed by water (2 × 30 mL). The organic layer was dried
over anhydrous sodium sulfate and evaporated. The crude
product was purified by column chromatography (EtOAc–
hexane, 1:2). The title compound 7 was obtained as an
amorphous white solid (3.97 g, 88%). [α]2D3 –30.3 (c 3.5,
Experimental section
General
Melting points were determined on a Fisher-Johns melting
point apparatus and are uncorrected. Optical rotations were
measured with a Rudolph Research Autopol II automatic
1
polarimeter. H NMR and 13C NMR spectra were recorded
on a Bruker AMX-400 NMR spectrometer at 400.13 MHz
and 100.6 MHz for proton and carbon, respectively. Chemi-
cal shifts are given in ppm downfield from TMS for those
spectra measured in CDCl3, CD3OD, (CH3)2CO, or toluene-
d8 and from 2,2-dimethyl-2-silapentane-5-sulfonate (DSS)
for those spectra measured in D2O. Chemical shifts and cou-
pling constants were obtained from a first-order analysis of
the spectra. All assignments were confirmed with the aid of
two-dimensional 1H/1H (COSYDFPT), 1H/13C (INVBTP),
1H (NOESYTP), and 1H (MLEVTP) experiments using stan-
dard Bruker pulse programs. Processing of the spectra was
performed with standard UXNMR (Bruker) and WINNMR
software. Zero filling of the acquired data (512 t1 values and
2 K data points in t2) led to a final data matrix of 1 K × 1 K
(F1 × F2) data points. MALDI-TOF mass spectra were ob-
tained for samples dispersed in a 2,5-dihydroxybenzoic acid
matrix using a PerSeptive Biosystems Voyager-DE instru-
ment. Analytical TLC was performed on aluminum plates
precoated with Merck silica gel 60F-254 as the adsorbent.
The developed plates were air-dried, exposed to UV light
and (or) sprayed with a solution containing 1% Ce(SO4)2
and 1.5% molybdic acid in 10% aq. H2SO4 and heated.
Compounds were purified by flash column chromatography
on Kieselgel 60 (230–400 mesh). Solvents were distilled be-
fore use and were dried, as necessary. Solvents were evapo-
rated under reduced pressure and below 50 °C.
1
CHCl3). H NMR (400 MHz, CDCl3) δ: 8.09–7.94 (6H, 3d,
3 × OBz ortho Hs), 7.64–7.34 (9H, m, 3 × OBz meta + para
H), 6.23 (1H, dd, J2,3 = 9.6 Hz, J3,4 = 10.4 Hz, H-3), 5.50
(1H, d, J3′,4′ = 3.4 Hz, J4′,5′ ≈ 0.0 Hz, H-4′), 5.31 (1H, dd,
J1′,2′ = 10.0 Hz, H-2′), 5.20 (1H, dd, J1,2 = 3.6 Hz, H-2),
5.17 (1H, d, H-1), 5.13 (1H, dd, J2′,3′ = 10.1 Hz, H-3′), 4.82
(1H, broad dd, J5,6a = 4.0 Hz, J6a,6b = 12.1 Hz, H-6a), 4.73
(1H, dd, J5,6b = 2.1 Hz, H-6b), 4.53–4.51 (2H, m, H-1′, H-5),
4.44–4.27 (3H, m, H-5′, H-6a′, H-6b′), 3.48 (3H, s, OMe),
3.11 (1H, dd, J4,5 = 10.4 Hz, H-4), 2.20–1.99 (12H, 4s, 4 ×
OAc). 13C NMR (400 MHz, CDCl3) δ: 170.38–169.42 (CO,
4 × OAc), 166.17–165.72 (CO, 3 × OBz), 133.29–128.36
(15C, Ph), 97.18 (C-1), 89.50 (br, C-1′), 74.51 (C-5′), 73.35
(C-2), 71.81 (C-3′), 69.62 (br, C-3), 67.58 (C-5), 66.87 (2C,
C-2′, C-4′), 63.56 (C-6), 60.35 (C-6′), 55.67 (OMe), 47.91
(C-4), 20.72–20.56 (Me, 4 × OAc). MALDI-TOF-MS calcd.
for C42H44O17S2: 884.20; found: 907.07 (M + Na)+. Anal.
calcd. for C42H44O17S2: C 57.01, H 5.01; found: C 57.28, H
5.08.
Methyl-4-S-(␤-D-galactopyranosyl-1′-thio)-4-thio-␣-D-
glucopyranoside (1)
The blocked disulfide 7 (1.06 g, 1.19 mmol) was treated
with 1 mol/L methanolic sodium methoxide (4 mL) at room
temperature for 10 min in dry methanol (40 mL). The reac-
tion mixture was then neutralized to pH 6.4 with Rexyn 101
2,3,4,6-Tetra-O-acetyl-␤-D-galactopyranosyl
methanethiosulfonate (5)
Acetobromogalactose 3 (1.00 g, 2.43 mmol) was added to
a solution of sodium methanethiosulfonate 4 (0.38 g,
© 2005 NRC Canada

Chakka et al.
935
H+. The neutralized solution was filtered and evaporated to
dryness in vacuo to give a white solid. The crude product
was purified by column chromatography on silica gel
(EtOAc–methanol–water, 6:3:1) to give the title compound
as a white crystalline solid (0.39 g, 82%); mp 151–153 °C
(EtOH). [α]2D3 –100 (c 1.15, D2O). 1H NMR (400 MHz,
D2O) δ: 4.81 (1H, d, J1,2 = 3.7 Hz, H-1), 4.36 (1H, d,
J1 ′,2 ′ = 9.5 Hz, H-1′), 4.07 (1H, dd, J2,3 ≈ J3,4 ≈ 9.9 Hz, H-
3), 4.00–3.94 (4H, m, H-4′, H-5′, H-6a, H-6b), 3.77 (1H,
dd, J2 ′,3 ′ = 9.6 Hz, H-2′), 3.76 (1H, dd, J5,6a = 6.9 Hz,
J6a,6b = 12.2 Hz, H-6a′), 3.73–3.66 (3H, m, H-5, H-3′, H-
6b′), 3.62 (1H, dd, H-2), 3.40 (3H, s, OMe), 2.65 (1H, dd,
J4,5 = 10.2 Hz, H-4). 13C NMR (400 MHz, D2O) δ: 102.06
(C-1), 91.84 (C-1′), 82.23 (C-5′), 76.53 (C-3′), 75.18 (C-2),
73.77 (C-4′), 71.22 (C-5), 71.09 (C-2′), 70.52 (C-3), 64.22
(C-6′), 63.96 (C-6), 57.84 (OMe), 52.61 (C-4). MALDI-
TOF-MS calcd. for C13H24O10S2: 404.1; found: 427.3 (M +
Na)+. Anal. calcd. for C13H24O10S2: C 38.61, H 5.98; found:
C 38.55, H 6.00.
Methyl-4-Se-(␤-D-galactopyranosyl-1′-thio)-4-seleno-␣-D-
glucopyranoside (2)
The blocked selenosulfide 9 (2.0 g, 2.15 mmol) was
treated with 1 mol/L methanolic sodium methoxide (6 mL)
at room temperature for 1 h in dry methanol (80 mL). The
reaction mixture was then adjusted to pH 6.4 with Rexyn
101 H+. The solution was filtered and evaporated to dryness
in vacuo to give a white solid. The crude product was puri-
fied by column chromatography on silica gel (EtOAc–meth-
anol–water, 6:3:1); the title compound was obtained as a
white crystalline solid (0.75 g, 77%); mp 122–124 °C
(EtOH). [α]2D3 –114 (c 2.75, D2O). 1H NMR (400 MHz,
D2O) δ: 4.63 (1H, d, J1,2 = 3.7 Hz, H-1), 4.37 (1H, d, J1′,2′
=
8.3 Hz, H-1′), 4.03 (1H, dd, J2,3 ≈ J3,4 = 9.6 Hz, H-3), 4.01–
3.93 (4H, m, H-5, H-4′, H-6a, H-6b), 3.79–3.65 (5H, m,
H-5′, H-6a′, H-6b′, H-2′, H-3′), 3.62 (1H, dd, H-2), 3.39
(3H, s, OMe), 2.94–2.83 (1H, second order multiplet, H-4).
13C NMR (400 MHz, D2O) δ: 102.15 (C-1), 90.56 (C-1′),
82.20 (C-5′), 76.39 (C-3′), 75.19 (C-2), 74.31 (C-4′), 72.68
(C-5), 71.39 (C-2′), 71.11 (C-3), 64.94 (C-6′), 63.94 (C-6),
57.87 (OMe), 48.62 (C-4). MALDI-TOF-MS calcd. for
C13H24O10SSe: 452.0; found: 475.1 (M + Na)+. Anal. calcd.
for C13H24O10SSe: C 34.59, H 5.36; found: C 34.27, H 5.50.
Methyl 2,3,6-tri-O-benzoyl-4-Se-(2′,3′,4′,6′-tetra-O-
acetyl-␤-D-galactopyranosyl-1′-thio)-4-seleno-␣-D-
glucopyranoside (9) and methyl 2,3,6-tri-O-benzoyl-4-
seleno-␣-D-glucopyranoside diselenide (10)
Methyl 4-seleno-␤-D-glucopyranoside diselenide (11)
The protected (4→4′) diselenide 10 (0.725 g, 0.62 mmol)
was treated with 1 mol/L methanolic sodium methoxide
(4 mL) at room temperature for 2.5 h in dry methanol
(40 mL). The reaction mixture was then neutralized to
pH 6.2 with Rexyn 101 H+. The neutralized solution was fil-
tered and evaporated to dryness in vacuo to give a yellow
solid. The crude product was purified by column chromatog-
raphy on silica gel (EtOAc–methanol–water, 6:3:1) to give
the title compound as a yellow crystalline solid (0.31 g,
98%); mp 95–97 °C. [α]2D1 –77 (c 0.4, D2O). 1H NMR
(400 MHz, D2O) δ: 4.83 (1H, d, J1,2 = 3.4 Hz, H-1), 3.99
(2H, d, H-6a, H-6b), 3.85 (1H, dd, J2,3 = 9.7 Hz, H-3), 3.72
(1H, ddd, J5,6a = 2.9 Hz, H-5), 3.64 (1H, dd, H-2), 3.78
(3H, s, OCH3), 2.85 (1H, dd, J3,4 = 10.7 Hz, H-4). MALDI-
TOF-MS calcd. for C14H26O10Se2: 514.0; found: 537.2 (M +
Na)+. Anal. calcd. for C14H26O10Se2: C 32.82, H 5.12;
found: C 33.09, H 5.37.
To a mixture of thiosulfonate 5 (2.20 g, 4.98 mmol) and
selenol 8 (3.68 g, 6.29 mmol) in EtOAc (55 mL) was added
phase-transfer catalyst, tetrabutylammonium hydrogensulfate
(2.56 g, 7.5 mmol), and saturated aqueous sodium hydro-
gencarbonate (40 mL). The reaction mixture was stirred at
room temperature under nitrogen overnight and diluted with
EtOAc (150 mL). The organic layer was then washed with
saturated sodium chloride solution (2 × 50 mL) followed by
water (2 × 100 mL). The organic layer was dried over anhy-
drous sodium sulfate and evaporated. The crude product was
then purified by column chromatography on silica gel
(EtOAc–hexane, 1:2.5). The title compound 9 was obtained
as a colorless amorphous solid (2.4 g, 52%) and the pro-
tected (4→4′) diselenide 10, a by-product, was obtained as a
yellow solid (1.43 g, 38% with respect to selenol 8). Com-
1
pound 9: [α]2D3 +66 (c 0.5, CHCl3). H NMR (400 MHz,
CDCl3) δ: 8.10–7.94 (6H, 3d, 3 × OBz ortho H), 7.62–7.32
(9H, m, 3 × OBz meta + para H), 6.21 (1H, dd, J2,3
=
9.2 Hz, J3,4 = 10.7 Hz, H-3), 5.51 (1H, d, J3 ′,4 ′ = 3.4 Hz,
J4 ′,5 ′ = 0.0 Hz, H-4′), 5.30 (1H, dd, J1 ′,2 ′ = 10.0 Hz, H-2′),
5.22 (1H, dd, J1,2 = 3.6 Hz, H-2), 5.20 (1H, d, H-1), 5.13
Acknowledgment
We are grateful to the Natural Sciences and Engineering
Research Council of Canada (NSERC) for financial support.
(1H, dd, J2 ′,3 ′ = 10.0 Hz, H-3′), 4.89 (1H, broad dd, J6a,6b
=
12.1 Hz, H-6a), 4.73 (1H, dd, J5,6b = 2.0 Hz, H-6b), 4.65
(1H, broad d, H-1′), 4.57 (1H, ddd, H-5), 4.40–4.28 (3H,
br m, H-5′, H-6a′, H-6b′), 3.48 (3H, s, OMe), 3.30 (1H, dd,
H-4), 2.21, 2.02, 2.00, 1.99 (12H, 4s, 4 × OAc). 13C NMR
(400 MHz, CDCl3) δ: 170.45–169.54 (CO, 4 × OAc),
166.20, 165.81, 165.57 (CO, 3 × OBz), 133.29–128.37
(18C, 3 × Ph), 97.35 (C-1), 87.0 (C-1′), 74.60 (C-5′), 73.35
(C-2), 71.77 (C-3′), 69.86 (C-3), 68.26 (C-5), 66.85 (C-
2′,4′), 64.39 (C-6), 60.36 (C-6′), 55.69 (OMe), 42.60 (C-4),
20.80–20.60 (Me, 4 × OAc). MALDI-TOF-MS calcd. for
C42H44O17SSe: 932.1; found: 955.5 (M + Na)+. Anal. calcd.
for C42H44O17SSe: C 54.14, H 4.76; found: C 54.03, H 4.90.
Compound 10: This product was found to have identical
physical constants and NMR data to those previously re-
ported (31).
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