Synthesis of branched dithiotrisaccharides via ring-opening reaction of sugar thiiranes

Article abstract of DOI:10.1021/jo2018685

Satisfactory procedures are described for the synthesis of 5,6- and 3,4-thiirane derivatives from the respective hexofuranose or hexopyranose epoxide precursors. The controlled ring-opening reaction of thiiranes by 1-thioaldoses was successfully accomplished to afford, regio- and stereoselectively, β-S-(1→4)-3,4-dithiodisaccharides. For instance, the regioselective attack of per-O-acetyl-1-thioglucose (16) to C-4 of 2-propyl 2,6-di-O-acetyl-3,4-epithio-α-d-galactopyranoside (14) gave the derivative of Glcp-β-S-(1→4)-3,4-dithioGlcp-O-iPr (17). This thiodisaccharide was accompanied by the (1→3)-disulfide 18, formed between 16 and 17, and the symmetric (3→3)-disulfide 19, which resulted from the oxidative dimerization of 17. However, the S-acetyl derivative of 17 could be obtained in good yield (62%) by LiAlH₄ reduction of the crude mixture 17-19, followed by acetylation. The same sequence of reactions starting from 14 and the 1-thiolate of Galp afforded the per-O,S-acetyl derivative of Galp-β-S-(1→4)-3,4-dithio-α-d-Glcp-O-iPr (23), which was selectively S-deacetylated to give 25. The dithiosaccharides 17 and 25 are 3,4-di-S-analogues of derivatives of the natural disaccharides cellobiose and lactose, respectively. The ring-opening reaction of 5,6-epithiohexofuranoses of d-galacto (8) or l-altro (11) configuration with 1-thioaldoses was also regio- and stereoselective to give the respective β-S-(1→6)-linked 5,6-dithiodisaccharides 26 or 29 in excellent yields. Glycosylation of the free thiol group of 17, 25, or 26, using trichloroacetimidates as glycosyl donors, led to the corresponding branched dithiotrisaccharides. Some of them are sulfur analogues of derivatives of branched trisaccharides found in natural polysaccharides.

Full text of DOI:10.1021/jo2018685

Article
pubs.acs.org/joc
Synthesis of Branched Dithiotrisaccharides via Ring-Opening
Reaction of Sugar Thiiranes
Evangelina Repetto, Veronica E. Manzano, María Laura Uhrig, and Oscar Varela*
́
́
CIHIDECAR-CONICET, Departamento de Química Organica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos
Aires, Argentina
S
* Supporting Information
ABSTRACT: Satisfactory procedures are described for the
synthesis of 5,6- and 3,4-thiirane derivatives from the
respective hexofuranose or hexopyranose epoxide precursors.
The controlled ring-opening reaction of thiiranes by 1-
thioaldoses was successfully accomplished to afford, regio-
and stereoselectively, β-S-(1→4)-3,4-dithiodisaccharides. For instance, the regioselective attack of per-O-acetyl-1-thioglucose
(16) to C-4 of 2-propyl 2,6-di-O-acetyl-3,4-epithio-α-D-galactopyranoside (14) gave the derivative of Glcp-β-S-(1→4)-3,4-
dithioGlcp-O-iPr (17). This thiodisaccharide was accompanied by the (1→3)-disulfide 18, formed between 16 and 17, and the
symmetric (3→3)-disulfide 19, which resulted from the oxidative dimerization of 17. However, the S-acetyl derivative of 17 could
be obtained in good yield (62%) by LiAlH4 reduction of the crude mixture 17−19, followed by acetylation. The same sequence
of reactions starting from 14 and the 1-thiolate of Galp afforded the per-O,S-acetyl derivative of Galp-β-S-(1→4)-3,4-dithio-α-D-
Glcp-O-iPr (23), which was selectively S-deacetylated to give 25. The dithiosaccharides 17 and 25 are 3,4-di-S-analogues of
derivatives of the natural disaccharides cellobiose and lactose, respectively. The ring-opening reaction of 5,6-epithiohexofuranoses
of D-galacto (8) or L-altro (11) configuration with 1-thioaldoses was also regio- and stereoselective to give the respective β-S-(1→
6)-linked 5,6-dithiodisaccharides 26 or 29 in excellent yields. Glycosylation of the free thiol group of 17, 25, or 26, using
trichloroacetimidates as glycosyl donors, led to the corresponding branched dithiotrisaccharides. Some of them are sulfur
analogues of derivatives of branched trisaccharides found in natural polysaccharides.
steric and electronic effects operating during the ring-opening
reaction.8 These effects have been well established for reactions
of oxirane derivatives of sugars with nucleophiles.9 However,
the analogous opening of episulfides by nucleophiles has been
less studied. In this type of reactions, the thiol group released
after the thiirane ring-opening competes with the attacking
nucleophile leading to polymerizations and other side
reactions.10 Thiiranes can also react with electrophiles and
are able to undergo oxidation or reduction at sulfur, and
thermal and photochemical reactions have also been reported.11
In the field of carbohydrates, some examples of ring-opening of
sugar thiiranes by nucleophiles have been reported. For
instance, the LiAlH4 reduction of a 5,6-epithio derivative of
α-D-glucofuranose afforded the expected 6-deoxy-5-thiofura-
nose, which upon attack to the unreacted thiirane, led to S-(5→
6)-linked oligomers as by products.12 A 1,2-episulfide has been
proposed as the intermediate formed by treatment of phenyl
1,2-dithio-α-D-mannopyranoside with alkali. The 1,2-episulfide
underwent ring-opening oligomerization to afford a family of
(1→2)-linked thiooligo-α-D-mannopyranosides.13 Derivatives
of 1,2:5,6-diepithio-D-alditols have been employed as mono-
meric precursors of thiosugar polymers that contain thiofur-
anose, thiopyranose, and open-chain residues.14
INTRODUCTION
■
Oligosaccharides are rarely considered for drug discovery due,
among other reasons, to the lability of the glycosidic bond. To
address the issue of the enzyme degradation of oligosaccharides
in organisms, the preparation of stable mimetics is a topic of
current interest.1 Thus, oligosaccharide analogues with the
glycosidic oxygen atom substituted by sulfur or other
heteroatoms have been synthesized.2,3 The thioglycosidic
linkage is usually stable to enzymatic processes, and the
thiooligosaccharides may display inhibitory activity against
glycosidases. These glycomimetics are also useful tools for
structural biology, as the sulfur atom may act as hydrogen bond
acceptor and the thiolinkage provides a higher degree of
flexibility between glycosyl units.4 Therefore, thiooligosacchar-
ides can change more easily their conformation, with respect to
their natural counterparts, to enable a better fit in the catalytic
site of enzymes. For all these reasons they are frequently
employed to study protein−carbohydrate interactions, as
binding and recognition events initiate immunological
responses to infections and signaling processes that occur in
inflammation and cancer metastasis.5
In the last years, we have been involved in a project on the
synthesis of thiooligosaccharides as potential enzyme inhib-
itors,6 and we have recently reported the diastereoselective
synthesis of thiodisaccharides based on the ring-opening of
sugar epoxides with 1-thioaldoses.7 The advantage of this
procedure relies upon the regio- and stereocontrol due to the
Received: September 8, 2011
Published: November 17, 2011
© 2011 American Chemical Society
253
dx.doi.org/10.1021/jo2018685 | J. Org. Chem. 2012, 77, 253−265

The Journal of Organic Chemistry
Article
Scheme 1. Synthesis of Thiirane Derivatives 8 and 11
We assumed that the controlled ring-opening of a sugar
thiirane by a 1-thiosugar nucleophile would allow the
installation of two contiguous sulfur-containing stereocenters
in a pyranose or furanose unit. The thiol group formed as result
of the opening of the episulfide may be glycosylated by
standard procedures to afford a branched dithiotrisaccharide. In
contrast to this rather direct methodology, the classical
approach for the synthesis of branched S,S-trisaccharides
based on standard SN2 displacement reaction,1−3 has been
limited to just a few examples because of its multistep
nature.15,16
Here we describe convenient procedures for the synthesis of
5,6-thiirane derivatives of furanoses and a 3,4-thiirane derivative
of a pyranose from the corresponding epoxide precursors. The
controlled ring-opening reaction of episulfides with 1-
thioaldoses was employed as key step for the preparation of
the S-glycosidic linkage with the concomitant release of a thiol
group in the vicinal carbon atom. The resulting products are
useful precursors for the synthesis of branched dithiotrisac-
charides.
2α,β with LiAlH4 in THF gave a product distribution that
showed to be highly dependent on the reaction conditions.
Thus, reduction of 2α,β with a slight excess (1.3 molar equiv)
of LiAlH4 at low temperature (−18 °C) for short periods (30
min) afforded the expected product 3a and 3b (major). Under
the same conditions but using longer reaction times (50 min),
2α,β underwent removal of the silyl ether at C-5 to give the 2,3-
di-O-silyl derivative 4 as the major product. This compound
was envisioned as an useful precursor for the stereoselective
synthesis of epoxides and thiiranes that belong to the D- or L-
series, as described below. Additionally, it was observed that
when the reaction was conducted at room temperature, the 5-O
→ 6-O migration of the TBS group in 3a,b occurred to give the
respective products having HO-5 free, although in a low
isolated yield. The migration of ester groups from 5-O to 6-O is
rather common in Galf derivatives19 and migrations of silyl
ethers in carbohydrates have also been reported.20
To obtain the 5,6-thiirane of galacto configuration from 4, a
double inversion of the C-5 configuration was required.
Therefore, the primary hydroxyl group of the diol 4 was
selectively pivaloylated to the 6-O-pivaloyl derivative 5. Further
tosylation of HO-5 afforded the 5-O-sulfonyl derivative 6,
which on treatment with 2 M NaOMe in MeOH at 0 °C led to
the epoxide 7 (α-L-altro configuration). The 1H NMR spectrum
of 7 showed characteristic signals of the oxirane ring protons
protected at 3.07 (H-5), 2.81 (H-6a), and 2.73 ppm (H-6b).
The 13C NMR spectrum of 7 exhibited the resonances of the
carbons, involved in the oxirane ring (C-5 and C-6), at
relatively high fields, in the region of 52−44 ppm. Epoxides are
usually converted into thiiranes by reaction with thiourea.21
Thus, treatment of 7 with thiourea in methanol at room
temperature afforded the episulfide 8 (D-galacto configuration).
The replacement of the oxygen atom by the sulfur atom in the
three-membered ring produces a further upfield shifting for the
signals of the protons and carbons involved in the thiirane, with
respect to those of the oxirane.
RESULTS AND DISCUSSION
■
To explore the strategy proposed for the synthesis of branched
dithiotrisaccharides, selectively protected sugar episulfides were
required. These key intermediates are usually obtained from
sugar epoxides, compounds that have been already prepared in
our laboratory.7 We considered that, similar to the 5,6-epoxides
of a hexofuranose, the 5,6-thiirane analogues are expected to
undergo regioselective ring-opening by attack of the
nucleophile to the less substituted C-6 position. For this
reason, and taking also into account the participation of
galactofuranose (Galf) in many biological processes in
microorganisms,17 we selected this sugar as starting compound.
Conveniently protected derivatives of Galf were prepared
starting from methyl (methyl-α,β-D-galactofuranosid)uronate
(1α,β),18 the product of methanolysis of D-galacturonic acid
(Scheme 1). Silylation of 1α,β with an excess of tert-
butyldimethylsilyl chloride (TBSCl) afforded the anomeric
mixture (β/α ∼9:1) of the 2,3,5-tri-O-silyl derivatives (2α,β) in
almost quantitative yield. Reduction of the ester function of
For the preparation of the 5,6-episulfide 11, that belongs to
the α-L-altro series, was needed retention of the C-5
configuration in the epoxide precursor. Hence, the selective
tosylation of HO-6 in 4 led to the 6-O-tosyl derivative 9. On
254
dx.doi.org/10.1021/jo2018685 | J. Org. Chem. 2012, 77, 253−265

The Journal of Organic Chemistry
Article
treatment with 2 M NaOMe/MeOH, compound 9 was
converted into the epoxide 10. Reaction of 10 with thiourea
in MeOH afforded the 5,6-episulfide 11. In the 13C NMR
spectrum of epoxides 7, 10 and episulfides 8 and 11 the change
of configuration at C-5 from D-galacto to L-altro produced a
downfield shifting for the signal of the vicinal carbon atoms C-4
and C-6. In particular, the C-4 signal in the altrofuranoside 11
is strongly deshielded (89.9 ppm).
Unfortunately, the reaction with thiourea that successfully
converted epoxides 7 or 10 into the corresponding thiiranes 8
or 11 failed when applied to 12, and no reaction took place
either under more drastic conditions. It is known that epoxides
with high SN2 reactivity produce thiiranes when treated with
potassium or ammonium thiocyanates.22,23 Under standard
conditions, the reaction of 12 with KSCN was unsuccessful,
and at higher temperatures the conversion of the epoxide into
the corresponding alkene was observed. However, the synthesis
of thiirane 13 could be successfully accomplished (81% yield)
by reaction of 12 with KSCN at pH = 8, in the presence of 18-
crown-6. Similar conditions have been employed by Bellomo
and Gonzalez24 for the conversion of epoxide derivatives of
inositols into episulfides. The absolute configuration for the C-
3 and C-4 stereocenters in 13 was confirmed by means of the
NOESY spectrum. The NOE contacts between H-3 and H-5,
and those of one methyl group of the isopropyl substituent with
H-3 and H-4 are indicative that the thiirane ring was located in
the β face of the molecule (D-galacto configuration). A 3,4-
thiirane derivative analogue of 13, methyl 2-O-acetyl-6-deoxy-
3,4-epithio-α-D-galactopyranoside, has been obtained as a
minor product by KSCN ring-opening reaction from a 3,4-
epoxide precursor.25
The epoxide 12 was employed as key precursor for the
synthesis of a thiirane derivative fused to a pyranose ring
(Scheme 2). Compound 12 has been readily prepared starting
Scheme 2. Synthesis of Thiirane Derivatives 13−15
In compound 13, the free hydroxyl group at C-2 is
conveniently disposed with respect to the vicinal 3,4-thiirane
ring for the intramolecular nucleophilic attack to C-3, as
observed for analogous epoxide systems.7,9 Therefore, the
alcohol function of 13 was acetylated or silylated under
standard conditions to afford, respectively, the 2-O-acetyl (14)
or 2-O-TBS (15) derivatives. It is worth mentioning that the
synthesis of thiiranes 14 or 15 starting from the 2-O-acetyl or 2-
O-TBS derivatives of the epoxide 12, under the above-
mentioned conditions, produced only very low yield of such
from a 2-acetoxy-per-O-acetyl-D-galactal.7 We have selected the
galacto configuration for the epithio pyranoside derivative as,
similar to the analogous epoxide, the controlled ring-opening
reaction with a 1-thioaldopyranose is expected to take place by
attack to C-4 to produce a 3,4-dithioglucose derivative.7
Glucose is a common component of polysaccharides and
glycoconjugates, whereas gulose is a rather rare sugar. The 3,4-
dithio derivative of gulose should be the result of the same
attack to the thiirane of opposite D-allo configuration.
Scheme 3. Ring-Opening Reaction of Thiirane 14 by 1-Thioaldoses
255
dx.doi.org/10.1021/jo2018685 | J. Org. Chem. 2012, 77, 253−265

The Journal of Organic Chemistry
Article
Scheme 4. Ring-Opening Reaction of Thiirane 8 and 11
products, indicating the strong effect of the substitution of the
HO-2 in the course of the reaction.
(J3,HS = 3.9 Hz). The J1′,2′ value (10.2 Hz) confirmed that the β
anomeric configuration was maintained for the 1-thioaldose
moiety, which showed the resonance of the anomeric proton
shifted upfield (δH‑1′ = 4.65) with respect to that of the O-
glycoside (δH‑1 = 5.09) because of the shielding effect of sulfur.
Similarly, the 13C NMR spectrum of 17 exhibited the C-1 signal
of the S-glycoside at higher field (δC‑1′ = 82.3) than that of the
Having the thiiranes 8, 11, and 13−15 in hand, the
episulfide-opening reaction was studied. We expected that the
nucleophilic opening of the thiirane ring in the pyranose
derivatives 13−15 should be more difficult than that in the
analogue furanoses (8 and 11), as the latter involves a terminal
methylene carbon in the ring. Therefore, we explored first the
reaction with the pyranose-derived thiirane 14 (Scheme 3).
Under the conditions optimized for the oxirane-ring-opening of
pyranoses with 1-thioaldoses (LiOMe−MeOH at 60 °C,
followed by acetylation),7 the reaction of the thiirane 15 with
the 1-thioglucose derivative 16a afforded unreacted material
together with the per-O-acetyl derivative of Glc-S-(1→1)-S-
Glc26 (the symmetric disulfide of 16) and 2-propyl 6-O-acetyl-
2-O-tert-butyldimethylsilyl-3,4-dideoxy-α-D-erythro-hex-3-eno-
pyranoside,7 the product of eliminative desulfuration of 15.
This one was the main product when the temperature of the
reaction was increased, in agreement with the fact that
unsaturated derivatives are usually obtained upon heating
alkaline solutions of episulfides.27 The opening of the thiirane
was also unsuccessful using acid catalysis28 (AcOH in DMF or
TMSI in CH2Cl2) as unreacted starting material was recovered.
However, attack to the episulfide ring of 14 took place using as
nucleophile the sodium thiolate 16b (prepared by reaction of
16a with NaH) in the presence of 18-crown-6. Column
chromatography of the reaction mixture afforded three
products; the first one was the expected thiodisaccharide 17,
which was isolated in low yield (6%). From the following
fractions of the column were obtained the disulfides 18 and 19,
in 48% and 6% yield, respectively.
O-glycoside (δC‑1 = 93.8). The HRMS of 17 was in agreement
with the structure proposed; whereas that of 18 was indicative
of the incorporation of an additional molecule of 1-thioaldose
into the molecule. The presence of three sulfur atoms suggested
1
the formation of a disulfide bond from 17. The H and 13C
NMR spectra confirmed this assumption, as 18 showed three
anomeric signals, two of them [1H: 5.09 (J1,2 = 3.7 Hz) and
4.63 ppm (J1″,2″ = 10.2 Hz); 13C: 94.2 (C-1) and 81.3 ppm (C-
1″)] similar to those observed for 17. The additional signal
detected in the respective spectra, at 4.51 ppm (J = 10.2 Hz)
and 89.5 ppm, were assigned to the H and C of the anomeric
center bonded to the disulfide. Thus, the anomeric carbon
atom signal is shifted downfield (∼8 ppm) with respect to the
same signal of the thioglycoside, and the resonance of C-3 is
also deshielded (∼9 ppm) with respect to that of C-3 in 17,
linked to the free thiol group. In contrast, the signal of the β
carbon bonded to sulfur (C-4) was shielded (∼5 ppm) in
comparison to same signal in 17.
Compound 18 should be produced by disulfide bond
formation between the free thiol groups of 17 and 16b,
whereas the oxidative dimerization of 17 would explain the
formation of the symmetric disulfide 19. The formation of
disulfides in ring-opening reactions of thiiranes with common
nucleophiles has been reported.10 The structure of 18 was also
confirmed as this disulfide was alternatively obtained by
reaction of 16b and 17, under the conditions employed for
the ring-opening reaction. Significantly, the dithiohexopyranose
unit of compounds 17−19 has the same gluco configuration.
This stereochemistry results from the regioselective attack of
16b to C-4 of the episulfide 17, with trans-opening of the ring.
The approach of the nucleophile to C-3 should experience
The structures of 17−19 were established on the basis of
their NMR spectra. Thus, the 1H NMR spectrum of 17 showed
at high fields (3.99 and 2.91 ppm) the signals of the protons
linked to sulfur (H-3 and H-4, respectively). The large values
(>11 Hz) for the coupling constant associated to these signals
(J2,3, J3,4, and J4,5) were indicative of a gluco configuration for the
reducing-end of the thiodisaccharide 17. Furthermore, the HS
signal appeared as a doublet because of the coupling with H-3
256
dx.doi.org/10.1021/jo2018685 | J. Org. Chem. 2012, 77, 253−265

The Journal of Organic Chemistry
Article
Scheme 5. Synthesis of Branched Dithiotrisaccharides 31, 34, and 36
gauche and 1,3-diaxial interactions with the respective vicinal
acetoxy group and 2-propyloxy group at C-1. The approach of
16b to C-4 of the thiirane 14 is free of such repulsive
interactions.
The thiodisaccharide 26 results, as expected, from the attack of
the nucleophile 22b to the less substituted ring carbon of the
episulfide 8. The H NMR spectrum of 26 confirmed that the
1
free thiol group was substituting C-5, as it was detected a
coupling between H-5 and the HS (1.92 ppm, J5,HS = 9.4 Hz).
Furthermore, in the 13C NMR spectrum of 26 the chemical
shift of the anomeric carbon of the furanose appeared, as
expected, downfield (109.0 ppm) with respect to that of the 1-
thiopyranose (83.7 ppm). The structure of the disulfide 27 was
confirmed on the basis of the 13C NMR data, which showed
clearly the additional signal for the anomeric carbon bonded to
the disulfide group, with a chemical shift value (91.4 ppm)
intermediate between those of the furanose (109.7 ppm) and
the 1-thiogalactopyranose units (84.5 ppm). As observed for
the analogue 18, the signal of the α carbon bonded to the
disulfide group was shifted downfield (∼13 ppm) and that of
the β carbon bonded to sulfur was shifted upfield (∼3 ppm),
with respect to the same signals in 26. Similar displacements
were detected for the C-5 and C-6 signals in 28 (C-5 downfield
12 ppm, and C-6 upfield 4 ppm). The molecular weights of
26−28, determined by HRMS, confirmed the structures
proposed for these compounds. Libraries of glycosyldisulfides
have been prepared using dynamic combinatorial chemistry,
exploiting the ready thiol-disulfide conversion.33 Evidence was
presented that the disulfides are biologically active ligands for
lectins. For instance, the dithiogalactosyldisulfide is an inhibitor
of human lectins and a plant A,B-type toxin.34
The reaction conditions for the synthesis of the dithiosac-
charide 26 were optimized. Thus, the ring-opening of thiirane 8
with the thiolate 22b was conducted in the presence of 18-
crown-6 and DTT. In contrast to the analogous reaction of the
pyranose episulfide 14 with 16b, in this case DTT prevented
efficiently the formation of 27 and 28, and the thiodisaccharide
26 was obtained in 98% yield. Under identical conditions, the
reaction of episulfide 11 with the thiolate 22b, in the presence
of 18-crown-6 and DTT, afforded the thiodisaccharide 29 in
87% yield. The structure of 29 was confirmed from the NMR
spectra, which was similar to that of the analogue 26.
The optimization of the conditions for the reaction between
14 and 16b was attempted, in order to avoid the formation of
the disulfides 18 and 19. The change of the solvent
(acetonitrile instead of THF) or a lowering in the temperature
(−18 °C) did not produce a decrease of such byproducts.
Although dithiothreitol (DTT) is usually employed to reduce
the formation of disulfide linkages,2,29 the incorporation of this
reagent to the reaction medium did not have any effect.
However, taking into account that compounds 18 and 19 can
be seen as derivatives of the thiodisaccharide 17, we considered
that the disulfide reduction of compounds 17−19 will produce
17 as main product. Although reductions with sodium
borohydride, Zn/AcOH, or Zn/Ac2O were unsuccessfully
attempted, we found that treatment of the crude mixture
17−19 with LiAlH4 and further acetylation afforded 20, the S-
acetyl derivative of 17, in 62% yield. As byproduct was isolated
2,3,4,6-tetra-O-acetyl-1-S-acetyl-1-thio-β-D-glucopyranose
(21),30 which may be formed from 18, and also by acetylation
of the excess of 16b employed for the ring-opening of thiirane
14.
Compound 14 was also allowed to react with the sodium salt
of per-O-acetyl-1-thio-β-D-galactopyranose (22b). Further
LiAlH4 reduction of the reaction mixture, followed by
acetylation, led to thiodisaccharide 23 (70% yield). This
product was accompanied with 24,31 the S-acetyl derivative of
22a. Selective removal of the thioacetyl group of 20 or 23 with
cysteamine29b,32 afforded, respectively, the thiodisaccharides 17
or 25. Interestingly, compounds 17 and 25 are the respective
3,4-dithio analogues of the natural disaccharides cellobiose and
lactose. Furthermore, an analogue of 17, a derivative of 3-S-
glycosyl-3,4-dithioglucose, has been previously synthesized as
the dithiodisaccharide precursor of the thio-linked sialyl Lewis
X.16
The reaction of the thiirane 8 with the sodium salt of per-O-
acetyl-1-thio-β-D-galactopyranose (22b) was studied (Scheme
4). Under the same conditions employed for the ring-opening
of 14, compound 8 afforded the mixture of thiodisaccharide 26
(5%) and the disulfides 27 and 28 (21% and 11%, respectively).
To accomplish the synthesis of the branched dithiotrisac-
charides, the glycosylation of the free thiol group in 17 was
attempted (Scheme 5). For this purpose, several glycosyl
donors were employed. The reaction of 17 with penta-O-acetyl-
257
dx.doi.org/10.1021/jo2018685 | J. Org. Chem. 2012, 77, 253−265

The Journal of Organic Chemistry
Article
β-D-glucopyranose in the presence of SnCl4 as Lewis acid,35 or
under neutral conditions using MoO2Cl2 as catalyst,36 were
unsuccessful. The glycosylation of 17 with per-O-acetyl
glucopyranosyl iodide37 in Et3N−CH2Cl2 led mostly to
decomposition. More satisfactory results were obtained using
the trichloroacetimidate 3038 as glycosyl donor. The reaction
between 17 and 30, under strictly dry conditions and catalysis
with trimethylsilyl triflate (TMSOTf), afforded the expected
branched dithiotrisaccharide 31, although in a moderate yield
(35%). The thiol group in 17 seems to be hindered by the
vicinal, gauche-disposed S-glucopyranose moiety at C-4 and the
acetoxy group at C-2. Probably because of the low reactivity of
HS-3, part of 30 is consumed in the formation of the (1→1)-O-
linked disaccharide 32, which was isolated from the reaction
mixture and showed properties coincident with those described
in the literature.39 The fact that disulfides 18 and 19 are formed
during the ring-opening reaction of episulfide 14, supports the
sterical hindrance to the HS group in 17, as 18 and 19, which
have longer S−S linkages than that of the thioglycoside in 31,
are more readily formed. Hence, the glycosylation was
conducted with a furanose derivative as less bulky glycosyl
donor, compared to the analogous pyranose. To have the 3,4-
dithiopyranose core substituted by two sugars sharing the same
configuration, and as the trichloroacetimidate of Galf 33 is
readily accessible from galactose,40 we studied the glycosylation
of 25 with 33. Under the conditions employed for the synthesis
of 31, the analogous dithiotrisaccharide 34 was obtained in 66%
yield (or 81%, if corrected with respect to the recovered
unreacted 25). The N-glycosyl trichloroacetamide 3541 was
isolated as a byproduct, which results from the rearrangement
of the trichloroacetimidate group of 33.
opening of 5,6-thiirane derivatives of furanoses proved to be
highly regio and stereselectively to afford glycosyl β-(1→6)-5,6-
dithiofuranosides in excellent yields. The same reaction applied
to a 3,4-thiirane-D-galactopyranoside analogue, was also regio
and stereselective to give the corresponding (1→4)-dithiodi-
saccharides, having a 3,4-dithio-D-glucopyranose as reducing
end. The dithiodisaccharides possess a thiol group free, and
hence they can serve as building blocks for the synthesis of
sugar disulfides, as potential biologically active molecules.33,34
Moreover, thiol-containing compounds have an essential role in
many biochemical reactions due to their ability to be readily
oxidized and then regenerated.42 Thiols can also act as radical-
trapping antioxidants.43 In this work, the free thiol group of the
thiodisaccharides, derived from thiiranes of pyranoses or
furanoses, could be successfully glycosylated using trichlor-
oacetimidates as glycosyl donors, to afford the corresponding
branched dithiotrisaccharides. Thus, diglycosyl-S,S-(1→3,4)-
3,4-dithio-D-glucopyranose and diglycosyl-S,S-(1→5,6)-5,6-di-
thio-D-galactofuranose have been prepared. The β-D-glucosyl
(1→3)- and (1→4)-linkages are common in linear poly-
saccharides present in the cell walls of cereal endosperm,44 and
a branched trisaccharide with glucosyl residues (1→3)- and
(1→4)-linked to a Glcp core has been found as a constituent of
the glucan isolated from the mushroom Calocybe indica.45
A
per-O-acetyl derivative 3,4-di-S-analogue of this trisaccharide
has been prepared. A similar pattern of a glucose core with
glycosyl residues at HO-3 and HO-4 is also found in the sialyl
Lewis X epitope.46
With regard to the branched dithiotrisaccharides with a 5,6-
dithio-Galf residue as reducing end, a compound of this kind
was synthesized as sulfur analogue of the motif β-D-Galp-(1→
6)-[β-D-Galf-(1→5)]-D-Galf, the repeating unit of the cell-wall
galactan of Bifidobacterium catenulatum YIT 4016.47 Other 5,6-
branched galacto-oligosaccharides have been reported in
structures isolated from natural sources.48
The glycosylation of the thiol group at C-5 of 26 was also
conducted. Such a thiol group is expected to be difficult to
substitute as it is hindered by the vicinal furanose ring and the
1-S-galactopyranose at C-6. However, the dithiotrisaccharide 36
could be obtained, in a moderate yield (40%), by the TMSOTf-
catalyzed reaction between 26 and the galactofuranose
trichloroacetimidate 33.
The structure of the dithiotrisaccharides 31, 34, and 36 were
confirmed by means of NMR spectroscopy and HRMS. The 1H
NMR spectra were fully assigned using 2D-experiments; and the
coupling constants measured for the anomeric protons of the
thioglycosides confirmed the β configuration for both the
EXPERIMENTAL SECTION
■
Methyl (Methyl 2,3,5-tri-O-tert-butyldimethylsilyl-α,β-D-
galactofuranosid)uronate (2α,β). Methyl (methyl α,β-D-
galactofuranosid)uronate (1α,β) was synthesized as already de-
scribed.18 To a solution of 1α,β (885 mg, 3.99 mmol) in dry
MeCN (12 mL), TBSCl (2 g, 13.27 mmol), and imidazole (1.80 g,
2.43 mmol) were added, and the suspension was stirred at room
temperature (rt) for 24 h. Evaporation of the solvent afforded a syrup
that was dissolved in CH2Cl2 (50 mL) and washed with water (2 × 25
mL). The organic extract was dried (MgSO4) and concentrated. Crude
compound 2α,β (2.23 g, 99%, β:α 9:1) showed by TLC a single spot
(Rf 0.58, hexane/EtOAc, 10:1), and it was pure enough for the next
pyranose (J1′,2′ ∼ J1″,2″ ∼ 10 Hz) and the furanose (J1′,2′ or J1″,2″
<
1.0 Hz) units. The 13C NMR spectra showed also the
characteristic chemical shifts for the anomeric carbons bonded
to sulfur. For example, the C-1′, C-1″ signals in 31 appeared at
81.8, 80.7 ppm; in contrast with the analogue disulfide 19, that
exhibited the resonance of the anomeric carbon bonded to S-S
at 89.5 ppm. In addition, the spectra of the dithiotrisaccharides
34 and 36 exhibited the respective C-1 signals of the S-linked
furanose (88.5 and 88.2 ppm) and pyranose (82.1 and 83.3
ppm) moieties. To identify the signals of each thioglucopyr-
anosyl residue in 31 (one bonded to C-3 and the other to C-4
of the reducing end) a NOESY-GPPH experiment was
conducted. The H-1′ and H-1″ signals were assigned according
to their respective NOE contacts with H-3 and H-4.
1
step of the reaction. An analytical sample showed the following H
NMR (CDCl3, 500 MHz) for the β anomer: δ 4.75 (d, 1H, J1,2 = 1.8
Hz, H-1), 4.34 (d, 1H, J4,5 = 3.1 Hz, H-5), 4.19 (dd, 1H, J2,3 = 2.6, J3,4
= 5.6 Hz, H-3), 4.16 (dd, 1H, J3,4 = 5.6, J4,5 = 3.1 Hz, H-4), 3.99 (dd,
1H, J1,2 = 1.8, J2,3 = 2.6 Hz, H-2), 3.75 (s, 3H, CH3CO2), 3.32 (s, 3H,
CH3O), 0.93, 0.88, 0.87 (3s, 27H, (CH3)3CSiMe2), 0.13, 0.09 (×2),
0.08, 0.07, 0.06 (5 s, 18H, (CH3)2SiBut); 13C NMR (CDCl3, 125.7
MHz) δ 172.0 (C-6), 109.5 (C-1), 85.4 (C-4), 84.3 (C-2), 79.2 (C-3),
72.1 (C-5), 55.0 (CH3O), 51.9 (CH3CO2) 25.9, 25.7 (×2)
[(CH3)3CSiMe2], 18.5, 17.9, 17.8 [(CH3)3CSiMe2], −4.1, −4.4,
−4.5 (×2), −4.9, −5.1 [(CH3)2SiBut]. Anal. Calcd for C26H56O7Si3:
C, 55.27; H, 9.99. Found: C, 55.39; H, 10.02.
Methyl 2,3,5-Tri-O-tert-butyldimethylsilyl-α-D-galactofura-
noside (3a), Methyl 2,3,5-Tri-O-tert-butyldimethylsilyl-β-D-gal-
actofuranoside (3b), and Methyl 2,3-Di-O-tert-butyldimethyl-
silyl-β-D-galactofuranoside (4). A solution of uronate 2 (564 mg,
1.00 mmol) in dry THF (15 mL) was cooled to −18 °C and LiAlH4
(50 mg, 1.30 mmol) was added. The reaction mixture was stirred for
CONCLUSIONS
■
The ring-opening reaction of sugar thiiranes by 1-thioaldoses
afforded diverse glycomimetics, with different stereochemistries
and presentation modes. Under optimized conditions, the ring-
258
dx.doi.org/10.1021/jo2018685 | J. Org. Chem. 2012, 77, 253−265

The Journal of Organic Chemistry
Article
50 min, and then EtOAc (15 mL), MeOH (15 mL), and AcOH (to
pH 7) were added in sequence, and finally the mixture was
concentrated. The solid obtained was suspended in CH2Cl2 and
centrifuged (4−5 times) to eliminate Li and Al salts. Evaporation of
the solvent afforded a residue that showed by TLC (hexane/EtOAc,
10:1) spots corresponding to 3a (Rf 0.47), 3b (Rf 0.43), and 4 (Rf
0.00) that were isolated by column chromatography (toluene/EtOAc
mmol) dissolved in dry pyridine (20 mL) was treated with tosyl
chloride (1.24 g, 6.48 mmol). The reaction mixture was stirred at rt for
3 days, and then MeOH (10 mL) was added. The syrup obtained after
evaporation of the solvent was dissolved in CH2Cl2, and the organic
layer was washed with water (20 mL), dried (MgSO4), and
concentrated. Analysis by TLC (toluene/EtOAc, 9:1) showed a
major product of Rf 0.71, which was purified by column
60:1→EtOAc). The yields and physical data are reported as follows.
chromatography (toluene/EtOAc, 60:1) to afford 6 (415 mg, 91%):
1
1
Compound 3a: 21 mg, 4%; [α]25 +42.2 (c 1.1, CHCl3); H NMR
[α]25 −12.0 (c 1.0, CHCl3); H NMR (CDCl3, 500 MHz) δ 7.83,
D
D
(CDCl3, 500 MHz) δ 4.77 (d, 1H, J1,2 = 3.8 Hz, H-1), 4.19 (t, 1H, J2,3
= J3,4 = 4.8 Hz, H-3), 3.94 (dd, 1H, J1,2 = 3.8, J2,3 = 4.8 Hz, H-2), 3.85
(ddd, 1H, J4,5 = 4.8 Hz, H-5), 3.83 (t, 1H, J3,4 = J4,5 = 4.8 Hz, H-4),
3.69 (dddd, 1H, J5,6a = 4.8, J6a,HO = 6.4, J6a,6b = 11.2 Hz, H-6a), 3.62
(dddd, 1H, J5,6b = 4.8, J6a,HO = 6.4, J6a,6b = 11.2 Hz, H-6b), 3.40 (s, 3H,
CH3O), 2.34 (t, 1H, J6b,HO = J6b,HO = 6.4 Hz, HO), 0.92, 0.90, 0.87 (3s,
27H, (CH3)3CSiMe2), 0.14, 0.12, 0.11, 0.10, 0.07, 0.06 (6s, 18H,
(CH3)2SiBut); 13C NMR (CDCl3, 125.7 MHz) δ 103.5 (C-1), 85.4
(C-4), 78.6 (C-2), 76.6 (C-3), 72.8 (C-5), 64.5 (C-6), 55.9 (CH3O),
25.9 (×2), 25.7 [(CH3)3CSiMe2], 18.3, 18.2, 17.9 [(CH3)3CSiMe2],
−3.8, −4.2, −4.5, −4.6, −4.7, −4.8 [(CH3)2SiBut]. Anal. Calcd for
7.36 (2d, 4H, J ∼ 8.2 Hz, H-aromatic), 4.97 (dddd, 1H, J4,5 = 3.9, J5,6a
= 5.3, J5,6b = 6.6 Hz H-5), 4.58 (d, 1H, J1,2 = 1.2 Hz, H-1), 4.37 (dd,
1H, J5,6a = 5.3, J6a,6b = 11.9 Hz, H-6a), 4.15 (dd, 1H, J5,6b = 6.6, J6a,6b
=
11.9 Hz, H-6b), 4.04 (dd, 1H, J2,3 = 2.2, J3,4 = 5.5 Hz, H-3), 4.02 (dd,
1H, J3,4 = 5.5, J4,5 = 3.9 Hz, H-4), 3.97 (dd, 1H, J1,2 = 1.2, J2,3 = 2.2 Hz,
H-2), 3.26 (s, 3H, CH3O), 2.43 (s, 3H, CH3Ph), 1.21 (s, 9H,
COC(CH3)3), 0.91, 0.88 (2s, 18H, (CH3)3CSiMe2), 0.11 (×2), 0.10,
0.08 (4s, 12H, (CH3)2SiBut); 13C NMR (CDCl3, 125.7 MHz) δ 177.9
(COC(CH3)3), 144.9, 144.6, 129.9, 129.6, 128.1, 127.9 (C-aromatic),
109.5 (C-1), 83.9 (C-3), 82.5 (C-2), 79.4 (C-4), 77.5 (C-5), 62.4 (C-
6), 56.2 (COC(CH3)3), 54.9 (CH3O), 27.1 (COC(CH3)3), 25.8, 25.7
[(CH3)3CSiMe2], 21.6 (CH3Ph), 17.9, 17.8 [(CH3)3CSiMe2], −4.3,
−4.5, −4.8, −4.9 [(CH3)2SiBut]; HRMS (ESI) m/z [M + Na]+ calcd
for C31H56NaO9SSi2 683.3076, found 683.3088.
C25H56O6Si3: C, 55.92; H, 10.51. Found: C, 55.76; H, 10.59.
1
Compound 3b: 86 mg, 16%; [α]25 −19.1 (c 1.1, CHCl3); H
D
NMR (CDCl3, 500 MHz) δ 4.74 (br s, 1H, H-1), 4.09 (dd, 1H, J2,3
=
2.0, J3,4 = 4.9 Hz, H-3), 4.01 (dd, 1H, J1,2 = 1.2, J2,3 = 2.0 Hz, H-2),
3.98 (t, 1H, J3,4 = J4,5 = 4.9 Hz, H-4), 3.89 (c, 1H, J4,5 = J5,6a = J5,6b = 4.9
Hz, H-5), 3.71 (ddd, 1H, J5,6a = 4.9, J6a,HO = 6.3, J6a,6b = 11.3 Hz H-6a),
3.66 (ddd, 1H, J5,6b = 4.9, J6b,HO = 6.3, J6a,6b = 11.3 Hz H-6b), 3.36 (s,
3H, CH3O), 2.35 (br s, 1H, HO), 0.94, 0.92, 0.90 (3s, 27H,
(CH3)3CSiMe2), 0.16, 0.15, 0.13, 0.12, 0.11 (×2) (5s, 18H,
(CH3)2SiBut); 13C NMR (CDCl3, 125.7 MHz) δ 109.2 (C-1), 86.8
(C-4), 83.7 (C-2), 79.4 (C-3), 72.5 (C-5), 64.5 (C-6), 54.8 (CH3O),
26.0, 25.7 (×2) [(CH3)3CSiMe2], 18.4, 17.9, 17.8 [(CH3)3CSiMe2],
−4.1, −4.4 (×2), −4.5, −4.6, −4.8 [(CH3)2SiBut]. Anal. Calcd for
Methyl 5,6-Anhydro-2,3-di-O-tert-butyldimethylsilyl-α-L-al-
trofuranoside (7). A solution of 6 (148 mg, 0.24 mmol) in
CH2Cl2 (6 mL) was cooled at 0 °C, and 1.3 mL of 2 M NaOMe/
MeOH solution was added. The mixture was stirred for 2 h at 0 °C;
TLC (hexane/EtOAc, 10:1) showed a main spot of Rf 0.48. The
reaction was diluted with CH2Cl2 (30 mL) and washed with water (2
× 25 mL). The organic phase was dried and concentrated and the
residue was purified by column chromatography (hexane/EtOAc,
40:1) to afford 7 (80 mg, 83% from 6a; 88 mg, 91% from 6b): [α]25
D
−40.1 (c 1.1, CHCl3); 1H NMR (CDCl3, 500 MHz) δ 4.74 (br s, 1H,
H-1), 4.03 (dd, 1H, J2,3 = 2.4, J3,4 = 4.4 Hz, H-3), 4.01 (dd, 1H, J1,2
∼
C25H56O6Si3: C, 55.92; H, 10.51. Found: C, 55.52; H, 10.89.
1
Compound 4: 262 mg, 62%; [α]25 −11.6 (c 1.0, CHCl3); H
1.0, J2,3 = 2.4 Hz, H-2), 3.77 (dd, 1H, J3,4 = 4.4, J4,5 = 5.6 Hz, H-4),
3.35 (s, 3H, CH3O), 3.07 (dddd, 1H, J4,5 = 5.7, J5,6a = 3.9, J5,6b = 2.7
Hz, H-5), 2.81 (dd, 1H, J5,6a = 3.9, J6a,6b = 5.2 Hz, H-6a), 2.73 (dd, 1H,
J5,6b = 2.7, J6a,6b = 5.2 Hz, H-6b), 0.89 (×2) (2s, 18H, (CH3)3CSiMe2),
0.11, 0.10 (×2), 0.09 (4s, 12H, (CH3)2SiBut); 13C NMR (CDCl3,
125.7 MHz) δ 110.1 (C-1), 84.7 (C-4), 83.4 (C-2), 81.2 (C-3), 55.0
(CH3O), 52.0 (C-5), 45.4 (C-6), 25.7 (×2) [(CH3)3CSiMe2], 17.9
(×2) [(CH3)3CSiMe2], −4.4, −4.7, −4.8, −4.9 [(CH3)2SiBut]. Anal.
Calcd for C19H40O5Si2: C, 56.39; H, 9.96. Found: C, 56.69; H, 10.26.
Methyl 2,3-Di-O-tert-butyldimethylsilyl-5,6-epithio-β-D-gal-
actofuranoside (8). To a solution of the epoxide 7 (85 mg, 0.21
mmol) in dry MeOH (3 mL) was added thiourea (42 mg, 0.55 mmol),
and the mixture was stirred at rt for 48 h. Upon concentration, the
residue was dissolved in CH2Cl2 (25 mL), washed with water (2 × 25
mL), dried (MgSO4), and concentrated. Analysis by TLC (hexane/
EtOAc, 10:1) showed a main compound of Rf 0.68, which was purified
D
NMR (CDCl3, 500 MHz) δ 4.72 (d, 1H, J1,2 = 1.4 Hz, H-1), 4.13 (dd,
1H, J2,3 = 3.1, J3,4 = 5.7 Hz, H-3), 3.99 (dd, 1H, J1,2 = 1.4, J2,3 = 3,1 Hz,
H-2), 3.94 (dd, 1H, J3,4 = 5.7, J4,5 = 1.7 Hz, H-4), 3.76−3.68 (m, 3H,
H-5, H-6a, H-6b), 3.35 (s, 3H, CH3O), 2.62, 2.23 (2d, 2H, J ∼ 7.7 Hz,
HO-5 y HO-6), 0.90, 0.88 (2s, 27H, (CH3)3CSiMe2), 0.11, 0.10, 0.90
(×2) (3s, 12H, (CH3)2SiBut); 13C NMR (CDCl3, 125.7 MHz) δ 109.7
(C-1), 84.9 (C-4), 83.1 (C-2), 79.1 (C-3), 69.8 (C-5), 65.3 (C-6), 55.1
(CH3O), 25.7 (×2) [(CH3)3CSiMe2], 17.9, 17.8 [(CH3)3CSiMe2],
−4.3, −4.7 (×2), −4.9 [(CH3)2SiBut]. Anal. Calcd for C19H42O6Si2: C,
53.99; H, 10.01. Found: C, 53.68; H, 10.10.
Methyl 2,3-Di-O-tert-butyldimethylsilyl-6-O-pivaloyl-β-D-
galactofuranoside (5). To a solution of the diol 4 (210 mg, 0.50
mmol) in dry pyridine (3.6 mL) was added pivaloyl chloride (135 μL,
1.10 mmol). The mixture was stirred at 0 °C for 3 h and then at rt for
1 h; TLC (toluene/EtOAc, 5:1) showed a main spot of Rf 0.66. The
mixture was poured into ice/water, extracted with CH2Cl2, and washed
with HCl 5%, water, and satd aq NaCO3H. The extract was dried
(MgSO4) concentrated, and the residue was purified by column
chromatography (toluene/EtOAc, 20:1) to afford 5 (185 mg, 74%):
[α]25D −30.0 (c 1.2, CHCl3); 1H NMR (CDCl3, 500 MHz) δ 4.72 (d,
1H, J1,2 = 1.0 Hz, H-1), 4.23 (dd, 1H, J5,6a = 6.5, J6a,6b = 11.0 Hz, H-
by column chromatography (hexane/EtOAc, 70:1) to afford 8 (73 mg,
1
83%): [α]25 −41.2 (c 0.8, CHCl3); H NMR (CDCl3, 500 MHz) δ
D
4.69 (d, 1H, J1,2 = 1.8 Hz, H-1), 4.00 (dd, 1H, J1,2 = 1.8, J2,3 = 4.1 Hz,
H-2), 3.90 (dd, 1H, J2,3 = 4.1, J3,4 = 7.0 Hz, H-3), 3.55 (t, 1H, J3,4 = J4,5
= 7.0 Hz, H-4), 3.34 (s, 3H, CH3O), 3.04 (ddd, 1H, J4,5 = 7.0, J5,6a
=
6.5, J5,6b = 5.4 Hz, H-5), 2.49 (dd, 1H, J5,6a = 6.5, J6a,6b = 1.1 Hz, H-6a),
2.37 (dd, 1H, J5,6b = 5.4, J6a,6b = 1.1 Hz, H-6b), 0.90, 0.89 (2s, 18H,
(CH3)3CSiMe2), 0.11, 0.10, 0.09, 0.08 (4s, 12H, (CH3)2SiBut); 13C
NMR (CDCl3, 125.7 MHz) δ 109.2 (C-1), 85.6 (C-4), 84.4 (C-2),
82.9 (C-3), 55.1 (CH3O), 35.3 (C-5), 25.8, 25.7 [(CH3)3CSiMe2],
21.8 (C-6), 17.9, 17.8 [(CH3)3CSiMe2], −4.1, −4.6 (×2), −4.9
[(CH3)2SiBut]; HRMS (ESI) m/z [M + Na]+ calcd for
C19H40NaO4SSi2 443.2084, found 443.2083. Anal. Calcd for
C19H40O4SSi2: C, 54.24; H, 9.58. Found: C, 54.50; H, 9.65.
Methyl 2,3-Di-O-tert-butyldimethylsilyl-6-O-tosyl-β-D-galac-
tofuranoside (9). To a solution of 4 (250 mg, 0.59 mmol) in dry
pyridine (6 mL) was added tosyl chloride (226 mg, 1.18 mmol) at 0
°C. The mixture was stirred for 10 h at that temperature and then at rt
for additional 50 h. The workup described for the tosylation of 5 was
followed to give 9 (337 mg, 99%). This compound showed to be pure
6a), 4.10 (dd, 1H, J3,4 = 5.6, J4,5 = 2.4 Hz, H-4), 4.09 (dd, 1H, J5,6b
6.5, J6a,6b = 11.0 Hz, H-6b), 4.00 (dd, 1H, J1,2 = 1.0, J2,3 = 1.8 Hz, H-2),
3.94 (dd, 1H, J2,3 = 1.8, J3,4 = 5.6 Hz, H-3), 3.88 (m, 1H, J5,6a = J5,6b
=
∼
6.5, J5,HO = 8.0 Hz, H-5), 3.34 (s, 3H, CH3O), 2.52 (d, 1H, J5,HO = 8.0
Hz, HO), 1.22 (s, 9H, COC(CH3)3), 0.90, 0.88 (2s, 18H,
(CH3)3CSiMe2), 0.11, 0.09 (×2), 0.08 (4s, 12H, (CH3)2SiBut); 13C
NMR (CDCl3, 125.7 MHz) δ 178.3 (COC(CH3)3), 109.5 (C-1), 83.4
(C-3), 83.2 (C-2), 79.1 (C-4), 67.9 (C-5), 65.3 (C-6), 54.9 (CH3O),
38.8 (COC(CH3)3), 27.2 (COC(CH3)3), 25.8, 25.7 [(CH3)3CSiMe2],
17.9, 17.8 [(CH3)3CSiMe2], −4.3, −4.6, −4.7, −4.9 [(CH3)2SiBut].
Anal. Calcd for C24H50O7Si2: C, 56.88; H, 9.94. Found: C, 56.93; H,
10.22.
Methyl 2,3-Di-O-tert-butyldimethylsilyl-6-O-pivaloyl-5-O-
tosyl-β-D-galactofuranoside (6). Compound 5 (350 mg, 0.69
259
dx.doi.org/10.1021/jo2018685 | J. Org. Chem. 2012, 77, 253−265

The Journal of Organic Chemistry
Article
enough for the next step (Rf 0.47, hexane/EtOAc, 4:1). An analytical
sample of 9 obtained by column chromatography gave [α]25D −25.5 (c
CH3CO), 1.20, 1.29 (2d, each 3H, J = 6.2 Hz, (CH3)2CHO); 13C
NMR (CDCl3, 125.7 MHz) δ 170.8 (CH3CO), 93.4 (C-1), 71.3
(Me2CHO), 66.7 (C-6), 65.4 (C-2), 64.1 (C-5), 35.2 (C-3), 35.0 (C-
4), 23.0, 21.7 [(CH3)2CHO], 20.8 (CH3CO); HRMS (ESI) m/z [M +
Na]+ calcd for C11H18NaO5S 285.0773, found 285.0786. Anal. Calcd
for C11H18O5S: C, 50.36; H, 6.92. Found: C, 50.68; H, 7.09.
1
0.9, CHCl3); H NMR (CDCl3, 500 MHz) δ 7.81, 7.34 (2d, 4H, J ∼
8.2 Hz, H-aromatic), 4.67 (br s, 1H, H-1), 4.08 (d, 2H, J5,6a = J5,6b
=
6.4 Hz, H-6a, H-6b), 4.05 (dddd, 1H, J2,3 = 2.6, J3,4 = 5.1 Hz, H-3),
3.96 (dd, 1H, J1,2 = 1.1, J2,3 = 2.6 Hz, H-2), 3.94 (dd, 1H, J3,4 = 5.1, J4,5
= 1.6 Hz, H-4), 3.89 (dddd, 1H, J4,5 = 1.6, J5,6a = J5,6b = 6.4, J5,HO = 7.3
Hz, H-5), 3.29 (s, 3H, CH3O), 2.64 (d, 1H, J5,HO = 7.3 Hz, HO), 2.44
(s, 3H, CH3Ph), 0.87 (×2) (2s, 18H, (CH3)3CSiMe2), 0.09, 0.07 (×2),
0.05 (4s, 12H, (CH3)2SiBut); 13C NMR (CDCl3, 125.7 MHz,) δ
144.8, 132.9, 129.8, 128.0 (C-aromatic), 109.5 (C-1), 83.4 (C-4), 82.7
(C-2), 79.0 (C-3), 70.7 (C-6), 67.8 (C-5), 54.9 (CH3O), 25.7 (×2)
[(CH3)3CSiMe2], 21.6 (CH3Ph), 17.8 (×2) [(CH3)3CSiMe2], −4.4,
−4.7, −4.8, −5.0 [(CH3)2SiBut]. Anal. Calcd for C26H48O8SSi2: C,
54.13; H, 8.39. Found: C, 54.03; H, 8.43.
From further fractions of the column was recovered unreacted 12
(40 mg, 16%) and the corrected yield for 13 was 81%.
2-Propyl 2,6-Di-O-acetyl-3,4-epithio-α-D-galactopyranoside
(14). Compound 13 (110 mg, 0.42 mmol) was acetylated with acetic
anhydride (1.5 mL) and pyridine (1.5 mL) at rt for 16 h. Examination
by TLC (hexane/EtOAc, 1:1) showed the complete conversion of 13
(Rf 0.59) into a faster moving product (Rf 0.74). The mixture was
concentrated and subjected to column chromatography (hexane/
EtOAc, 8.5:1.5) to give 14 (125 mg, 98%): [α]25 +71.4 (c 1.4,
D
CHCl3); 1H NMR (CDCl3, 500 MHz) δ 5.09 (d, 1H, J1,2 = 4.7 Hz, H-
1), 5.02 (dd, 1H, J1,2 = 4.7, J2,3 = 1.1 Hz, H-2), 4.67 (m, 1H, J4,5 = 2.8,
J5,6a = 4.5, J5,6b = 7.4 Hz, H-5), 4.30 (dd, 1H, J5,6a = 4.5, J6a,6b = 11.4 Hz,
H-6a), 4.13 (dd, 1H, J5,6b = 7.4, J6a,6b = 11.4 Hz, H-6b), 3.86 (m, 1H, J
= 6.2 Hz, Me2CHO), 3.20 (dd, 1H, J3,4 = 6.8, J4,5 = 2.8 Hz, H-4), 3.15
(dd, 1H, J2,3 = 1.1, J3,4 = 6.8 Hz, H-3), 2.10, 2.13 (2s, each 3H,
CH3CO), 1.12, 1.27 (2d, each 3H, J = 6.2 Hz, (CH3)2CHO); 13C
NMR (CDCl3, 125.7 MHz) δ 170.7, 170.0 (CH3CO), 92.1 (C-1), 71.3
(Me2CHO), 68.4 (C-2), 66.7 (C-6), 63.8 (C-5), 34.5 (C-4), 32.3 (C-
3), 23.0, 21.7 [(CH3)2CHO], 20.8, 20.7 (CH3CO); HRMS (ESI) m/z
[M + Na]+ calcd for C13H20NaO6S 327.0872, found 327.0875. Anal.
Calcd for C13H20O6S: C, 51.30; H, 6.62. Found: C, 51.29; H, 6.54.
2-Propyl 6-O-Acetyl-2-O-tert-butyldimethylsilyl-3,4-epithio-
α-D-galactopyranoside (15). The silylation of 13 (40 mg, 0.15
mmol) was performed with TBSCl (29 mg, 0.19 mmol) and imidazole
(20 mg, 0.30 mmol) in MeCN (1 mL). After 4 h, TLC (hexane/
EtOAc, 4:1) revealed the complete formation of a faster moving
product (Rf 0.58). The reaction mixture was concentrated, and the
residue was dissolved in CH2Cl2 (15 mL) and extracted with water (15
mL). The organic phase was dried (MgSO4) and concentrated, and
the resulting syrup was purified by column chromatography (hexane/
EtOAc, 24:1) to afford 15 (52 mg, 92%): [α]25D +28.7 (c 1.1, CHCl3);
1H NMR (CDCl3, 500 MHz) δ 4.70 (d, 1H, J1,2 = 4.4 Hz, H-1), 4.65
Methyl 5,6-Anhydro-2,3-di-O-tert-butyldimethylsilyl-β-D-
galactofuranoside (10). A solution of crude 9 (337 mg, 0.58
mmol) in CH2Cl2 (14 mL) was treated with 2 M NaOMe/MeOH (3
mL) at 0 °C for 1 h; monitoring by TLC (toluene) showed a main
spot of Rf 0.40. The mixture was diluted with CH2Cl2 (25 mL),
extracted with water (2 × 15 mL), dried, and concentrated to afford
crude 10 (221 mg, 94%) with a high degree of purity. An analytical
sample was obtained by column chromatography: [α]25D −10.4 (c 1.0,
CHCl3); 1H NMR (CDCl3, 500 MHz) δ 4.68 (d, 1H, J1,2 = 2.0 Hz, H-
1), 4.01 (dd, 1H, J1,2 = 2.0, J2,3 = 4.4 Hz, H-2), 3.98 (dd, 1H, J2,3 = 4.4,
J3,4 = 7.3 Hz, H-3), 3.62 (dd, 1H, J3,4 = 7.3, J4,5 = 6.0 Hz, H-4), 3.36 (s,
3H, CH3O), 3.09 (dddd, 1H, J4,5 = 6.0, J5,6a = 4.3, J5,6b = 2.7 Hz, H-5),
2.83 (dd, 1H, J5,6a = 4.3, J6a,6b = 5.2 Hz, H-6a), 2.75 (dd, 1H, J5,6b = 2.7,
J6a,6b = 5.2 Hz, H-6b), 0.90, 0.88 (2s, 18H, (CH3)3CSiMe2), 0.10, 0.09,
0.08, 0.07 (4s, 12H, (CH3)2SiBut); 13C NMR (CDCl3, 125.7 MHz) δ
109.4 (C-1), 84.3 (C-2), 82.4 (C-4), 80.1 (C-3), 55.3 (CH3O), 51.7
(C-5), 44.2 (C-6), 25.8, 25.6 [(CH3)3CSiMe2], 17.9 (×2)
[(CH3)3CSiMe2], −4.2, −4.6, −4.9 (×2) [(CH3)2SiBut]; HRMS
(ESI) m/z [M + Na]+ calcd for C19H40NaO5Si2 427.2307, found
427.2320.
Methyl 2,3-Di-O-tert-butyldimethylsilyl-5,6-epithio-α-L-al-
trofuranoside (11). Crude compound 10 (221 mg, 0.55 mmol)
was treated with thiourea as described for the synthesis of 8. The
product which showed by TLC (toluene) Rf 0.57 was purified by
(m, 1H, J4,5 = 3.3, J5,6a = 4.5, J5,6b = 7.6 Hz, H-5), 4.29 (dd, 1H, J5,6a
=
4.5, J6a,6b = 11.3 Hz, H-6a), 4.11 (dd, 1H, J5,6b = 7.6, J6a,6b = 11.3 Hz, H-
6b), 4.07 (dd, 1H, J1,2 = 4.4, J2,3 = 1.6 Hz, H-2), 3.89 (m, 1H, J = 6.2
Hz, Me2CHO), 3.19 (dd, 1H, J3,4 = 7.0, J4,5 = 3.2 Hz, H-4), 3.09 (dd,
1H, J3,4 = 7.0, J2,3 = 1.6 Hz, H-3), 2.10 (s, 3H, CH3CO), 1.19, 1.29 (2d,
each 3H, J = 6.2 Hz, (CH3)2CHO), 0.94 (s, 9H, (CH3)3CSiMe2), 0.12,
0.15 (2s, each 3H, (CH3)2SiBut); 13C NMR (CDCl3, 125.7 MHz) δ
170.7 (CH3CO), 95.1 (C-1), 71.2 (Me2CHO), 69.5 (C-2), 66.9 (C-6),
64.2 (C-5), 36.6 (C-3), 35.5 (C-4), 25.8 [(CH3)3CSiMe2], 23.0, 21.8
[(CH3)2CHO], 20.8 (CH3CO), 18.2 [(CH3)3CSiMe2], −4.7, −4.8
[(CH3)2SiBut]; HRMS (ESI) m/z [M + Na]+ calcd for
C17H32NaO5SSi 399.1635, found 399.1625. Anal. Calcd for
C17H32O5SSi: C, 54.22; H, 8.56. Found: C, 54.29; H, 8.49.
2-Propyl 2,6-Di-O-acetyl-4-S-(2,3,4,6-tetra-O-acetyl-β-D-glu-
copyranosyl)-3,4-dithio-α-D-glucopyranoside (17), 2-Propyl
2,6-Di-O-acetyl-4-S-(2,3,4,6-tetra-O-acetyl-β-D-glucopyrano-
syl)-3-S-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)disulfide-
3,4-dithio-α-D-glucopyranoside (18), and Bis[2-Propyl 2,6-Di-
O-acetyl-4-S-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3,4-
dithio-α-D-glucopyranos-3-yl]disulfide (19). A solution of the 1-
thioaldose 16a30a,49 (76 mg, 0.21 mmol) and NaH (10 mg) in dry
THF (3.5 mL) was stirred at rt under nitrogen until the evolution of
gas ceased (∼1 h). The yellowish solution was concentrated, the
resulting salt (16b) was dissolved in THF (1.0 mL) and cooled at −18
°C, and the thiirane 14 (50 mg, 0.16 mmol) dissolved in dry THF (1.0
mL) was added. The mixture was stirred at rt for 10 min, and 18-
crown-6 (5 mg, 0.02 mmol) was added. After 30 min, an additional
amount of 18-crown-6 (5 mg, 0.02 mmol) was incorporated, and the
mixture was stirred at rt for 24 h. When TLC (toluene/EtOAc, 1:1)
showed the complete conversion of 14 (Rf 0.72) into an elongated
spot of Rf 0.23, the mixture was concentrated and purified by column
chromatography. The faster moving component isolated was the
starting thiirane 14 (18 mg). The next component that eluted from the
column chromatography (hexane/EtOAc, 50:1) and identified as 11
1
(138 mg, 60%): [α]25 −17.3 (c 0.7, CHCl3); H NMR (CDCl3, 500
D
MHz) δ 4.78 (br s, 1H, H-1), 4.04 (dd, 1H, J2,3 = 2.1, J3,4 = 3.7 Hz, H-
3), 3.99 (dd, 1H, J1,2 = 0.8, J2,3 = 2.1 Hz, H-2), 3.51 (dd, 1H, J3,4 = 3.7,
J4,5 = 8.2 Hz, H-4), 3.34 (s, 3H, CH3O), 3.04 (dddd, 1H, J4,5 = 8.2, J5,6a
= 6.1, J5,6b = 5.3 Hz, H-5), 2.53 (dd, 1H, J5,6a = 6.1, J6a,6b = 1.2 Hz, H-
6a), 2.30 (dd, 1H, J5,6b = 5.3, J6a,6b = 1.2 Hz, H-6b), 0.90, 0.89 (2s,
18H, (CH3)3CSiMe2), 0.11 (×2), 0.10 (×2) (4s, 12H, (CH3)2SiBut);
13C NMR (CDCl3, 125.7 MHz) δ 110.4 (C-1), 89.9 (C-4), 83.2 (C-2),
82.6 (C-3), 54.9 (CH3O), 34.5 (C-5), 25.8, 25.7 [(CH3)3CSiMe2],
23.5 (C-6), 17.9 (×2) [(CH3)3CSiMe2], −4.3, −4.5, −4.6, −4.8
[(CH3)2SiBut]; HRMS (ESI) m/z [M + Na]+ calcd for
C19H40NaO4SSi2 443.2084, found 443.2083. Anal. Calcd for
C19H40O4SSi2: C, 54.24; H, 9.58. Found: C, 54.07; H, 9.81.
2-Propyl 6-O-Acetyl-3,4-epithio-α-D-galactopyranoside
(13). To a solution of 127 (0.25 g, 1.01 mmol) in MeCN (9 mL)
was added KSCN (345 mg, 3.55 mmol), and the pH was maintained
alkaline (8−9) with Et3N. After the addition of 18-crown-6 (62.5 mg,
0.24 mmol) the solution was stirred at 65 °C for 36 h, when TLC
(hexane/EtOAc, 1:1.5) showed the conversion of 12 (Rf 0.53) into a
less polar product (Rf 0.76). The solvent was evaporated, and the
residue was dissolved in CH2Cl2 (15 mL) and extracted with H2O (2
× 15 mL). The organic layer was dried (MgSO4) and concentrated.
The residue was purified by column chromatography (hexane/EtOAc,
6:1→2:1) to afford 13 (180 mg, 68%): [α]25 +29.5 (c 0.8, CHCl3);
D
1H NMR (CDCl3, 500 MHz) δ 4.89 (d, 1H, J1,2 = 4.9 Hz, H-1), 4.60
(m, 1H, J4,5 = 2.6, J5,6a = 4.5, J5,6b = 7.4 Hz, H-5), 4.27 (dd, 1H, J5,6a
=
4.5, J6a,6b = 11.4 Hz, H-6a), 4.13 (dd, 1H, J5,6b = 7.4, J6a,6b = 11.4 Hz, H-
6b), 4.09 (dd, 1H, J1,2 = 4.9, J2,OH = 9.6 Hz, H-2), 3.97 (m, 1H, J = 6.2
Hz, Me2CHO), 3.17 (dd, 1H, J3,4 = 6.8, J4,5 = 2.6 Hz, H-4), 3.14 (d,
1H, J3,4 = 6.8 Hz, H-3), 2.84 (d, 1H, J2,OH = 9.6 Hz, HO), 2.10 (s, 3H,
260
dx.doi.org/10.1021/jo2018685 | J. Org. Chem. 2012, 77, 253−265

The Journal of Organic Chemistry
Article
column was identified as thiodisaccharide 17 (3.5 mg, 6%): [α]25
2-Propyl 2,6-Di-O-acetyl-3-S-acetyl-4-S-(2,3,4,6-tetra-O-ace-
tyl-β-D-glucopyranosyl)-3,4-dithio-α-D-glucopyranoside (20)
and Its Conversion into 17. The reaction of thiirane 14 (100
mg, 0.32 mmol) and the sodium thiolate 16b (175 mg, 0.49 mmol) in
THF (2 mL) was conducted in the presence of 18-crown-6 (20 mg
total), as previously described. The crude mixture of 17−19 obtained
upon evaporation of the solvent was dissolved in dry THF (22 mL)
and cooled to 0 °C. To this stirred solution was added LiAlH4 (160
mg, 4.20 mmol) in portions during 1 h. The solution was allowed to
reach rt, and the stirring was continued for 6 h. The excess of reducing
agent was destroyed by addition, at 0 °C, of EtOAc (10 mL) followed
by MeOH (10 mL). Finally, the mixture was neutralized with AcOH,
and the solvents were evaporated. The dry residue was treated with
pyridine (4 mL) and Ac2O (4 mL) for 12 h, when TLC (toluene/
EtOAc, 1:1) showed two main spots of Rf 0.65 and 0.55. The mixture
was concentrated and the residue extracted with CH2Cl2 (2 × 20 mL).
The organic layer was washed with H2O (2 × 20 mL), dried (MgSO4),
filtered, and concentrated. The residue was subjected to column
chromatography (hexane/EtOAc, 9:1→2:1).
D
+38.4 (c 0.8, CHCl3); 1H NMR (CDCl3, 500 MHz) δ 5.21 (t, 1H, J2′,3′
= J3′,4′ = 9.6 Hz, H-3′), 5.09 (d, 1H, J1,2 = 3.4 Hz, H-1), 5.08 (t, 1H, J3′,4′
= J4′, 5′ = 9.6 Hz, H-4′), 4.99 (dd, 1H, J1′,2′ = 10.2, J2′,3′ = 9.3 Hz, H-2′),
4.75 (dd, 1H, J1,2 = 3.4, J2,3 = 11.5 Hz, H-2), 4.65 (d, 1H, J1′,2′ = 10.2
Hz, H-1′), 4.48 (dd, 1H, J5,6a = 2.3, J6a,6b = 12.0 Hz, H-6a), 4.45 (dd,
1H, J5,6b = 3.8, J6a,6b = 12.0 Hz, H-6b), 4.16 (m, 2H, H-6′a, 6′b), 4.10
(ddd, J4,5 = 11.5, J5,6a = 2.3, J5,6b = 3.8 Hz, H-5), 3.87 (m, 1H, J = 6.2
Hz, Me2CHO), 3.67 (ddd, 1H, J4′,5′ = 9.6, J5′,6′a = 3.0, J5′,6′b = 4.8 Hz, H-
5′), 3.99 (dt, 1H, J2,3 = J3,4 = 11.5, J3,HS = 3.9 Hz, H-3), 2.91 (t, 1H, J3,4
= J4,5 = 11.5 Hz, H-4), 2.32 (d, 1H, J3,HS = 3.9 Hz, HS), 2.14, 2.11,
2.10, 2.09, 2.04, 2.01 (6s, 18H, CH3CO), 1.23, 1.12 (2d, each 3H, J =
6.2 Hz, (CH3)2CHO); 13C NMR (CDCl3, 125.7 MHz) δ 170.5−169.2
(CH3CO), 93.8 (C-1), 82.3 (C-1′), 75.8, 74.8, 73.7, 71.0, 69.9, 69.6,
68.1 (C2, 5, 2′, 3′, 4′, 5′, Me2CHO), 63.9 (C-6), 62.1 (C-6′), 50.2 (C-
4), 40.2 (C-3), 23.2, 21.6 [(CH3)2CHO], 20.8−20.6 (CH3CO);
HRMS (ESI) m/z [M + Na]+ calcd for C27H40NaO15S2 691.1701,
found 691.1717.
The first compound isolated was the byproduct 2,3,4,6-tetra-O-
acetyl-1-S-acetyl-1-thio-β-D-glucopyranose (21, 66 mg) which showed
properties identical to those described in the literature.30 From
following fractions from the column was obtained compound 20 (142
mg, 61%): [α]25D +16.2 (c 0.8, CHCl3); 1H NMR (CDCl3, 500 MHz)
Further fractions from the column afforded 18 (54 mg, 48%):
[α]25D −15.9 (c 1.1, CHCl3); 1H NMR (CDCl3, 500 MHz) δ 5.23 (t,
1H, J2″,3″ = J3″,4″ = 9.7 Hz, H-3″), 5.21 (t, 1H, J2′,3′ = J3′,4′ = 9.6 Hz, H-3′),
5.14 (t, 1H, J3′, 4′ = J4′, 5′ = 9.6 Hz, H-4′), 5.09 (d, 1H, J1,2 = 3.7 Hz, H-
δ 5.20 (t, 1H, J2′,3′ = J3′,4′ = 9.4 Hz, H-3′), 5.08 (t, 1H, J3′,4′ = J4′, 5′ = 9.4
Hz, H-4′), 5.07 (d, 1H, J1,2 = 3.7 Hz, H-1), 4.95 (dd, 1H, J1′,2′ = 10.0,
J2′,3′ = 9.4 Hz, H-2′), 4.92 (dd, 1H, J1,2 = 3.7, J2,3 = 11.3 Hz, H-2), 4.69
(d, 1H, J1′,2′ = 10.0 Hz, H-1′), 4.50 (dd, 1H, J5,6a = 2.1, J6a,6b = 12.0 Hz,
H-6a), 4.44 (dd, 1H, J5,6b = 4.1, J6a,6b = 12.0 Hz, H-6b), 4.26 (ddd, J4,5
1), 5.08 (t, 1H, J3″, 4″ = J4″, 5″ = 9.7 Hz, H-4″), 5.02 (t, 1H, J1′,2′ = J2′,3′
=
9.6 Hz, H-2′), 4.96 (dd, 1H, J1″,2″ = 10.2, J2″,3″ = 9.7 Hz, H-2″), 4.90 (dd,
1H, J1,2 = 3.7, J2,3 = 10.3 Hz, H-2), 4.63 (d, 1H, J1″,2″ = 10.2 Hz, H-1″),
4.61 (dd, 1H, J5,6a = 1.8, J6a,6b = 11.8 Hz, H-6a), 4.51 (d, 1H, J1′,2′ = 9.6
Hz, H-1′), 4.44 (dd, 1H, J5,6b = 5.3, J6a,6b = 11.8 Hz, H-6b), 4.39 (dd,
= 11.1, J5,6a = 2.1, J5,6b = 4.0 Hz, H-5), 4.23 (dd, 1H, J5′,6′a = 4.4, J6′a,6′b
=
1H, J5′,6′a = 4.2, J6′a,6′b = 12.5 Hz, H-6′a), 4.24 (ddd, J4,5 = 10.6, J5,6a
=
12.5 Hz, H-6′a), 4.17 (dd, 1H, J5′,6′b = 2.5, J6′a,6′b = 12.5 Hz, H-6′b), 3.99
(dd, 1H, J2,3 = 11.3, J3,4 = 12.0 Hz, H-3), 3.87 (m, 1H, J = 6.2 Hz,
Me2CHO), 3.71 (ddd, 1H, J4′,5′ = 9.4, J5′,6′a = 4.4, J5′,6′b = 2.5 Hz, H-5′),
1.8, J5,6b = 5.3 Hz, H-5), 4.20 (dd, 1H, J5″,6″a = 4.8, J6″a,6″b = 12.5 Hz, H-
6″a), 4.13 (dd, 2H, J5′,6′b = J5′,6′b = 2.4, J6′a,6′b = J6″a,6″b = 12.5 Hz, H-6′b,
H-6″b), 3.89 (m, 1H, J = 6.2 Hz, Me2CHO), 3.71 (ddd, 1H, J4′,5′ = 9.6,
3.12 (dd, 1H, J3,4 = 12.0, J4,5 = 11.1 Hz, H-4), 2.34 (s, 3H, CH3COS),
2.11, 2.10, 2.05, 2.03 (×2), 1.99 (5s, 18H, CH3CO), 1.25, 1.13 (2d,
each 3H, J = 6.2 Hz, (CH3)2CHO); 13C NMR (CDCl3, 125.7 MHz) δ
193.8 (CH3COS) 170.6, 170.5, 170.1, 170.0, 169.3, 169.2 (CH3CO),
94.1 (C-1), 81.7 (C-1′), 75.6 (C-5′), 73.9 (C-3′), 71.1 (Me2CHO),
71.0 (C-5), 70.2 (C-2), 70.0 (C-2′), 68.0 (C-4′), 64.2 (C-6), 61.8 (C-
6′), 45.9 (C-4), 44.4 (C-3), 30.6 (CH3COS), 23.1, 21.6
[(CH3)2CHO], 20.8−20.6 (CH3CO). Anal. Calcd for C29H42O16S2:
C, 49.01; H, 5.96. Found: C, 49.15; H, 5.74.
J
5′,6′a = 4.2, J5′,6′b = 2.4 Hz, H-5′), 3.65 (ddd, 1H, J4″,5″ = 9.7, J5″,6″a = 4.8,
J5″,6″b = 2.4 Hz, H-5″), 3.27 (dd, 1H, J3,4 =11.3, J4,5 = 10.6 Hz, H-4),
3.20 (dd, 1H, J2,3 = 10.4, J3,4 =11.3 Hz, H-3), 2.17, 2.11, 2.10, 2.09,
2.07 2.05, 2.04, 2.03, 2.02, 2.00 (10 s, 30H, CH3CO), 1.25, 1.15 (2d,
each 3H, J = 6.2 Hz, (CH3)2CHO); 13C NMR (CDCl3, 125.7 MHz) δ
193.7 (CH3COS) 170.6−169.2 (CH3CO), 94.2 (C-1), 89.5 (C-1′
observed by HMQC), 81.3 (C-1″), 76.5 (C-5′), 75.7 (C-5″), 74.0 (C-
3′), 73.6 (C-3″), 70.9 (C-2), 70.6 (Me2CHO), 69.9 (C-2″), 69.6 (C-2′),
69.0 (C-5), 68.0 (C-4″), 67.6 (C-4′), 64.1 (C-6), 62.0 (C-6″), 61.6 (C-
6′), 48.5 (C-3), 44.3 (C-4), 23.2, 21.6 [(CH3)2CHO], 20.8−20.7
(CH3CO); HRMS (ESI) m/z [M + Na]+ calcd for C41H58NaO24S3
1053.2372, found 1053.2340. Anal. Calcd for C41H58O24S3: C, 47.76;
H, 5.67. Found: C, 48.02; H, 5.60.
Compound 20 (76 mg, 0.11 mmol) was S-deacetylated by stirring
with 2-aminoethanethiol (10 mg, 0.13 mmol) in MeCN (0.3 mL) at
65 °C for 1 h. Analysis by TLC (toluene/EtOAc, 1:1) showed the
complete conversion of 20 (Rf 0.52) into the less polar product 17 (Rf
0.60). The mixture was concentrated, the residue dissolved in CH2Cl2
(20 mL) and washed in water (2 × 15 mL). The organic phase was
dried (MgSO4), filtered, and concentrated. The resulting syrup was
purified by column chromatography (hexane/EtOAc, 4:1→2.3:1) to
afford 17 (47 mg, 66%). This product showed properties identical to
those of the one obtained from the reaction between 14 and 16b.
2-Propyl 2,6-Di-O-acetyl-3-S-acetyl-4-S-(2,3,4,6-tetra-O-ace-
tyl-β-D-galactopyranosyl)-3,4-dithio-α-D-glucopyranoside
(23). Tetra-O-acetyl-1-thio-β-D-galactopyranose 22a50 (175 mg, 0.49
mmol) was converted into the sodium salt 22b, as previously described
for 16a. The reaction of 22b with the episulfide 14 (100 mg, 0.32
mmol) was performed under the conditions employed for the
analogous reaction with 16b. The crude mixture obtained was
dissolved in dry THF (22 mL) and treated with LiAlH4 (160 mg,
4.19 mmol) as described for the preparation of 17. After the same
workup and acetylation, the mixture showed by TLC (toluene/EtOAc,
1:1) two main spots of Rf 0.67 and 0.51. Purification by column
chromatography (hexane/EtOAc, 4:1 → 1.5:1) afforded first 2,3,4,6-
tetra-O-acetyl-1-S-acetyl-1-thio-β-D-galactopyranose 24, which showed
the same properties as the product already reported.31
Finally, it was isolated the symmetric disulfide 19 (8 mg, 6%):
1
[α]25 +17.2 (c 1.0, CHCl3); H NMR (CDCl3, 500 MHz) δ 5.23 (t,
D
1H, J2′,3′ = J3′,4′ = 9.3 Hz, H-3′), 5.08 (d, 1H, J1,2 = 3.4 Hz, H-1), 5.08
(dd, 1H, J3′,4′ = 9.3, J4′, 5′ = 10.0 Hz, H-4′), 4.97 (dd, 1H, J1′,2′ = 10.1, J2′,3′
= 9.3 Hz, H-2′), 4.88 (dd, 1H, J1,2 = 3.4, J2,3 = 11.4 Hz, H-2), 4.69 (d,
1H, J1′,2′ = 10.1 Hz, H-1′), 4.57 (dd, 1H, J5,6a = 1.9, J6a,6b = 11.9 Hz, H-
6a), 4.39 (dd, 1H, J5,6b = 5.4, J6a,6b = 11.9 Hz, H-6b), 4.21 (dd, 1H, J5′,6′a
= 4.6, J6′a,6′b = 12.4 Hz, H-6′a), 4.18 (ddd, J4,5 = 11.4, J5,6a = 1.9, J5,6b
=
5.4 Hz, H-5), 4.14 (dd, 1H, J5′,6′b = 2.5, J6′a,6′b = 12.4 Hz, H-6′b), 3.87
(m, 1H, J = 6.2 Hz, Me2CHO), 3.67 (ddd, 1H, J4′,5′ = 10.0, J5′,6′a = 4.6,
J5′,6′b = 2.5 Hz, H-5′), 3.20 (t, 1H, J2,3 = J3,4 = 11.4 Hz, H-3), 3.00 (t,
1H, J3,4 = J4,5 = 11.4 Hz, H-4), 2.16, 2.10 (×2), 2.09, 2.03, 2.00 (6 s,
18H, CH3CO), 1.25, 1.13 (2d, each 3H, J = 6.2 Hz, (CH3)2CHO);
13C NMR (CDCl3, 50,3 MHz) δ 170.5−169.2 (CH3CO), 94.0 (C-1),
82.2 (C-1′), 75.8, 73.8, 71.2, 70.9, 70.1, 69.8, 68.0 (C-2, 5, 2′, 3′, 4′, 5′,
Me2CHO), 64.3 (C-6), 61.9 (C-6′), 51.4 (C-4), 46.7 (C-3), 23.2, 21.6
[(CH3)2CHO], 20.9−20.6 (CH3CO); HRMS (ESI) m/z [M + Na]+
calcd for C54H78NaO30S4 1357.3353, found 1357.3308. Anal. Calcd for
C54H78O30S4: C, 48.57, H, 5.89. Found: C, 48.97, H, 5.86.
Further fractions of the column afforded 23 as a syrup (Rf 0.51, 160
mg, 70% for the three steps of reaction): [α]25D +15.7 (c 0.9, CHCl3);
1H NMR (CDCl3, 500 MHz) δ 5.43 (dd, 1H, J3′,4′ = 3.4, J4′, 5′= 1.0 Hz,
261
dx.doi.org/10.1021/jo2018685 | J. Org. Chem. 2012, 77, 253−265

The Journal of Organic Chemistry
Article
H-4′), 5.13 (t, 1H, J1′,2′ = J2′,3′ =10.0 Hz, H-2′), 5.07 (d, 1H, J1,2 = 3.6
Hz, H-1), 5.02 (dd, 1H, J2′,3′ = 10.0, J3′,4′ = 3.4 Hz, H-3′), 4.93 (dd, 1H,
H-4), 4.15 (dd, 1H, J5′,6′a = 6.7, J6′a,6′b = 11.3 Hz, H-6′a), 4.13 (dd, 1H,
J5′,6′b = 6.7, J6′a,6′b = 11.3 Hz, H-6′b), 4.01 (dd, 1H, J1,2 = 2.0, J2,3 = 3.9
Hz, H-2), 3.92 (ddd, 1H, J4′,5′ = 0.9, J5′,6′a = J5′,6′b = 6.7 Hz, H-5′), 3.32
J
1,2 = 3.6, J2,3 = 11.2 Hz, H-2), 4.68 (d, 1H, J1′,2′ = 10.0 Hz, H-1′), 4.50
(dd, 1H, J5,6a = 4.1, J6a,6b = 12.0 Hz, H-6a), 4.46 (dd, 1H, J5,6b = 2.4,
J6a,6b = 12.0 Hz, H-6b), 4.25 (ddd, J4,5 = 11.0, J5,6a = 4.1, J5,6b = 2.4 Hz,
H-5), 4.09 (dd, 1H, J5′,6′a = 6.7, J6′a,6′b = 11.2 Hz, H-6′a), 4.08 (dd, 1H,
(s, 3H, CH3O), 3.14 (dd, 1H, J5,6a = 5.5, J6a,6b = 12.5 Hz, H-6a), 3.04
(m, 1H, J4,5 = 1.8, J5,6a = 5.5, J5,6b = 8.3, J5,HS = 9.4 Hz, H-5), 3.00 (dd,
1H, J5,6b = 8.3, J6a,6b = 12.5 Hz, H-6b), 2.16, 2.07, 2.06, 1.98 (4s, 12H,
CH3CO), 1.92 (d, 1H, J5,HS = 9.4 Hz, HS), 0.90, 0.89 (2s, 18H,
(CH3)3CSiMe2), 0.11, 0.10, 0.09, 0.08 (4s, 12H, (CH3)2SiBut); 13C
NMR (CDCl3, 125.7 MHz) δ 170.2 (×2), 170.0, 169.5 (CH3CO),
109.0 (C-1), 84.3 (C-2), 83.7 (C-1′), 81.2 (C-4), 80.2 (C-3), 74.4 (C-
5′), 71.8 (C-3′), 67.2 (C-2′), 67.1 (C-4′), 61.2 (C-6′), 55.0 (CH3O),
41.7 (C-5), 36.7 (C-6), 25.8, 25.7 [(CH3)3CSiMe2], 21.4, 20.7, 20.6,
20.5 (CH3CO), 17.8 (×2) [(CH3)3CSiMe2], −4.1, −4.3, −4.6, −4.9
[(CH3)2SiBut]; HRMS (ESI) m/z [M + Na]+ calcd for
C33H60NaO13S2Si2 807.2906, found 807.2918. Anal. Calcd for
C33H60O13S2Si2: C, 50.48; H, 7.70. Found: C, 50.80; H, 7.46.
J
5′,6′b = 6.7, J6′a,6′b = 11.2 Hz, H-6′b), 3.99 (dd, 1H, J2,3 = 11.2, J3,4 = 12.1
Hz, H-3), 3.92 (ddd, 1H, J4′,5′ = 1.0, J5′,6′a = J5′,6′b = 6.7 Hz, H-5′), 3.87
(m, 1H, J = 6.2 Hz, Me2CHO), 3.12 (dd, 1H, J3,4 = 12.1, J4,5 = 11.0 Hz,
H-4), 2.33 (s, 3H, CH3COS), 2.16, 2.09, 2.05, 2.04, 2.03, 1.96 (6s,
18H, CH3CO), 1.26, 1.13 (2d, each 3H, J = 6.2 Hz, (CH3)2CHO);
13C NMR (CDCl3, 125.7 MHz) δ 193.7 (CH3COS) 170.5, 170.2,
170.1, 170.0, 169.9, 169.4, 169.3 (CH3CO), 94.0 (C-1), 82.2 (C-1′),
74.1 (C-5′), 71.8 (C-3′), 71.1 (C-2), 70.9 (Me2CHO), 70.1 (C-5), 67.1
(C-2′), 67.0 (C-4′), 64.2 (C-6), 61.1 (C-6′), 45.9 (C-4), 44.5 (C-3),
30.7 (CH3COS), 23.1, 21.5 [(CH3)2CHO], 20.8−20.5 (CH3CO);
HRMS (ESI) m/z [M + Na]+ calcd for C29H42NaO16S2 733.1807,
found 733.1806.
From the next fractions of the column was obtained the symmetric
1
disulfide 28 (20 mg, 11%): [α]25 +12.3 (c 1.0, CHCl3); H NMR
D
(CDCl3, 500 MHz) δ 5.45 (dd, 1H, J3′,4′ = 3.4, J4′,5′ = 1.0 Hz, H-4′),
2-Propyl 2,6-Di-O-acetyl-4-S-(2,3,4,6-tetra-O-acetyl-β-D-gal-
actopyranosyl)-3,4-dithio-α-D-glucopyranoside (25). A solution
of 23 (60 mg, 0.08 mmol) in MeCN (0.25 mL) was treated with 2-
aminoethanethiol (8 mg, 0.10 mmol). The reaction was stirred at 65
°C for 1 h, until TLC (toluene/EtOAc, 1:1) showed the complete
conversion of the initial compound (Rf 0.51) into 25 (Rf 0.48). The
reaction mixture was concentrated and extracted with CH2Cl2/H2O.
The organic phase was dried with MgSO4 and purified by column in
5.20 (t, 1H, J1′,2′ = J2′,3′ = 10.0 Hz, H-2′), 5.07 (dd, 1H, J2′,3′ = 10.0, J3′,4′
= 3,4 Hz, H-3′), 4.65 (d, 1H, J1,2 = 1.6 Hz, H-1), 4.58 (d, 1H, J1′,2′
=
10.0 Hz, H-1′), 4.30 (dd, 1H, J3,4 = 6.7, J4,5 = 2.3 Hz, H-4), 4.17 (m,
2H, H-6′a, H-6′b), 4.16 (dd, 1H, J2,3 = 3.5, J3,4 = 6.8 Hz, H-3), 3.99 (m,
1H, H-5′), 3.98 (dd, 1H, J1,2 = 1.6, J2,3 = 3.5 Hz, H-2), 3.32 (s, 3H,
CH3O), 3.21−3.09 (m, 3H, H-5, H-6a, H-6b), 2.16, 2.07, 2.04, 1.98
(4s, 12H, CH3CO), 0.90, 0.89 (2s, 18H, (CH3)3CSiMe2), 0.12 (×2),
0.09, 0.08 (4s, 12H, (CH3)2SiBut); 13C NMR (CDCl3, 125.7 MHz) δ
170.3, 170.2, 170.0, 169.5 (CH3CO), 109.0 (C-1), 84.5 (C-1′), 84.1
(C-2), 82.1 (C-4), 80.0 (C-3), 74.3 (C-5′), 71.8 (C-3′), 67.6 (C-2′),
67.1 (C-4′), 61.0 (C-6′), 55.1 (CH3O), 54.0 (C-5), 32.6 (C-6), 25.8
(×2)[(CH3)3CSiMe2], 20.8, 20.7 (×2), 20.6 (CH3CO), 17.9, 17.8
[(CH3)3CSiMe2], −4.0, −4.2, −4.5, −4.9 [(CH3)2SiBut]; HRMS
(ESI) m/z [M + Na]+ calcd for C66H118NaO26S4Si4 1589.5763, found
1589.5712. Anal. Calcd for C66H118O26S4Si4: C, 50.55; H, 7.58. Found:
C, 50.52; H, 7.57.
silica gel (hexane/EtOAc, 4:1→2.3:1) to give 25 (40 mg, 71%): [α]25
D
1
+40.5 (c 1.0, CHCl3); H NMR (CDCl3, 500 MHz) δ 5.43 (dd, 1H,
J3′,4′ = 3.4, J4′, 5′ = 1.0 Hz, H-4′), 5.17 (t, 1H, J1′,2′ = J2′,3′ =10.0 Hz, H-2′),
5.09 (d, 1H, J1,2 = 3.5 Hz, H-1), 5.04 (dd, 1H, J2′,3′ = 10.0, J3′,4′ = 3.4
Hz, H-3′), 4.76 (dd, 1H, J1,2 = 3.5, J2,3 = 10.9 Hz, H-2), 4.61 (d, 1H,
J1′,2′ = 10.0 Hz, H-1′), 4.49 (dd, 1H, J5,6a = 4.0, J6a,6b = 12.0 Hz, H-6a),
4.45 (dd, 1H, J5,6b = 2.3, J6a,6b = 12.0 Hz, H-6b), 4.12 (dd, 1H, J5′,6′a
=
7.0, J6′a,6′b = 11.4 Hz, H-6′a), 4.10 (ddd, J4,5 = 11.3, J5,6a = 4.0, J5,6b = 2.3
Hz, H-5), 4.08 (dd, 1H, J5′,6′b = 6.2, J6′a,6′b = 11.4 Hz, H-6′b), 3.89 (ddd,
1H, J4′,5′ = 1.0, J5′,6′a = 7.0, J5′,6′b = 6.2 Hz, H-5′), 3.87 (m, 1H, J = 6.2
The last component of the mixture isolated from the column was
1
the disulfide 27 (30 mg, 21%): [α]25 −0.6 (c 1.0, (CH3)2CO); H
D
NMR [(CD3)2CO, 500 MHz] δ 5.47, 5.45 (2dd, 2H, H-4′, H-4″),
5.28−5.16 (m, 4H, H-2′, H-2″, H-3′, H-3″), 4.91 (d, 1H, J1′,2′ = 9.9 Hz,
Hz, Me2CHO), 3.51 (td, 1H, J2,3 = 10.9, J3,4 = 11.3, J3,SH = 3.8 Hz, H-
3), 2.89 (t, 1H, J3,4 = J4,5 = 11.3 Hz, H-4), 2.32 (d, 1H, J3,SH = 3.8 Hz,
SH), 2.18, 2.14, 2.11 (x2), 2.05, 1.99 (5s, 18H, CH3CO), 1.24, 1.13
(2d, each 3H, J = 6.2 Hz, (CH3)2CHO); 13C NMR (CDCl3, 125.7
MHz) δ 170.2, 170.0, 169.9, 169.4 (CH3CO), 93.7 (C-1), 82.8 (C-1′),
74.8 (C-2), 74.4 (C-5′), 71.8 (C-3′), 70.9 (Me2CHO), 69.6 (C-5), 67.0
(C-2′), 66.9 (C-4′), 63.9 (C-6), 61.5 (C-6′), 50.3 (C-4), 40.2 (C-3),
23.1, 21.6 [(CH3)2CHO], 20.8−20.6 (CH3CO); HRMS (ESI) m/z
[M + Na]+ calcd for C27H40NaO15S2 691.1701, found 691.1719.
Methyl 6-S-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyl)-
2,3-di-O-tert-butyldimethylsilyl-5,6-dithio-β-D-galactofurano-
side (26), Methyl 6-S-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyra-
nosyl)-5-S-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)-
disulfide-2,3-di-O-tert-butyldimethylsilyl-5,6-dithio-β-D-galac-
tofuranoside (27), and Bis[methyl 2,3-Di-O-tert-
butyldimethylsilyl-6-S-(2,3,4,6-tetra-O-acetyl-β-D-galactopyra-
nosyl)-5,6-dithio-β-D-galactofuranos-5-S-yl]disulfide (28). The
sodium salt of 2,3,4,6-tetra-O-acetyl-1-thio-β-D-galactopyranose (22b),
prepared as described from 22a50 (90 mg, 0.25 mmol), was dissolved
in THF (1 mL) and added to a solution of the episulfide 8 (52 mg,
0.12 mmol) in dry THF (2 mL) cooled at 0 °C. After 10 min, 18-
crown-6 (26 mg, 0.10 mmol) was added, and the stirring was
continued for 1 h, when TLC (toluene/EtOAc, 2:1) showed three
main spots of Rf 0.72, 0.54, and 0.44. This mixture was fractionated by
column chromatography (toluene/EtOAc, 7:1→EtOAc) which
H-1′), 4.87 (d, 1H, J1″,2″ = 9.7 Hz, H-1″), 4.72 (d, 1H, J1,2 = 1.2 Hz, H-
1), 4.43 (d, 2H, H-6″a, H-6″b), 4.42 (dd, 1H, J3,4 = 6.8, J4,5 ∼ 3.0 Hz,
H-4), 4.36 (ddd, 1H, J4′,5′ = 1.2, J5′,6′a ∼ J5′,6′b ∼ 6.6 Hz, H-5′), 4.28 (dd,
1H, J2,3 = 3.0, J3,4 = 6.8 Hz, H-3), 4.25−4.16 (m, 3H, H-5″, H-6′a, H-
6′b), 4.07 (dd, 1H, J1,2 = 1.2, J2,3 = 3.0 Hz, H-2), 3.54 (dd, 1H, H-6a),
3.36 (s, 3H, CH3O), 3.35 (m, 1H, H-5), 3.18 (dd, 1H, J5,6b = 8.7, J6a,6b
= 13.4 Hz, H-6b), 2.17, 2.16, 2.07 (×2), 2.05, 2.03, 1.94 (×2) (8s,
24H, CH3CO), 0.96, 0.95 (2s, 18H, (CH3)3CSiMe2), 0.22, 0.20, 0.16,
0.15 (4s, 12H, (CH3)2SiBut); 13C NMR [(CD3)2CO, 125.7 MHz] δ
170.8 (×2), 170.6, 170.5, 170.1 (×2), 170.0, 169.8 (CH3CO), 109.7
(C-1), 91.4 (C-1′), 85.5 (C-2), 84.6 (C-1″), 83.2 (C-4), 81.6 (C-3),
75.6 (C-5′), 75.1 (C-5″), 72.5, 72.4 (C-3′, 3″), 68.4, 68.3, 68.2 (×2) (C-
2′, 2″, 4′, 4″), 62.2, 62.0, (C-6′, 6″), 55.5, 55.2 (C-5, CH3O), 33.4 (C-6),
26.3 ( × 3) [(CH3)3CSiMe2], 20.8 ( × 3), 20.7 (×2), 20.6, 20.5 (×2)
(CH3CO), 18.5 (×2) [(CH3)3CSiMe2], −3.7, −3.8, −4.2, −4.6
[(CH3)2SiBut]; HRMS (ESI) m/z [M + Na]+ calcd for
C47H78NaO22S3Si2 1169.3578, found 1169.3538. Anal. Calcd for
C47H78O22S3Si2·5H2O: C, 45.61; H, 7.17. Found: C, 45.42; H, 6.49.
Alternatively, the thiodisaccharide 26 was obtained under optimized
conditions and in the presence of dihiothreitol (DTT) as follows. The
salt 22b, prepared from 22a (142 mg, 0.39 mmol), was dissolved in
THF (2 mL) and added to a cold solution (0 °C) of the episulfide 8
(82 mg, 0.19 mmol) and DTT (32 mg, 0.21 mmol) in dry THF (4
mL). After 10 min, 18-crown-6 (20 mg, 0.08 mmol) was added and
the stirring was continued for 30 min, when an additional amount of
18-crown-6 (20 mg, 0.08 mmol) was added. After 30 min of stirring,
TLC (toluene/EtOAc, 2:1) showed a main spot of Rf 0.72. Purification
by column chromatography as above afforded the thiodisaccharide 26
(146 mg, 98%).
afforded first the less polar product, the thiodisaccharide 26 (7 mg,
1
5%): [α]25 −37.8 (c 0.9, CHCl3); H NMR (CDCl3, 500 MHz) δ
D
5.43 (dd, 1H, J4′,5′ = 0.9, J3′,4′ = 3.3 Hz, H-4′), 5.24 (t, 1H, J1′,2′ = J2′,3′
=
10.0 Hz, H-2′), 5.02 (dd, 1H, J3′,4′ = 3.3, J2′,3′ = 10.0 Hz, H-3′), 4.66 (d,
1H, J1,2 = 2.0 Hz, H-1), 4.55(d, 1H, J1′,2′ = 10.0 Hz, H-1′), 4.21 (dd,
1H, J2,3 = 3.9, J3,4 = 7.4 Hz, H-3), 4.18 (dd, 1H, J4,5 = 1.8, J3,4 = 7.4 Hz,
262
dx.doi.org/10.1021/jo2018685 | J. Org. Chem. 2012, 77, 253−265

The Journal of Organic Chemistry
Article
nosyl)-3,4-dithio-α-D-glucopyranoside (34). The reaction be-
tween 25 (30 mg, 0.045 mmol) and 3340 (84 mg, 0.11 mmol),
under catalysis with TMSOTf (2 μL) in CH2Cl2 (1.5 mL), was
performed in the same conditions described above for the synthesis of
31. When analysis by TLC (CH2Cl2/EtOAc, 3:1) showed complete
conversion of the starting 25 and 33 (Rf 0.27 and 0.64) into two
products of Rf 0.54 y 0.19, the mixture was processed and subjected to
column chromatography as for the previous reaction. The first
compound isolated from the column (Rf 0.54) was the N-
glycosyltrichloroacetamide 3541 (50 mg).
Methyl 6-S-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyl)-
2,3-di-O-tert-butyldimethylsilyl-5,6-dithio-α-L-altrofuranoside
(29). The optimized procedure described for the opening of episulfide
8 was applied to the thiirane 11 (100 mg, 0.24 mmol). However, in
this case the total reaction time was 2.5 h. Examination of the reaction
mixture by TLC (toluene) showed a main spots of Rf 0.67. Purification
by column chromatography (toluene/EtOAc, 7:1→EtOAc) afforded
the thiodisaccharide 29 (163 mg, 87%): [α]25D −29.5 (c 0.9, CHCl3);
1H NMR (CDCl3, 500 MHz) δ 5.43 (dd, 1H, J3′,4′ = 3.4, J4′,5′ = 0.9 Hz,
H-4′), 5.23 (t, 1H, J1′,2′ = J2′,3′ = 10.0 Hz, H-2′), 5.04 (dd, 1H, J2′,3′
=
Further fractions of the column afforded the starting compound 25
(5 mg), and then the product with Rf 0.19, which was UV active, was
obtained. This compound was identified as 34 (38 mg, 66%, corrected
yield 81%): [α]25D +0.3 (c 1.0, CHCl3); 1H NMR (CDCl3, 500 MHz)
δ 8.10−7.15 (m, 20H, H-aromatic), 6.09 (m, J4′,5′ = 4.5, J5′,6′a = 3.5, J5′,6′b
= 7.7 Hz, H-5′), 5.85 (s, 1H, H-1′), 5.66 (d, 1H, J3′, 4′ = 4.5 Hz, H-3′),
5.42 (s, 1H, H-2′), 5.32 (dd, 1H, J3″,4″ = 3.4, J4″,5″ = 0.7 Hz, H-4″), 5.14
(t, 1H, J1″, 2″ = J2″, 3″ = 10.0 Hz, H-2″), 4.97 (d, 1H, J1,2 = 4.5 Hz, H-1),
4.96 (dd, 1H, J2″,3″ = 10.0, J3″, 4″ = 3.4 Hz, H-3″), 4.89 (dd, 1H, J1,2 =4.5,
10.0, J3′,4′ = 3.4 Hz, H-3′), 4.74 (s, 1H, H-1), 4.59 (d, 1H, J1′,2′ = 10.0
Hz, H-1′), 4.14 (d, 2H, H-6a, H-6b), 4.12 (dd, 1H, J2,3 = 1.2, J3,4 = 3.4
Hz, H-3), 3.98−3.92 (m, 3H, H-2, H-4, H-5′), 3.32 (s, 3H, CH3O),
3.24 (dd, 1H, J5,6a = 4.0, J6a,6b = 13.4 Hz, H-6a), 3.19 (dddd, 1H, J4,5
∼
J5,6a = 4.0, J5,6b = 7.5 Hz, H-5), 2.97 (dd, 1H, J5,6b = 7.5, J6a,6b = 13.4 Hz,
H-6b), 2.16, 2.08, 2.04, 1.99 (4s, 12H, CH3CO), 0.89, 0.88 (2s, 18H,
(CH3)3CSiMe2), 0.12 (×2), 0.10, 0.09 (4s, 12H, (CH3)2SiBut); 13C
NMR (CDCl3, 125.7 MHz) δ 170.3, 170.2, 170.0, 169.5 (CH3CO),
110.2 (C-1), 89.0(C-4), 85.0 (C-1′), 82.4 (C-2), 80.7 (C-3), 74.4 (C-
5′), 71.9 (C-3′), 67.6 (C-2′), 67.1 (C-4′), 61.2 (C-6′), 54.7 (CH3O),
43.0 (C-5), 36.6 (C-6), 25.7 (×2) [(CH3)3CSiMe2], 20.8, 20.6 ( × 3)
(CH3CO), 17.8 (×2) [(CH3)3CSiMe2], −4.3, −4.4, −4.7, −4.8
[(CH3)2SiBut]; HRMS (ESI) m/z [M + Na]+ calcd for
C33H60NaO13S2Si2 807.2906, found 807.2916. Anal. Calcd for
C33H60O13S2Si2: C, 50.48; H, 7.70. Found: C, 50.81; H, 7.81.
J
2,3 = 11.0 Hz, H-2), 4.88 (t, 1H, J3′,4′ = J4′,5′ = 4.5 Hz, H-4′), 4.80 (dd,
1H, J5′,6′a = 3.2, J6′a,6′b = 12.1 Hz, H-6′a), 4.76 (d, 1H, J1″,2″ = 10.0 Hz, H-
1″), 4.68 (dd, 1H, J5′,6′b = 8.0, J6′a,6′b = 12.1 Hz, H-6′b), 4.45 (dd, 1H,
J
5,6a = 2.1, J6a,6b = 11.9 Hz, H-6a), 4.40 (dd, 1H, J5,6b = 4.1, J6a,6b = 11.9
Hz, H-6b), 4.18 (ddd, 1H, J4,5 = 11.0, J5,6a = 2.1, J5,6b = 4.1 Hz, H-5),
2-Propyl 2,6-Di-O-acetyl-3,4-di-S-(2,3,4,6-tetra-O-acetyl-β-D-
glucopyranosyl)-3,4-dithio-α-D-glucopyranoside (31). A sus-
pension of 17 (44 mg, 0.07 mmol), the trichloroacetimidate 3038
(65 mg, 0.13 mmol), and freshly activated powdered molecular sieves
(4 Å) in CH2Cl2 (1.5 mL) was stirred at room temperature for 1.5 h.
The mixture was cooled to −18 °C, and TMSOTf (3 μL, 0.02 mmol)
was added. Monitoring by TLC (CH2Cl2/EtOAc, 3:1) showed gradual
conversion of the starting compounds 17 (Rf 0.63) and 30 (Rf 0.73)
into other two more polar products (Rf 0.40 and 0.28). After 4 h, Et3N
(5 μL, 0.03 mmol) was added and the mixture was concentrated. The
residue was subjected to column chromatography using CH2Cl2/
EtOAc, 9:1→4:1 as solvent. The first fractions of the column afforded
unreacted 17 (18 mg), and from the next fractions was isolated 2,3,4,6-
tetra-O-acetyl-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-1-β-D-gluco-
pyranoside (32, 23 mg), which showed spectroscopic and physical data
in agreement with those described in the literature.39
4.02 (dd, 1H, J5″,6″a = 6.4, J6″a,6″b = 11.3 Hz, H-6″a), 3.93 (dd, 1H, J5″,6″b
= 7.2, J6″a,6″b = 11.3 Hz, H-6″b), 3.80 (ddd, J4″,5″ = 0.7, J5″,6″a = 6.4, J5″,6″b
= 7.2 Hz, H-5″), 3.77 (m, 1H, J = 6.2 Hz, Me2CHO), 3.36 (dd, 1H, J2,3
= 11.0, J3,4 = 11.4 Hz, H-3), 3.03 (dd, 1H, J3,4 =11.4, J4,5 = 11.0 Hz, H-
4), 2.01, 1.97, 1.95, 1.91, 1.87, 1.86 (6s, 18H, CH3CO), 1.16, 1.03 (2d,
3H each, J = 6.2 Hz, (CH3)2CHO); 13C NMR (CDCl3, 125.7 MHz) δ
170.2−169.5 (CH3CO), 166.1−165.3 (PhCO), 133.7−128.2 (C-
aromatic), 93.8 (C-1), 88.5 (C-1′), 82.7 (C-2′), 82.1 (C-1″), 82.0
(C-4′), 77.8 (C-3′), 74.0 (C-5′), 73.9 (C-2), 71.9 (C-3″), 71.0
(Me2CHO), 70.5 (C-5), 70.2 (C-5″), 67.2 (C-2″), 66.9 (C-4″), 64.2
(C-6), 61.4 (C-6′), 61.0 (C-6″), 45.3 (C-4), 44.7 (C-3), 23.1, 21.6
[(CH3)2CHO], 20.9−20.5 (CH3CO); HRMS (ESI) m/z [M + Na]+
calcd for C61H66NaO24S2 1269.3278, found 1269.3246.
Methyl 6-S-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyl)-5-
S-(2,3,5,6-tetra-O-benzoyl-β-D-galactofuranosyl)-2,3-di-O-tert-
butyldimethylsilyl-5,6-dithio-β-D-galactofuranoside (36). The
reaction of the trichloroacetimidate 3340 (195 mg, 0.26 mmol) with
the thiodisaccharide 26 (82 mg, 0.10 mmol) was performed as in the
two previous reactions, using catalysis with TMSOTf (12 μL, 0.07
mmol). After 2 h TLC (hexane/EtOAc, 2:1), showed the formation of
a main spot of Rf 0.24. The usual workup and purification by column
chromatography (hexane/EtOAc, 5:1→2:1) gave the branched
The more polar product obtained from the column was identified as
1
31 (16 mg, 35%, corrected): [α]25 +28.3 (c 0.9, CHCl3); H NMR
D
(CDCl3, 500 MHz) δ 5.14 (t, 1H, J2′,3′ = J3′,4′ = 9.4 Hz, H-3′), 5.14 (t,
1H, J2″,3″ = J3″,4″ = 9.4 Hz, H-3″), 5.04 (d, 1H, J1,2 = 3.5 Hz, H-1), 4.99
(t, 2H, J3′,4′ = J4′,5′ = J3″,4″ = J4″,5″ = 9.4 Hz, H-4′, 4″), 4.90 (dd, 1H, J1′,2′
=
10.2, J2′,3′ = 9.4 Hz, H-2′), 4.84 (dd, 1H, J1″, 2″ = 10.2, J2″,3″ = 9.4 Hz, H-
dithiotrisaccharide 36 (55 mg, 40%): [α]25 −36.8 (c 1, CHCl3);
D
2″), 4.74 (dd, 1H, J1,2 = 3.5, J2,3 = 11.4 Hz, H-2), 4.69 (d, 1H, J1″,2″
10.2 Hz, H-1″), 4.64 (d, 1H, J1′,2′ = 10.2 Hz, H-1′), 4.49 (dd, 1H, J5,6a
=
=
1H NMR (CDCl3, 500 MHz) δ 8.09−7.28 (H-aromatic), 6.10 (dddd,
1H, J5′,6′a = 3.6, J4′,5′ = 4.6, J5′,6′b = 7.3 Hz, H-5′), 5.95 (br s, 1H, H-1′),
5.73 (d, 1H, J3′,4′ = 4.7 Hz, H-3′), 5.58 (br s, 1H, H-2′), 5.39 (d, 1H,
J3″,4″ = 3.4 Hz, H-4″), 5.22 (t, 1H, J1″,2″ = J2″,3″ = 10.0 Hz, H-2″), 5.07
(dd, 1H, J3″,4″ = 3.4, J2″,3″ = 10.0 Hz, H-3″), 4.86 (t, 1H, J3′,4′ = J4′,5′ = 4.6
Hz, H-4′), 4.82 (dd, 1H, J5′,6′a = 3.6, J6′a,6′b = 12.1 Hz, H-6′a), 4.73 (dd,
1H, J5′,6′b = 7.3, J6′a,6′b = 12.1 Hz, H-6′b), 4.68 (d, 1H, J1,2 = 1.8 Hz, H-
4.3, J6a,6b = 12.0 Hz, H-6a), 4.42 (dd, 1H, J5,6b = 2.0, J6a,6b = 12.0 Hz, H-
6b), 4.23 (dd, 1H, J5″,6″a = 4.5, J6″a,6″b = 12.5 Hz, H-6″a), 4.14 (ddd, 1H,
J
4,5 = 10.9, J5,6a = 4.3, J5,6b = 2.0 Hz, H-5), 4.10 (m, 3H, H-6′a,H-6′b, H-
6″b), 3.82 (m, 1H, J = 6.2 Hz, Me2CHO), 3.64 (ddd, 1H, J4′,5′ = 9.4,
J
J
5′,6′a = 4.3, J5′,6′b = 2.3 Hz, H-5′), 3.58 (ddd, 1H, J4″,5″ = 9.4, J5″,6″a = 4.5,
5″,6″b = 2.9 Hz, H-5″), 3.31 (t, 1H, J2,3 = J3,4 = 11.4 Hz, H-3), 2.77 (dd,
1), 4.63 (d, 1H, J1″,2″ = 10.0 Hz, H-1″), 4.36 (dd, 1H, J4,5 = 2.1, J3,4
=
1H, J3,4 = 11.4, J4,5 = 10.9 Hz, H-4), 2.08, 2.05, 2.04, 2.03, 2.02, 1.97,
1.96, 1.95, 1.93 (×2) (9 s, 30H, CH3CO), 1.17, 1.07 (2d, 3H each, J =
6.2 Hz, (CH3)2CHO); 13C NMR (CDCl3, 125.7 MHz) δ 170.6−169.5
(CH3CO), 93.9 (C-1), 81.8 (C-1″), 80.7 (C-1′), 76.1 (C-5′), 75.6 (C-
5″), 73.7, 73.6 (C-3′,3″), 73.3 (C-2), 70.8 (Me2CHO), 69.9 (C-5),
69.6, 69.5 (C-2′,2″), 68.0, 67.8 (C-4′, 4″), 64.1 (C-6), 62.0, 61.7 (C-
6′,6″), 45.0 (C-4), 44.2 (C-3), 23.2, 21.6 [(CH3)2CHO], 20.7−20.5
(CH3CO); HRMS (ESI) m/z [M + Na]+ calcd for C41H58NaO24S2
1021.2652, found 1021.2671. Anal. Calcd for C41H58O24S2: C, 49.29;
H, 5.85. Found: C, 49.48; H, 5.84.
7.2 Hz, H-4), 4.22 (dd, 1H, J2,3 = 4.0, J3,4 = 7.2 Hz, H-3), 4.10 (m, 2H,
H-6″a, H6″b), 4.00 (dd, 1H, J1,2 = 1.8, J2,3 = 4.0 Hz, H-2), 3.94 (t, 1H,
H-5″), 3.33 (dd, 1H, J5,6a = 5.6, J6a,6b = 13.0 Hz, H-6a), 3.31 (s, 3H,
CH3O), 3.27 (ddd. 1H, J4,5 = 1.9, J5,6a = 5.6, J5,6b = 8.3 Hz, H-5), 3.19
(dd, 1H, J5,6b = 8.3, J6a,6b = 13.0 Hz, H-6b), 2.09, 1.99, 1.96, 1.92 (4s,
12H, CH3CO), 0.85, 0.84 (2s, 18H, (CH3)3CSiMe2), 0.09, 0.07 (×2),
0.06 (4s, 12H, (CH3)2SiBut); 13C NMR (CDCl3, 125.7 MHz) δ 170.2
(×2), 169.9, 169.5 (MeCO), 166.0, 165.6, 165.4, 165.2 (PhCO),
133.5−128.3 (C-aromatic), 108.9 (C-1), 88.2 (C-1′), 84.4 (C-2), 83.3
(C-1″), 83.1 (C-2′), 82.4 (C-4), 81.9 (C-4′), 80.1 (C-3), 77.7 (C-3′),
74.2 (C-5″), 71.8 (C-3″), 70.4 (C-5′), 67.5 (C-2″), 67.1 (C-4″), 63.7
2-Propyl 2,6-Di-O-acetyl-4-S-(2,3,4,6-tetra-O-acetyl-β-D-gal-
actopyranosyl)-3-S-(2,3,5,6-tetra-O-benzoyl-β-D-galactofura-
263
dx.doi.org/10.1021/jo2018685 | J. Org. Chem. 2012, 77, 253−265

The Journal of Organic Chemistry
Article
(C-6′), 61.0 (C-6″), 55.1 (CH3O), 46.3 (C-5), 33.1 (C-6), 25.8, 25.7
[(CH3)3CSiMe2], 20.6 ( × 3), 20.5 (CH3CO), 17.8, 17.7
[(CH3)3CSiMe2], −4.2, −4.3, −4.5, −4.9 [(CH3)2SiBut]; HRMS
(ESI) m/z [M + Na]+ calcd for C67H86NaO22S2Si2 1385.4483, found
1385.4498. Anal. Calcd for C67H86O22S2Si2: C, 59.01; H, 6.36. Found:
C, 58.73; H, 5.96.
(16) Eisele, T.; Toepfer, A.; Kretzschmar, G.; Schmidt, R. R.
Tetrahedron Lett. 1996, 37, 1389−1392.
(17) (a) Richards, M. R.; Lowary, T. L. ChemBioChem 2009, 10,
1920−1938. (b) Peltier, P.; Euzen, R.; Daniellou, R.; Nugier-Chauvin,
̀
C.; Ferrieres, V. Carbohydr. Res. 2008, 343, 1897−1923. (c) Lowary, T.
L. Mini-Rev. Med. Chem. 2003, 3, 689−702. (d) Lowary, T. L. Curr.
Opin. Chem. Biol. 2003, 7, 749−756. (e) Houseknecht, J. B.; Lowary,
T. L. Curr. Opin. Chem. Biol. 2001, 5, 677−682. (f) Lederkremer, R.
M.; Colli, W. Glycobiology 1995, 5, 547−552.
ASSOCIATED CONTENT
■
S
* Supporting Information
Details on general experimental methods; copies of 1H and 13
C
(18) Bordoni, A.; Lima, C.; Marino, K.; Lederkremer, R. M.; Marino,
̃
C. Carbohydr. Res. 2008, 343, 1863−1869.
NMR spectra for all new compounds and selected COSY and
HMQC. This material is available free of charge via the Internet
at http://pubs.acs.org.
(19) (a) Pathak, A. K.; Pathak, V.; Seitz, L.; Maddry, J. A.; Gurcha, S.
S.; Besra, G. S.; Suling, W. J.; Reynolds, R. C. Bioorg. Med. Chem. 2001,
9, 3129−3143. (b) Completo, G. C.; Lowary, T. L. J. Org. Chem. 2008,
73, 4513−4525.
AUTHOR INFORMATION
Corresponding Author
*Fax: +5411- 4576-3352. E-mail: varela@qo.fcen.uba.ar.
(20) Beaucage, S. L.; Iyer, R. P. Tetrahedron 1992, 48, 2223−2311.
(21) (a) Whistler, R. L.; Lake, W. C. Methods Carbohydr. Chem. 1972,
6, 286−291. (b) Jesudason, M. V.; Owen, L. N. J. Chem. Soc., Perkin
Trans. 1 1974, 2019−2024. (c) Culvenor, C. C. J.; Davies, W.;
Pausacker, K. H. J. Chem. Soc. 1946, 1050−1052.
(22) (a) Dittmer, D. C. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Lwowski, W., Eds.; Pergamon: New York,
1984; Vol. 7, pp 131−184. (b) Sander, M. Chem. Rev. 1966, 66, 297−
339.
■
ACKNOWLEDGMENTS
We are indebted to the University of Buenos Aires (Project
UBACyT X227, 2008-2011), the National Research Council of
■
Republica Argentina (CONICET, Project PIP 0064), and the
́
National Agency for Promotion of Science and Technology
(ANPCyT, Project PICT 2007-00291) for financial support.
O.V. and M.L.U. are Research Members of CONICET.
(23) Vedejs, E.; Krafft, G. A. Tetrahedron 1982, 38, 2857−2881.
(24) Bellomo, A.; Gonzalez, D. Tetrahedron Lett. 2007, 48, 3047−
3051.
(25) Boigegrain, R.-A.; Gross, B. Carbohydr. Res. 1975, 41, 135−142.
(26) (a) Ferrier, R. J.; Furneaux, R. H.; Tyler, P. C. Carbohydr. Res.
1977, 58, 397−404. (b) Tsuzuki, Y.; Tanabe, K.; Akagi, M.; Tejima, S.
Bull. Chem. Soc. Jpn. 1965, 38, 270−274.
(27) (a) Wiegand, B. C.; Friend, C. M. Chem. Rev. 1992, 92, 491−
504. (b) Roberts, J. T.; Friend, C. M. J. Am. Chem. Soc. 1987, 109,
7899−7900.
(28) Iranpoor, N.; Firouzabadi, H.; Jafari, A. A. Synth. Commun. 2003,
33, 2321−2327.
(29) (a) Hummel, G.; Hindsgaul, O. Angew. Chem., Int. Ed. 1999, 38,
1782−1784. (b) Schou, C.; Rasmussen, G.; Schulein, M.; Henrissar,
B.; Driguez, H. J. Carbohydr. Chem. 1993, 12, 743−752.
(30) (a) Horton, D. Methods Carbohydr. Chem. 1963, 2, 433−437.
(b) Bonner, W. A. J. Am. Chem. Soc. 1951, 73, 2659−2666.
(31) (a) Horton, D.; Miller, M. J. Carbohydr. Res. 1965, 1, 335−337.
(b) Kartha, K. P. R.; Field, R. A. In The Carbohydrates; Osborn, H. M.
I., Ed.; Academic: Oxford, 2003; pp 126−128.
REFERENCES
■
(1) Koester, D. C.; Holkenbrink, A.; Werz, D. B. Synthesis 2010,
3217−3242.
́
(2) Szilagyi, L.; Varela, O. Curr. Org. Chem. 2006, 10, 1745−1770.
(3) Pachamuthu, K.; Schmidt, R. R. Chem. Rev. 2006, 106, 160−187.
(4) (a) Driguez, H. ChemBioChem 2001, 2, 311−318. (b) Driguez,
H. Top. Curr. Chem. 1997, 187, 85−116.
(5) (a) Varki, A. Glycobiology 1993, 3, 97−130. (b) Dwek, R. A.
Chem. Rev. 1996, 96, 683−720. (c) Dube, D. H.; Bertozzi, C. R. Nat.
Rev. Drug Disc. 2005, 4, 477−488.
(6) (a) Uhrig, M. L.; Manzano, V. E.; Varela, O. Eur. J. Org. Chem.
2006, 162−168. (b) Uhrig, M. L.; Szilagyi, L.; Kover, K. E.; Varela, O.
́
́
̈
Carbohydr. Res. 2007, 342, 1841−1849. (c) Repetto, E.; Marino, C.;
Uhrig, M. L.; Varela, O. Eur. J. Org. Chem. 2008, 540−547.
(d) Repetto, E.; Marino, C.; Uhrig, M. L.; Varela, O. Bioorg. Med.
Chem. 2009, 17, 2703−2711. (e) Cagnoni, A. J.; Uhrig, M. L.; Varela,
O. Bioorg. Med. Chem. 2009, 17, 6203−6212. (f) Cagnoni, A. J.; Varela,
O.; Gouin, S. G.; Kovensky, J.; Uhrig, M. L. J. Org. Chem. 2011, 76,
3064−3077.
(32) (a) Blanc-Muesser, M.; Vigne, L.; Driguez, H.; Lehmann, J.;
Steck, J.; Urbahns, K. Carbohydr. Res. 1992, 224, 59−71. (b) Defaye, J.;
Guillot, J.-M. Carbohydr. Res. 1994, 253, 185−194. (c) Endo, T.; Oda,
K.; Mukaiyama, T. Chem. Lett. 1974, 3, 443−444.
(7) Manzano, V. E.; Uhrig, M. L.; Varela, O. J. Org. Chem. 2008, 73,
7224−7235.
(33) Andre,
Bioorg. Med. Chem. 2006, 14, 6314−6326.
(34) Martín-Santamaría, S.; Andre, S.; Buzamet, E.; Caraballo, R.;
Fernandez-Cureses, G.; Morando, M.; Ribeiro, J. P.; Ramírez-Gualito,
K.; Pascual-Teresa, B.; Canada, F. J.; Menendez, M.; Ramstrom, O.;
́
S.; Pei, Z.; Siebert, H.-C.; Ramstrom, O.; Gabius, H.-J.
̈
(8) Schneider, C. Synthesis 2006, 3919−3944.
̌
́
(9) Cerny, M. Adv. Carbohydr. Chem. Biochem. 2003, 58, 121−198.
́
́
(10) Iranpoor, N.; Firouzabadi, H.; Chitsazi, M.; Jafari, A. A.
́
̃
̈
Tetrahedron 2002, 58, 7037−7042.
(11) (a) Warkentin, J.; Plazuk, D. In Comprehensive Heterocyclic
́
Jimenez-Barbero, J.; Solís, D.; Gabius, H.-J. Org. Biomol. Chem. 2011,
̇
9, 5445−5455.
Chemistry III; Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V.,
Taylor, R. J. K., Padwa, A., Eds.; Pergamon: New York, 2008; Vol. 1,
pp 299−390. (b) Vilaivan, T.; Chavasiri, W.; Rashatasakhon, P. In
Comprehensive Heterocyclic Chemistry III; Katritzky, A. R., Ramsden, C.
A., Scriven, E. F. V., Taylor, R. J. K., Padwa, A., Eds.; Pergamon: New
(35) Xue, J. L.; Cecioni, S.; He, L.; Vidal, S.; Praly, J.-P. Carbohydr.
Res. 2009, 344, 1646−1653.
(36) Weng, S.-S.; Lin, Y.-D.; Chen, C.-T. Org. Lett. 2006, 8, 5633−
5636.
(37) (a) Murakami, T.; Sato, Y.; Shibakami, M. Carbohydr. Res. 2008,
343, 1297−1308. (b) Lam, S. N.; Gervay-Hague, J. J. Org. Chem. 2005,
70, 8772−8779.
York, 2008; Vol. 1, pp 391−431.
́
(12) Bozo,
́
E.; Boros, S.; Kuszmann, J.; Gac
́
s-Baitz, E. Carbohydr. Res.
1996, 290, 159−173.
(38) Schmidt, R. R.; Stumpp, M. Liebigs Ann. Chem. 1983, 1249−
1256.
(13) Knapp, S.; Malolanarasimhan, K. Org. Lett. 1999, 1, 611−613.
(14) Satoh, T.; Imai, T.; Sugie, N.; Hashimoto, H.; Kakuchi, T. J.
Polym. Sci., Part A: Polym. Chem. 2005, 43, 4118−4125.
(39) Gagnaire, D. Y.; Taravel, F. R.; Vignon, M. R. Carbohydr. Res.
1976, 51, 157−168.
(15) (a) Contour-Galcera, M.-O.; Guillot, J.-M.; Ortiz-Mellet, C.;
Pflieger-Carrara, F.; Defaye, J.; Gelas, J. Carbohydr. Res. 1996, 281,
99−118. (b) Contour-Galcera, M. O.; Ding, Y.; Ortiz-Mellet, C.;
Defaye, J. Carbohydr. Res. 1996, 281, 119−128.
(40) (a) Gallo-Rodriguez, C.; Gandolfi, L.; Lederkremer, R. M. Org.
Lett. 1999, 1, 245−248. (b) Choudhury, A. K.; Roy, N. Carbohydr. Res.
1998, 308, 207−211.
264
dx.doi.org/10.1021/jo2018685 | J. Org. Chem. 2012, 77, 253−265

The Journal of Organic Chemistry
Article
(41) Gandolfi-Donadío, L.; Gola, G.; Lederkremer, R. M.; Gallo-
Rodriguez, C. Carbohydr. Res. 2006, 341, 2487−2497.
(42) Glantzounis, G. K.; Yang, W.; Koti, R. S.; Mikhailidis, D. P.;
Seifalian, A. M.; Davidson, B. R. Curr. Pharm. Des. 2006, 12, 2891−
2901.
(43) Fotia, M. C.; Amorati, R. J. Pharm. Pharmacol. 2009, 61, 1435−
1448.
(44) McCleary, B. V. In Methods in Enzymology; Wood, W. A.,
Kellogg, S. T., Eds.; Academic: San Diego, 1988; Vol. 160, pp 511−
514.
(45) Mandal, S.; Maity, K. K.; Bhunia, S. K.; Dey, B.; Patra, S.; Sikdar,
S. R.; Islam, S. S. Carbohydr. Res. 2010, 345, 2657−2663.
(46) (a) Bevilaqua, M. P.; Stengelin, S.; Gimbrone, M. A. Jr.; Seed, B.
Science 1989, 243, 1160−1165. (b) Lasky, L. A. Science 1992, 258,
964−969.
(47) (a) Nagaoka, M.; Hashimoto, S.; Shibata, H.; Kimura, I.;
Kimura, K.; Sawada, H.; Yokokura, T. Carbohydr. Res. 1996, 281, 285−
291. (b) Zhang, G.; Fu, M.; Ning, J. Tetrahedron: Asymmetry 2005, 16,
733−738.
(48) Wang, H.; Ning, J. J. Org. Chem. 2003, 68, 2521−2524.
(49) (a) Horton, D.; Wolfrom, M. L. J. Org. Chem. 1962, 27, 1794−
1800. (b) Ibatullin, F. M.; Shabalin, K. A.; Janis, J. V.; Shavva, A. G.
̈
Tetrahedron Lett. 2003, 44, 7961−7964. (c) Joseph, B.; Rollin, P. J.
Carb. Chem. 1993, 12, 719−729.
̌
́
̌ ́
(50) Cerny, M.; Stanek, J.; Pacak, J. Monatsh. Chem. 1963, 94, 290−
296.
265
dx.doi.org/10.1021/jo2018685 | J. Org. Chem. 2012, 77, 253−265