Synthesis of α-glycosyl thiols by stereospecific ring-opening of 1,6-anhydrosugars

Article abstract of DOI:10.1021/jo202069y

Treatment of 1,6-anhydrosugars with commercially available bis(trimethylsilyl) sulfide in the presence of trimethylsilyl triflate led to the formation of α-glycosyl thiols. All the reactions were highly stereoselective and afforded the α-glycosyl thiols in good to excellent yields. By this procedure, a variety of 1,6-anhydrosugars, differing in their sugar units, glycosidic linkages, and protecting group pattern, were converted smoothly into the corresponding α-glycosyl thiols, which could be of great utility in thioglycoside chemistry. It is noteworthy that 1,6-anhydrosugars carrying the 2-O-acyl group and 1,6-anhydrosugar-containing oligosaccharides could also be ring-opened stereospecifically under the same conditions to give rise to the corresponding 1-thiosugars in high yields. Thus, a very concise and efficient access to α-glycosyl thiols of great value was established (Figure presented).

Full text of DOI:10.1021/jo202069y

Article
pubs.acs.org/joc
Synthesis of α-Glycosyl Thiols by Stereospecific Ring-Opening of
1,6-Anhydrosugars
Xiangming Zhu,*,†,‡ Ravindra T. Dere,† Junyan Jiang,‡ Lei Zhang,‡ and Xiaoxia Wang‡
†Centre for Synthesis and Chemical Biology, UCD School of Chemistry and Chemical Biology, University College Dublin, Belfield,
Dublin 4, Ireland
‡College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua 321004, China
S
* Supporting Information
ABSTRACT: Treatment of 1,6-anhydrosugars with commercially available
bis(trimethylsilyl) sulfide in the presence of trimethylsilyl triflate led to the
formation of α-glycosyl thiols. All the reactions were highly stereoselective and
afforded the α-glycosyl thiols in good to excellent yields. By this procedure, a
variety of 1,6-anhydrosugars, differing in their sugar units, glycosidic linkages, and
protecting group pattern, were converted smoothly into the corresponding α-glycosyl thiols, which could be of great utility in
thioglycoside chemistry. It is noteworthy that 1,6-anhydrosugars carrying the 2-O-acyl group and 1,6-anhydrosugar-containing
oligosaccharides could also be ring-opened stereospecifically under the same conditions to give rise to the corresponding
1-thiosugars in high yields. Thus, a very concise and efficient access to α-glycosyl thiols of great value was established.
In addition to their wide application in S-glycoside synthesis,
glycosyl thiols are also useful in the synthesis of many other
carbohydrate contexts, such as methylene exo-glycal8 and
C-glycoside synthesis,9 glycosyl sulfenamide and glycosyl
sulfonamide synthesis,10 and glycosyl disulfide synthesis.11
Also, glycosyl thiol was a key intermediate in the construction
of a structurally challenging α-SO2-galacturonylsphingolipid
mimetic,12 which otherwise would be troublesome to get by
conventional glycosidation procedure due to the low reactivity
of glycuronide donors. Glycosyl thiols have also been employed
to prepare carbohydrate thionolactones,13 which could be
useful in the construction of spiro-C/O-glycoside-containing
natural products. Recently, glycosyl thiols were converted into a
new class of glycoslating agents, glycosyl N-phenyl-trifluor-
othioacetimidates,14 which could be activated effectively with
catalytic amounts of Lewis acid. In addition, novel sugar species
have been developed from glycosyl thiols, such as GTM-Cl,15
which could be applied in the synthesis of various neo-
glycoconjugates. Recently, glycosyl thiol was also used to
generate the transient species, glycosylsulfenic acid.16
The great utility and potential that glycosyl thiols have
exhibited in contemporary carbohydrate chemistry brought
great impetus to develop procedures for the stereoselective pre-
paration of both α- and β-glycosyl thiols. Of them, β-glycosyl
thiols, such as β-glucosyl thiol and β-galactosyl thiol, could be
readily obtained by treatment of the corresponding α-glycosyl
halides with thiourea followed by hydrolysis with alkali metal
disulfite.17 However, prior to our work,18,19 in the literature no
direct procedure for the stereoselective preparation of normal
α-glycosyl thiols has been reported,20 although α-GlcNAc- and
α-GalNAc-derived anomeric thiols could be readily prepared
INTRODUCTION
■
Among glycomimetics, thioglycosides have been the subject of
significant interest as they often exhibit higher stability against
chemical and enzymatic hydrolysis and similar solution
conformation compared to the corresponding O-glycosides.1
The higher stability of thioglycosides could be ascribed to the
lower proton affinity of sulfur in comparison to O-glycosides.
According to the hard−soft acid−base (HSAB) theory, sulfur
behaves more like soft base while oxygen is a hard base; a hard
acid like proton is thus prone to attack the hard base O-
glycosides, not the soft base thioglycosides. A similar solution
conformation of thioglycosides may result from the relatively
small difference between the positions of the atoms along the
glycosidic linkage compared to O-glycosides. The C−S bond is
longer than the C−O bond, but the C−S−C bond angle is
smaller than the C−O−C angle, which renders thioglycoside
sharing a similar overall conformation with the corresponding
O-glycosides. Moreover, thioglycosides usually possess similar
or even more potent bioactivities compared to O-glycosides.
Owing to these properties, thioglycosides, including thiooligo-
saccharides and S-glycoconjugates, have frequently been the
synthetic targets in carbohydrate chemistry in the past few
decades.2,3
Glycosyl thiols4 (sometimes called 1-thiosugars) or their
precursors, such as anomeric thioacetates,5 which can be
S-deacetylated in situ to generate the desired glycosyl thiols, are
becoming the key building blocks for the construction of
various thiooligosaccharides and S-glycoconjugates.2,6 Unlike
the normal sugar hemiacetals, which could mutarotate easily
under most conditions, glycosyl thiols are quite stable in terms
of configuration, and their mutarotation does not occur readily.
In contrast, it is highly restricted, and even blocked under basic
conditions,7 as such, the anomeric configuration of glycosyl
thiols can be maintained during the glycosylation process.
Received: October 5, 2011
Published: November 7, 2011
© 2011 American Chemical Society
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from the corresponding per-acetylated sugars by virtue of their
neighboring acetamide groups.21 So far, only β-glycosyl
chlorides have been used occasionally to prepare α-glycosyl
thiols in a multistep procedure;20a nevertheless, the reprodu-
cibility of this procedure is very low due to the highly reactive
β-chlorides. Recently, Davis et al. reported an efficient
procedure for the preparation of glycosyl thiols in which the
Lawesson reagent was found capable of directly converting
reducing sugars or unprotected sugars into the corresponding
glycosyl thiols.22 However, in this procedure configurationally
unpure glycosyl thiols were often produced.
structural complexity. Known benzyl group-protected 1,6-
anhydrosugars 123 and 224 (Figure 2) were first prepared
Therefore, the development of a direct and stereoselective
procedure for the synthesis of α-glycosyl thiols seems to be of
great importance. Such a procedure would not only facilitate
the synthesis of α-S-linked saccharides and glycoconjugates
but also expand greatly other applications of glycosyl thiols,
eventually expediting the development of thioglycoside
chemistry. In a previous communication,18 we reported a
stereospecific method for the synthesis of α-glycosyl thiols by
ring-opening of 1,6-anhydrosugars with bis(trimethylsilyl)
sulfide. We describe here a full account of the method and
its applicability to a wide range of substrates including 2-O-acyl
group-protected 1,6-anhydrosugars and oligosaccharides.
Figure 2. Prepared 1,6-anhydrosugars 1−5.
from methyl 2,3,4-tri-O-benzyl-α-D-galactopyranoside and
methyl 2,3,4-tri-O-benzyl-α-D-glucopyranoside, respectively,
according to the literature procedures.24 1,6-Anhydrosugars
3,25 4, and 5 were also prepared readily from the corresponding
methyl glycosides following the same procedure. Here it should
be mentioned that 1,6-anhydrosugars can also be easily
prepared by other different procedures,26 and many 1,6-
anhydrosugars are commercially available as well.
In order to investigate the effect of electron-withdrawing acyl
groups on the above proposed ring-opening reactions, we also
synthesized a number of partially acylated 1,6-anhydrosugars.
As shown in Scheme 1, compound 1 was first treated with one
RESULTS AND DISCUSSION
■
The major challenge associated with the synthesis of α-glycosyl
thiols lies in the stereoselectivity, i.e., how to α-selectively
introduce a sulfhydryl group onto an anomeric center. In
principle, this can be implemented by activating a glycosyl
donor without neighboring participating group in the presence
of a proper sulfur nucleophile; however, such a normal
glycosidation procedure did not always lead to the predominant
formation of α-thiosugars. On the contrary, sometimes
significant amounts of β-products were also produced in the
glycosidation reactions,5a and the subsequent isolation of
α-glycosyl thiols from the resulting α/β-mixture could be
very tedious and difficult. Furthermore, in this way two or even
more steps are usually required in order to obtain the thiols.
Seeing that most glycosidation reactions involving a donor
without neighboring participating group generate a mixture of
α- and β-glycosides, a procedure precluding such a normal
glycosyl donor would be desirable in order to obtain α-glycosyl
thiols in a highly stereoselective way. We envisioned that 1,6-
anhydrosugars could serve perfectly as glycosylating agents for
the synthesis of α-glycosyl thiols because they differ from
normal glycosyl donors in structure and may thus undergo
unusual glycosidation pathway (Figure 1). Conceivably, if
a
Scheme 1. Synthesis of 1,6-Anhydrosugars 6−11
a
Reagents: (a) 1.0 equiv of SnCl4, CH2Cl2, 6 (46%), 7 (34%); (b) 1.3
equiv of SnCl4, CH2Cl2, 6 (14%), 7 (9%), 8 (63%); (c) Ac2O, Py, 9
(82%), 10 (86%), 11 (77%).
equivalent of SnCl4 to produce the intermediates 627 and 727 in
46% and 34% yields, respectively, which could be separated by
flash column chromatography. This regioselective debenzyla-
tion reaction could also give 828 (63%) as the major product
and 6 (14%) and 7 (9%) as the minor products when 1 was
exposed to an excess of SnCl4 for a prolonged time.
Subsequently, 6, 7, and 8 were acetylated to give the
corresponding 1,6-anhydrosugars 9,29 10, and 11 in 82%,
86%, and 77% yields, respectively.
Figure 1. Proposed procedure for the synthesis of α-glycosyl thiols.
1,6-anhydrosugars are attacked by a nucleophile in an SN2-type
mode, it would give glycosides in α-only selectivity because
β-face of 1,6-anhydrosugars is blocked by the intramolecular
dioxolane ring.
Synthesis of 1,6-Anhydrosugars. To accomplish the
chemistry outlined in Figure 1, we prepared a series of 1,6-
anhydrosugars with different protecting group patterns and
Meanwhile, regioselective protection of commercially avail-
able levoglucosan with BnBr in the presence of BaO could
generate smoothly the intermediate 12,30 which was acetylated
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subsequently to give 1,6-anhydrosugars 1331 in 89% yield, as
shown in Scheme 2. Also, levoglucosan could be monobenzylated
To examine if the ring-opening procedure is applicable to
more complex structures, we also synthesized a group of
anhydrosugar-containing oligosaccharides, as shown in Scheme 3.
a
Scheme 2. Synthesis of 1,6-Anhydrosugars 12−23
Scheme 3. Synthesis of Anhydrosugar-Containing
a
Oligosaccharides
a
Reagents and conditions: (a) BnBr, BaO, DMF, 60 °C, 96%;
(b) BnBr, (Bu3Sn)2O, N-methylimidazole, toluene, 120 °C, 30%;
(c) Ac2O, Py, 13 (89%), 15 (72%); (d) BzCl, Py, 16 (81%), 17 (85%),
21 (79%); (e) PivCl, Py, 91%.
regioselectively with BnBr under the action of (Bu3Sn)2O to
afford the intermediates 14,32 which was again subjected to
normal acetylation to furnish the fully protected levoglucosan
15.32 Thus, two groups of 1,6-anhydrosugars, i.e., 9, 10, and
13 carrying one acetyl group at 4-O, 2-O, and 3-O positions,
respectively, and 11 and 15 carrying two acetyl groups at 2,4-O
and 3,4-O positions, respectively, are ready for testing the ring-
opening reaction with appropriate thionucleophiles.
To extend the range and nature of the substituents on the
sugar ring, benzoyl and pivaloyl groups were also introduced
onto anhydrosugars, as depicted in Scheme 2. Compounds 6 and
7 were both benzoylated with BzCl to give the corresponding
levoglucosan derivatives 1627 and 1727 in 81% and 85% yields,
respectively. 7 was also acylated with pivaloyl chloride to provide
the pivaloate 18 in 91% yield. Following literature procedure,33
commercially available galactosan was also converted into the
partially benzoylated derivative 21 via the intermediates 1933 and
2033 in very good overall yield. As azido group is the most
common precursor to amino group and plays often an
irreplaceable role in aminoglycoside synthesis, it would also be
important to introduce azido group onto 6-anhydrosugars to
trial the ring-opening reactions. Thus, we synthesized the azide
derivative of levoglucosan 23 as well from commercially available
mannosan 22 following the literature procedures.27
a
Reagents and conditions: (a) TMSOTf, 4 Å MS, CH2Cl2, −50 to
0 °C, 25 (85%), 26 (89%), 33 (65%); (b) HCl−dioxane, 78%;
(c) AgOTf, CH2Cl2, 29 (70%), 31 (72%).
Of them, 2-O-glucosylated levoglucosan 25 and galactosan 26
were synthesized readily in 85% and 89% yields, respectively, by
glycosylation of the corresponding acceptors 7 and 19 with
glucosyl trichloroacetimidate 24.34 Considering that the acid-
labile isopropylidene protecting group may not survive under
the ring-opening conditions, 26 was treated subsequently with
HCl in dioxane to remove the isopropylidene group to provide
the disaccharide 27 in 78% yield. Two 3-O-glycosylated
levoglucosans 29 and 31 were also synthesized by glycosylation
of 12 with glucosyl bromide 2835 and maltosyl bromide 30,36
respectively, in order to further explore the ring-opening
procedure. Both were produced in very good yields. Finally, to
ensure that 4-O-glycosylated anhydrosugars could also be
transformed effectively to 1-thiosugars, the known maltose-
derived disaccharide 3237 was prepared and subsequently
subjected to Schmidt glycosidation conditions38 with donor 24
furnished the tetrasaccharide 33 in very good yield.
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Synthesis of α-Glycosyl Thiols. Having the 1,6-anhy-
drosugar substrates in hand, attention was then focused on their
transformation into α-glycosyl thiols, i.e., the development of
appropriate ring-opening conditions to stereoselectively open
the 1,3-dioxolane rings with thionucleophiles. Undoubtedly, it
would be crucial to identify an appropriate nucleophile equi-
valent to a sulfhydryl group in order to achieve one-step direct
synthesis of α-glycosyl thiols from these 1,6-anhydrosugars.
We anticipated that commercially available bis(trimethylsilyl)
sulfide could act as the required sulfur nucleophile to directly
introduce the sulfhydryl group in view of the acid lability of the
trimethylsilyl group which could be cleaved in situ under most
glycosidation conditions.
To verify this hypothesis, the per-benzylated 1,6-anhydro-
sugars 1 and 2 were first chosen as the substrates as the ether-
type protecting groups are thought to be arming groups and
can usually enhance the reactivity of glycosyl donors, thereby
could compensate for the low reactivity of 1,6-anhydrosugars.39
Hence, 1 and 2 were both treated with a small excess of
bis(trimethylsilyl) sulfide (TMS)2S in the presence of catalytic
amounts of TMSOTf (0.4 equiv), but unfortunately, no
reaction took place at room temperature. Some attempts,
such as increase of the amount of TMSOTf, change of pro-
moter, and extension of reaction time, failed to bring about
the expected ring-opening reactions. Fortunately, when the
reactions were heated at 50 °C, the reactions occurred, and to
our delight, the desired glycosyl thiols 34 and 35 were isolated
from the reaction mixtures in 88% and 90% yields, respectively.
More importantly, both thiols were produced as exclusively the
α-anomers (Table 1, entries 1 and 2); i.e., no trace of β-isomers
was produced in both reactions, which made the purification
very simple and straightforward. The α-anomeric configuration
of thiols 34 and 35 was readily determined by the coupling
3
constant JH1−H2 value, which is about 5.0 Hz, whereas
3
analogous β-glycosyl thiols usually have JH1−H2 value of 7−
10 Hz.15 The ready formation of 34 and 35 offered a
preliminary suggestion that the present procedure may provide
a convenient means to α-glycosyl thiols. Indeed, the yields
and stereoselectivities with most investigated substrates were
invariably high, as shown in Tables 1−4, and the one-step
mode as well as the simplicity of the reaction conditions makes
this approach a very attractive way of synthesizing α-glycosyl
thiols.
Subsequently, the per-allylated levoglucosan 3 was subjected
to the same conditions, and as expected, the reaction took place
smoothly and gave rise to α-thiol 36 in 78% yield (Table 1,
entry 3). Similarly, treatment of armed 1,6-anhydrosugars 4 and
5 with (TMS)2S under the same conditions also led to the
desired α-thiols 37 and 38 in very high yields (Table 1, entries
4 and 5). It is important to note that all the reactions were
stereospecific, and no trace of β-glycosyl thiol was produced.
We speculated that the ring-opening reactions underwent
very possibly a concerted SN2-type process, which was also
evidenced by the ring-opening of 2-O-acylated anhydrosugars
(vide infra), but the precise mechanistic details remain to be
investigated.
To obtain more information on the ring-opening reaction,
we then turned to investigating partially unprotected substrates.
The results are summarized in Table 2. Levoglucosan 7 with
a
Table 2. Synthesis of α-Glycosyl Thiols 39−43
a
Table 1. Synthesis of α-Glycosyl Thiols 34−38
a
b
See the Experimental Section for details. Isolated yield following
chromatography.
2-OH unprotected was first treated with (TMS)2S under the
above conditions, as expected, glucosyl thiol 39 was gene-
rated in very high yield and α-only selectivity. Exposure of
anhydrosugar 12 carrying one free OH group at the 3-position
a
b
See the Experimental Section for details. Isolated yield following
chromatography.
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a
to (TMS)2S under the same conditions led also to thiol 40 in
very high yield and α-selectivity (Table 2, entry 2). Similarly,
ring-opening of 4-OH-free anhydrosugar 6 with (TMS)2S in
the presence of catalytic amounts of TMSOTf also proceeded
smoothly to give thiol 41 in 83% yield and α-only selectivity. At
this point, we reasoned that anhydrosugars 8 and 20 with two
free OH groups could also work under the ring-opening
conditions, and indeed, as shown in entries 4 and 5 in Table 2,
when 8 and 20 were treated with (TMS)2S according to the
same procedure, thiols 42 and 43 were isolated in 76% and 83%
yields, respectively, and TLC indicated no trace of their
β-isomers were produced as well. These results further
demonstrate the efficiency of the methodology for the
preparation of α-thiols; moreover, conceivably these partially
unprotected thiols 39−43 could be used for further protecting
group manipulation, thereby providing a convenient and
effective access to α-thiols with other different protecting
groups.
Table 3. Synthesis of α-Glycosyl Thiols 44−52
To further demonstrate the power of this method in the
synthesis of α-glycosyl thiols, 1,6-anhydrosugars carrying acyl
protecting groups were subjected to the ring-opening reaction
under the above conditions. In carbohydrate chemistry, the use
of protecting groups goes far beyond the simple blocking of
hydroxyl groups. Protecting groups often play important roles
in modulating the reactivity of glycosyl donors and acceptors
and directing the stereochemistry of glycosidation reactions.40
On the basis of the results in Tables 1 and 2, we anticipated
that one or two acyl protecting groups on a substrate would not
ruin the ring-opening reactions, although they could deteriorate
the reactivity of 1,6-anhydrosugars and even intervene the
stereocontrol of the reactions. To verify this, the monoacylated
levoglucosans 9, 16, 13, and 10 were chosen as the substrates
for the first set of experiments. As anticipated, 4-O-acetylated
levoglucosan 9 could be converted smoothly into thiol 44
under similar conditions in very high yield (84%) and α-only
selectivity (Table 3, entry 1). Notably, in comparison with the
above non-acylated substrates, compound 9 (and all other
partially acylated anhydrosugars in Table 3, see Experimental
Section) required more Lewis acid (0.8 equiv) and a prolonged
reaction time (10−15 h) to be converted into the
corresponding α-thiol, presumably due to its reduced reactivity.
Similarly, the dioxolane ring of 4-O-benzoylated levoglucosan
16 could also be opened stereospecifically to give rise to α-thiol
45 in 66% yield (Table 3, entry 2). The reaction of 3-O-
acetylated levoglucosan 13 with (TMS)2S proceeded also very
cleanly as indicated by TLC to produce stereospecifically α-
thiol 46 in 89% yield. Thus, introducing one acyl group onto
the sugar seems not to do much harm to the ring-opening
process, and importantly, these results forebode the feasibility
of performing the ring-opening reaction on even less reactive
anhydrosugars (vide infra). More interestingly, the 2-O-acetyl
group did not impair the α-selectivity as the substrate 10 could
also undergo the ring-opening reaction under the above
conditions to give solely the desired α-thiol 47 in high yield
(Table 3, entry 4). This is a very interesting result as the
conventional neighboring group participation did not occur in
spite of the presence of neighboring acetyl group. We
speculated that the possible SN2-type ring-opening pathway
a
b
See the Experimental Section for details. Isolated yield following
chromatography.
presence of TMSOTf; as expected, the reactions proceeded
well, and the corresponding α-thiols 48 and 49 were both
produced stereospecifically and in very good yields (Table 3,
entries 5 and 6).
In this context, 2-azido-anhydrosugar 23 was also subjected to
the ring-opening reaction with (TMS)2S under the above
conditions; as expected, thiol 50 was generated in very high yield
(Table 3, entry 7). Apparently, 50 could be used as a building
block for the construction of α-S-linked aminoglycosides.
To further explore the scope of this procedure, we proceeded
to use the less reactive 1,6-anhydrosugars 11, 15, and 21 with
two electron-withdrawing groups as the substrates for the ring-
opening reaction. We feared that the substrates might not be
reactive enough to undergo the ring-opening process; indeed,
reaction of 11 with (TMS)2S under the above conditions failed
to gave any product and 11 was not affected even after a
1
and the C4 conformation of the substrate might both restrain
the neighboring group participation, thereby favoring the
formation of α-product. To confirm the absence of neighboring
group participation, 2-O-benzoylated and pivaloylated levoglu-
cosan 17 and 18 were also treated with (TMS)2S in the
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prolonged reaction time. Attempts to convert 11 to the
corresponding thiol by increasing the amount of TMSOTf and/
or the reaction temperature led to the loss of α-stereo-
specificity. Similarly, under the same conditions, ring-opening
of 15 with (TMS)2S occurred very slowly and led to the desired
α-thiol 51 in relatively low yield with most starting material
recovered (Table 3, entry 9). These results indicate that
protecting groups on a sugar ring have great impact on the ring-
opening process. Subsequently, galactosan 21 was also treated
with (TMS)2S according to the same procedure, and
fortunately, α-thiol 52 was isolated in reasonably good yield
(Table 3, entry 10). It should be noted that α-thiols carrying
two acyl groups, such as the ring-opening product of 11 and 51,
could also be prepared from the products in Table 2 through
protecting group manipulation.
53 in 58% yield and α-only selectivity. 2-O-Glucosylated
galactosan 27 could also be converted into thiol 54 in a
stereospecific manner and 67% yield under the same conditions
(Table 4, entry 2). Again, ring-opening of 3-O-glycosylated
anhydrosugars 29 and 31 with (TMS)2S under the action of
TMSOTf also led to the corresponding α-thiols 55 and 56 in
very good yields, and TLC indicated no β-isomers were
produced in both reactions (Table 4, entries 3 and 4). It is
worth noting that these smooth reactions, together with
the following reactions, provided a convenient access to
α-oligosaccharidyl thiols, which can be used for chemical ligation
with various electrophilic aglycones to synthesize biologically
important α-S-glycoconjugates. Similarly, when 4-O-glycosy-
lated anhydrosugars 32 and 33 were treated with (TMS)2S in
the presence of catalytic amounts of TMSOTf, the correspond-
ing α-thiols 57 and 58 were also produced readily in 74% and
81% yields, respectively, without observable contamination of
β-isomers.
The scope and utility of the ring-opening procedure in the
synthesis of α-glycosyl thiols is further illustrated in Table 4.
a
Table 4. Synthesis of α-Glycosyl Thiols 53−58
CONCLUSION
■
In this report, a series of α-glycosyl thiols were synthesized
directly from the readily available 1,6-anhydosugars in a
stereospecific way. To the best of our knowledge, this is the
first direct stereospecific procedure for the synthesis of
α-glycosyl thiols. A great advantage of this procedure is that
most α-glycosyl thiols were isolated in good to excellent yields
as exclusively the α-anomer. No trace of β-isomers was
produced in all the reactions. Notably, by this procedure 1,6-
anhydrosugars carrying a 2-O-acyl group could also be ring-
opened stereospecifically to give rise to α-glycosyl thiols in high
yields. Thus, this one-step procedure provided a convenient
and efficient access to α-glycosyl thiols, which could be used to
synthesize various α-S-glycoconjugates.
EXPERIMENTAL SECTION
■
General Remarks. All chemicals used were reagent grade and
used as supplied except where noted. Reactions were performed in
oven-dried glassware under a nitrogen atmosphere using dry solvents.
Solvents were evaporated under reduced pressure while maintaining
the water bath temperature below 40 °C. All reactions were monitored
by thin-layer chromatography (TLC) using silica gel 60 F254 coated on
an aluminum sheet, and the compounds were visualized by UV or by
treatment with 8% H2SO4 in methanol followed by heating. Flash
chromatography was performed with the appropriate solvent system
using 40−60 μm silica gel. Optical rotations were measured at 20 °C
1
with a Perkin-Elmer 343 polarimeter (1 dm cell). H NMR spectra
were obtained on a 300, 400, and 500 MHz and reported in parts per
million (δ) relative to the response of the solvent or to TMS (0.00
ppm). Coupling constants (J) are reported in hertz (Hz). 13C NMR
spectra were recorded at 75, 100, or 125 MHz by using CDCl3 as
solvent and are reported in δ relative to the response of the solvent.
Yields refer to chromatographically pure compounds and are
calculated based on reagents consumed.
1,6-Anhydro-2,3-di-O-allyl-4-O-benzyl-β-D-glucopyranose
(4). To a stirred solution of methyl 2,3-di-O-allyl-4-O-benzyl-α-D-
glucopyranoside41 (0.20 g, 0.59 mmol) in CH3CN (10 mL) was added
Fe(ClO4)3·(H2O)6 (21 mg, 0.06 mmol). The mixture was refluxed for
6 h and was then diluted with CH2Cl2 and filtered through a short pad
of silica gel. The filtrates were concentrated in vacuo to give a residue,
which was purified by flash column chromatography (petroleum
ether/EtOAc, 5:1) to afford the anhydrosugar 4 (135 mg, 74%) as a
a
b
See the Experimental Section for details. Isolated yield following
1
colorless syrup: [α]D = +52.6 (c 1.0 CHCl3). H NMR (400 MHz,
chromatography.
CDCl3): δ 7.38−7.28 (m, 5H), 5.92−5.80 (m, 2H), 5.43 (br s, 1H),
5.32 (d, J = 1.5 Hz, 1H), 5.27 (dd, J = 6.4, 1.5 Hz, 2H), 5.19 (dd, J =
12.0, 1.2 Hz, 2H), 4.67 (br s, 2H), 4.56 (d, J = 5.6 Hz, 1H), 4.10 (d,
J = 5.4 Hz, 1H), 3.84 (d, J = 7.1 Hz, 1H), 3.65 (t, J = 6.8 Hz, 1H), 3.53
Treatment of 1,2-linked disaccharides 25 with (TMS)2S in the
presence of 0.6 equiv of TMSOTf afforded the desired α-thiol
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(d, J = 1.0 Hz, 1H), 3.27 (d, J = 15.0 Hz, 1H). 13C NMR (100 MHz,
CDCl3): δ 138.0, 134.6, 134.5, 128.4, 127.8, 117.4, 117.1, 100.7, 77.5,
77.4, 77.1, 76.9, 76.8, 74.5, 71.3, 71.2, 65.6. ESI-MS m/z 355.4 [M +
Na]+. ESI-HRMS calcd for C19H24O5Na [M + Na]+ 355.1521; found
355.1528.
(5 mL) was added BzCl (0.25 mL, 2.14 mmol) at 0 °C. The mixture was
stirred at room temperature for 5 h and was then diluted with EtOAc,
washed successively with 5% HCl, saturated aqueous NaHCO3, and
brine, dried with MgSO4, and concentrated in vacuo. The residue was
purified by flash column chromatography (petroleum ether/EtOAc, 3:1)
to give the anhydrosugar 21 (317 mg, 79%) as an amorphous solid: [α]D
−27.0 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3): δ 8.13 (d, J = 7.2
Hz, 2H), 8.04 (d, J = 7.2 Hz, 2H), 7.86 (d, J = 7.2 Hz, 2H), 7.61 (q, J =
7.5 Hz, 2H), 7.49 (m, 3H), 7.43−7.28 (m, 4H), 5.77 (d, J = 4.5 Hz, 1H),
5.64 (t, J = 4.6 Hz, 1H), 5.48 (br s, 1H), 4.73−4.68 (m, 2H), 4.93 (d, J =
12.0 Hz, 1H), 4.57 (d, J = 7.5 Hz, 1H), 3.84 (t, J = 6.1 Hz, 1H), 3.67 (br
s, 1H). 13C NMR (75 MHz, CDCl3): δ 171.4, 165.6, 137.2, 133.7, 133.3,
130.1, 129.6, 128.6, 128.5, 128.4, 128.3, 128.0, 100.6, 72.3, 72.0, 67.7,
66.1, 64.5. ESI-MS m/z 483.3 [M + Na]+. ESI-HRMS calcd for
C27H24O7 [M + H]+ 461.1600; found 461.1605.
1,6-Anhydro-2,3-di-O-allyl-4-O-benzyl-β-D-galactopyranose
(5). Methyl 2,3-di-O-allyl-α-D-galactopyranoside42 was smoothly
transformed into methyl 2,3-di-O-allyl-4-O-benzyl-α-D-galactopyrano-
side by successive tritylation, benzylation, and detritylation, which was
then treated with Fe(ClO4)3·(H2O)6 following the procedure
described for the synthesis of 4. The anhydrosugar 5 was obtained,
after purification by flash column chromatography (petroleum ether/
EtOAc, 5:1), as colorless syrup in 67% yield: [α]D = +37.9 (c 1.0
1
CHCl3). H NMR (400 MHz, CDCl3): δ 7.34−7.27 (m, 5H), 5.95−
5.81 (m, 2H), 5.37−5.24 (m, 3H), 5.18 (dd, J = 9.1, 5.4 Hz, 2H), 4.64
and 4.58 (AB peak, J = 11.8 Hz, 2H), 4.45 (d, J = 6.8 Hz, 1H), 4.39 (d,
J = 3.7 Hz, 1H), 4.11 (m, 2H), 4.06−3.99 (m, 2H), 3.83 (d, J = 3.8 Hz,
1H), 3.75 (d, J = 3.7 Hz, 1H), 3.58 (t, J = 5.6 Hz, 1H), 3.51 (br s, 1H).
13C NMR (100 MHz, CDCl3): δ 138.3, 134.9, 134.4, 128.4, 127.8,
O-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-(1→2)-1,6-an-
hydro-3,4-di-O-benzyl-β-D-glucopyranose (25). A suspension of
imidate 24 (0.8 g, 1.62 mmol), acceptor 7 (450 mg, 1.31 mmol), and
activated powdered molecular sieves (4 Å, 400 mg) in CH2Cl2
(20 mL) was stirred at room temperature for 15 min and then cooled
to −50 °C, and a solution of TMSOTf (3.2 mL, 0.05 M) in CH2Cl2
was slowly added. After stirring for 30 min, the reaction mixture was
quenched with Et3N and filtered. The filtrates were concentrated in
vacuo to give a residue, which was purified by flash column
chromatography (petroleum ether/EtOAc, 3:1) to yield the title
compound 25 (749 mg, 85%) as a white foam: [α]D = −63.5 (c 1.0
127.6, 100.1, 77.6, 76.9, 76.6, 74.4, 73.1, 72.7, 72.3, 71.3, 71.1, 64.3.
ESI-MS m/z 355.5 [M + Na]+. ESI-HRMS calcd for C19H24O5Na
[M + Na]+ 355.1521; found 355.1532.
1,6-Anhydro-2-O-acetyl-3,4-di-O-benzyl-β-D-glucopyranose
(10). To a stirred solution of 7 (0.25 g, 0.73 mmol) in Py (4 mL) was
added Ac2O (0.1 mL, 0.9 mmol). The mixture was stirred overnight at
room temperature and was then diluted with EtOAc, washed
successively with 5% HCl, saturated aqueous NaHCO3, and brine,
dried with MgSO4 and concentrated in vacuo. The residue was
purified by flash column chromatography (petroleum ether/EtOAc,
5:1) to afford the anhydrosugar 10 (243 mg, 86%) as colorless syrup:
[α]D −28.0 (c 2.5 CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.37−7.27
(m, 10H), 5.45 (s, 1H), 4.75−4.72 (m, 2H), 4.61 (d, J = 5.2 Hz, 1H),
4.54 (dd, J = 12.4, 7.2 Hz, 2H), 4.45 (d, J = 12.4 Hz, 1H), 4.06 (d, J =
7.2 Hz, 1H), 3.72 (t, J = 6.4 Hz, 1H), 3.53 (d, J = 1.2 Hz, 1H), 3.34
(br s, 1H), 2.11 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 170.3, 137.7,
137.6, 128.5, 128.4, 127.9, 127.78, 127.77, 99.4, 75.9, 74.8, 74.2, 71.8,
71.1, 69.1, 65.0, 21.1. ESI-MS m/z 407.4 [M + Na]+. ESI-HRMS calcd
for C22H25O6 [M + H]+ 385.1651; found 385.1639.
1,6-Anhydro-2,4-di-O-acetyl-3-O-benzyl-β-D-glucopyranose
(11). The reaction procedure was identical to that described for 10.
The anhydrosugar 11 was obtained, after purification by flash column
chromatography (petroleum ether/EtOAc, 3:1), as a colorless syrup in
77% yield: [α]D −64.4 (c 0.35 CHCl3). 1H NMR (400 MHz, CDCl3):
δ 7.36−7.27 (m, 5H), 5.47 (s, 1H), 4.78−4.75 (m, 3H), 4.69 (d, J =
12.4 Hz, 1H), 4.61 (d, J = 5.2 Hz, 1H), 4.22 (d, J = 7.6 Hz, 1H), 3.78
(dd, J = 7.2, 6.0 Hz, 1H), 3.48 (d, J = 1.6 Hz, 1H), 2.13 (s, 3H), 2.11
(s, 3H). 13C NMR (100 MHz, CDCl3): δ 170.1, 169.9, 137.4, 128.3,
127.7, 127.5, 99.5, 75.5, 73.7, 72.2, 70.9, 69.1, 65.1, 21.0, 20.9. ESI-MS
m/z 359.3 [M + Na]+. ESI-HRMS calcd for C17H20O7Na [M + Na]+
359.1107; found 359.1109.
1,6-Anhydro-3,4-di-O-benzyl-2-O-pivaloyl-β-D-glucopyra-
nose (18). Compound 7 (290 mg, 0.85 mmol) was dissolved in Py
(10 mL), and PivCl (0.13 mL, 1.06 mmol) was added to this mixture
at 0 °C. The resulting mixture was stirred at room temperature
overnight and was then diluted with EtOAc, washed successively with
5% HCl, saturated aqueous NaHCO3, and brine, dried with MgSO4,
and concentrated in vacuo. The residue was purified by flash column
chromatography (petroleum ether/EtOAc, 6:1) to afford the
anhydrosugar 18 (329 mg, 91%) as a colorless syrup: [α]D = −22.6
(c 1.0 CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.34−7.25 (m, 10H),
5.47 (s, 1H), 4.69 (d, J = 2.9 Hz, 1H), 4.67 (s, 1H), 4.61 and 4.40 (AB
peak, J = 11.8 Hz, 2H), 4.50 (m, 1H), 4.45 (s, 1H), 4.09 (d, J = 7.3 Hz,
1H), 3.72 (dd, J = 7.2, 6.0 Hz, 1H), 3.52 (br s, 1H), 3.35 (br s, 1H);
1.23 (s, 6H), 1.21 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 175.9,
137.7, 128.4, 128.3, 127.9, 127.8, 127.7, 100.8, 77.3. 77.1, 77.0, 76.7,
75.6, 74.4, 72.4, 72.1, 71.7, 65.8, 38.8, 27.0. ESI-MS m/z 449.5 [M +
Na]+. ESI-HRMS calcd for C25H30O6Na [M + Na]+ 449.1940; found
449.1946.
1
CHCl3). H NMR (400 MHz, CDCl3): δ 7.36−7.29 (m, 10H), 5.43
(s, 1H), 5.19 (t, J = 9.4 Hz, 1H), 5.09 (t, J = 9.5 Hz, 1H), 4.99 (t, J =
9.0 Hz, 1H), 4.81 (d, J = 8.0 Hz, 1H), 4.62−4.53 (m, 4H), 4.43 (d, J =
12.1 Hz, 1H), 4.19 (dd, J = 12.4, 4.6 Hz, 1H), 4.06 (dd, J = 10.4, 1.9
Hz, 1H), 3.96 (d, J = 7.2 Hz, 1H), 3.76 (s, 1H), 3.73 (d, J = 6.5 Hz,
1H), 3.68 (s, 1H), 3.64−3.60 (m, 1H), 3.34 (s, 1H), 2.04(s, 3H), 2.03
(s, 6H), 1.97 (s. 3H). 13C NMR (100 MHz, CDCl3): δ 170.6, 170.3,
169.4, 169.2, 137.8, 137.7, 128.5, 127.9, 127.8, 127.6, 100.8, 99.3, 77.6,
77.3, 77.2, 76.7, 76.5, 75.8, 73.9, 72.8, 71.9, 71.4, 71.3, 68.2, 65.4, 61.8,
20.7, 20.6. ESI-MS m/z 695.7 [M + Na]+. ESI-HRMS calcd for
C34H40O14Na [M + Na]+ 695.2316; found 695.2326.
O-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-(1→2)-1,6-an-
hydro-β-D-galactopyranose (27). The reaction procedure for the
synthesis of disaccharide 26 was identical to that described for 25,
except that acceptor 19 was used instead of 7. The crude product was
purified by flash column chromatography (petroleum ether/EtOAc,
2:1) to give 26 as a white foam in 89% yield, which was then treated
with 4 M HCl/dioxane solution to cleave the isopropylidene
protecting group to provide the title compound 27 as an amorphous
1
solid in 78% yield: [α]D +28.1 (c 1.0, CHCl3). H NMR (300 MHz,
CDCl3): δ 5.51 (s, 1H), 5.19 (t, J = 9.4 Hz, 1H), 5.10−4.97 (m, 2H),
4.67 (d, J = 7.8 Hz, 1H), 4.43 (t, J = 4.5 Hz, 1H), 4.22−4.17 (m, 3H),
3.93−3.82 (m, 3H), 3.74−3.69 (m, 1H), 3.63 (dd, J = 7.8, 5.1 Hz,
1H), 2.88 (d, J = 8.2 Hz, 1H), 2.72 (d, J = 6.9 Hz, 1H), 2.09 (s, 3H),
2.04 (s, 3H), 2.03 (s, 3H), 2.00 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 170.6, 170.2, 169.3, 169.0, 108.6, 100.8, 100.1, 78.4, 74.6,
72.7, 72.0, 71.8, 71.3, 69.1, 68.2, 63.0, 61.8, 25.7, 24.2, 20.6, 20.5. ESI-
MS m/z 515.4 [M + Na]+. ESI-HRMS calcd for C20H28O14Na [M +
Na]+ 515.1377; found 515.1386.
O-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-(1→3)-1,6-an-
hydro-2,4-di-O-benzyl-β-D-glucopyranose (29). To a stirred
solution of 28 (198 mg, 0.48 mmol) and 13 (150 mg, 0.43 mmol)
in CH2Cl2 (5 mL) was added 4 Å molecular sieves. AgOTf (123 mg,
0.48 mmol) was then added to the above mixture at 0 °C. After being
stirred overnight at room temperature, the reaction was quenched with
Et3N and filtered through a pad of Celite. The filtrates were diluted
with EtOAc, washed successively with water and brine, dried with
MgSO4, and concentrated in vacuo. The residue was purified by flash
column chromatography (petroleum ether/EtOAc, 3:1) to give the
title compound 29 (189 mg, 70%) as an amorphous solid: [α]D −1.2
1
(c 0.5 CHCl3). H NMR (400 MHz, CDCl3) δ 7.39−7.29 (m, 10H),
5.45 (s, 1H), 5.33 (d, J = 3.2 Hz, 1H), 5.08 (dd, J = 10.0, 8.4 Hz, 1H),
4.85 (dd, J = 10.8, 3.2 Hz, 1H), 4.77 (dd, J = 17.6, 12.8 Hz, 2H), 4.64
(d, J = 12.8 Hz, 1H), 4.55 (d, J = 12.0 Hz, 2H), 4.09 (d, J = 6.8 Hz,
1,6-Anhydro-3,4-di-O-benzoyl-2-O-benzyl-β-D-galactopyra-
nose (21). To a stirred solution of 20 (225 mg, 0.89 mmol) in Py
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13C NMR (100 MHz, CDCl3): δ 138.7, 138.2, 137.7, 128.66, 128.65,
128.6, 128.22, 128.20, 128.17, 128.13, 128.09, 127.8, 81.8, 79.5, 78.9,
77.1, 75.9, 75.2, 72.6, 72.0, 61.9. ESI-MS m/z 489.2 [M + Na]+. ESI-
HRMS calcd for C27H30NaO5S [M + Na]+ 489.1712; found 489.1698.
2,3,4-Tri-O-benzyl-1-thio-α-D-galactopyranose (35). Thiol 35
was obtained, after purification by flash column chromatography
(petroleum ether/EtOAc, 4:1), as a colorless syrup in 90% yield: [α]D
2H), 3.95 (d, J = 8.4 Hz, 1H), 3.85 (br s, 1H), 3.79 (d, J = 7.2 Hz,
1H), 3.65−3.59 (m, 2H), 3.41 (br s, 1H), 3.13 (br s, 1H), 2.13 (s,
3H), 2.01 (s, 3H), 1.99 (s, 3H), 1.97 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 170.2, 170.1, 170.0, 169.4, 137.9, 137.7, 128.7, 128.5, 128.4,
128.3, 127.8, 127.7, 99.7, 77.2, 76.2, 74.7, 74.3, 74.1, 72.3, 71.2, 70.7,
70.5, 68.1, 66.9, 64.8, 61.2, 20.7, 20.64, 20.61, 20.5. ESI-MS m/z 695.6
[M + Na]+. ESI-HRMS calcd for C34H40O14Na [M + Na]+ 695.2316;
found 695.2329.
1
+93.6 (c 0.8 CHCl3). H NMR (500 MHz, CDCl3): δ 7.38−7.24 (m,
O-(2,3,4,6-Tetra-O-acetyl-α-D-glucopyranosyl)-(1→4)-O-
(2,3,6-tri-O-acetyl-β-D-glucopyranosyl)-(1→3)-1,6-anhydro-2,4-
di-O-benzyl-β-D-glucopyranose (31). The reaction procedure was
identical to that described for 29, except that bromide 30 was used
instead of 28. The crude product was purified by flash column
chromatography (petroleum ether/EtOAc, 1:1) to give 31 as an
15H), 5.84 (t, J = 5.0, 4.5 Hz, 1H), 4.93 and 4.65 (AB peak, J = 11.5
Hz, 2H), 4.84 and 4.69 (AB peak, J = 12.0 Hz, 2H), 4.72 and 4.69 (AB
peak, J = 11.0 Hz, 2H), 4.25 (dd, J = 5.0, 9.5 Hz, 1H), 4.15 (t, J = 6.0,
5.5 Hz, 1H), 3.89 (br s, 1H), 3.81(dd, J = 2.5, 9.5 Hz, 1H), 3.72 (dd,
J = 6.5, 11.5 Hz, 1H), 3.54−3.49 (m, 1 H), 1.83 (d, J = 4.0 Hz, 1H).
13C NMR (125 MHz, CDCl3): δ 138.4, 138.0, 137.8, 128.6, 128.5,
128.44, 128.39, 128.0, 127.9, 127.8, 127.7, 127.6, 79.4, 78.6, 75.9, 74.6,
74.4, 73.6, 72.6, 71.6, 62.0. ESI-MS m/z 489.2 [M + Na]+. ESI-HRMS
calcd for C27H30NaO5S [M + Na]+ 489.1712; found 489.1712.
2,3,4-Tri-O-allyl-1-thio-α-D-glucopyranose (36). Thiol 36 was
obtained, after purification by flash column chromatography
(petroleum ether/EtOAc, 3:1), as a colorless syrup in 78% yield:
1
amorphous solid in 72% yield: [α]D +32.1 (c 0.8 CHCl3). H NMR
(400 MHz, CDCl3): δ 7.41−7.25 (m, 10H), 5.42 (s, 1H), 5.40−5.35
(m, 2H), 5.12 (t, J = 9.2 Hz, 1H), 5.05 (t, J = 9.8 Hz, 1H), 4.87 (dd,
J = 10.4, 4.0 Hz, 1H), 4.74−4.68 (m, 3H), 4.62−4.56 (m, 2H), 4.53−
4.50 (m, 1H), 4.44 (dd, J = 12.0, 2.4, 1H), 4.26 (dd, J = 12.8, 4.0 Hz,
1H), 4.16−4.10 (m, 2H), 4.06 (d, J = 12.0, 1H), 3.96−3.92 (m, 1H),
3.90 (d, J = 9.2 Hz, 1H), 3.84 (br s, 1H), 3.72 (d, J = 7.2 Hz, 1H), 3.58
(t, J = 6.6 Hz, 1H), 3.41−3.39 (m, 1H), 3.35 (br s, 1H), 3.15 (br s,
1
[α]D +173.1 (c 2.0 CHCl3). H NMR (500 MHz, CDCl3): δ 5.99−
5.87 (m, 3H), 5.70 (t, J = 5.0 Hz, 1H), 5.29 (m, 3H), 5.18 (m, 3H),
4.37−4.08 (m, 6H), 4.01 (dt, J = 3.5, 10.0 Hz, 1H), 3.82 (dd, J = 2.0,
12.0 Hz, 1H), 3.75 (d, J = 11.5 Hz, 1H), 3.58 (overlapped m, 2H),
3.35 (t, J = 9.0, 9.5 Hz, 1H), 1.88 (d, J = 5.0 Hz, 1H). 13C NMR (125
MHz, CDCl3): δ 135.1, 134.6, 134.3, 117.5, 117.1, 116.6, 81.0, 78.96,
78.80, 77.0, 74.3, 73.8, 71.8, 71.5, 61.7. ESI-MS m/z 339.1 [M + Na]+.
ESI-HRMS calcd for C15H25O5S [M + H]+ 317.1423; found 317.1436.
2,3-Di-O-allyl-4-O-benzyl-1-thio-α-D-glucopyranose (37). Thiol
37 was obtained, after purification by flash column chromatography
(petroleum ether/EtOAc, 3:1), as a colorless syrup in 85% yield: [α]D
1H), 2.09−2.06 (m, 9H), 2.03−2.01 (m, 6H), 1.98−1.95 (m, 6H). 13
C
NMR (100 MHz, CDCl3): δ 170.4, 170.2, 170.0, 169.9, 169.5, 169.3,
137.9, 137.6, 128.6, 128.4, 128.3, 128.2, 127.8, 127.7, 109.9, 99.8, 98.9,
95.5, 76.1, 75.08, 75.05, 74.8, 74.3, 72.6, 72.3, 72.2, 71.4, 71.1, 70.0,
69.3, 68.5, 68.0, 64.9, 62.5, 61.4, 60.3, 29.6, 20.8, 20.60, 20.57, 20.54,
20.52. ESI-MS m/z 983.7 [M + Na]+. ESI-HRMS calcd for
C46H56O22Na [M + Na]+ 983.3161; found 983.3146.
O-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-(1→4)-O-
[2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl-(1→6)]-O-(2,3-di-O-
benzyl-α-D-glucopyranosyl)-(1→4)-1,6-anhydro-2,3-di-O-ben-
zyl-β-D-glucopyranose (33). The reaction procedure was identical
to that described for 29, except that acceptor 32 was used instead of
13. The crude product was purified by flash column chromatography
(CH2Cl2/MeOH, 10:1) to give 33 as an amorphous solid in 65%
yield: [α]D +8.9 (c 0.9 CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.32−
7.27 (m, 20H), 5.50 (d, J = 8.0 Hz, 1H), 5.32−5.16 (m, 1H), 5.13−
5.04 (m, 2H), 5.04−4.88 (m, 4H), 4.72−4.65 (m, 2H), 4.59−4.47 (m,
5H), 4.26−4.20 (m, 2H), 4.14−4.02 (m, 4H), 4.00−3.95 (m, 2H),
3.89−3.80 (m, 2H), 3.78−3.70 (m, 5H), 3.60−3.47(m, 2H), 3.55−
3.47 (m, 2H), 3.39 (br s, 2H), 2.08−1.99 (m, 24H). 13C NMR (100
MHz, CDCl3): δ 171.3, 170.70, 170.69, 170.64, 170.62, 169.61,
169.60, 169.5, 138.6, 138.0, 137.9, 137.87, 137.80, 137.71, 137.70,
128.60, 128.58, 128.49, 128.45, 128.42, 128.3, 128.0, 127.9, 127.80,
127.79, 127.76, 127.73, 127.71, 127.60, 127.58, 127.55, 127.4, 124.7,
100.7, 100.6, 97.2, 81.0, 79.4, 77.1, 75.2, 75.1, 73.2, 72.7, 72.5, 72.4,
72.1, 72.04, 71.98, 71.9, 71.6, 71.49, 71.46, 71.3, 71.0, 70.7, 70.6, 68.3,
67.9, 67.5, 65.7, 62.5, 31.9, 30.2, 29.7, 29.6, 29.3, 26.8, 22.6, 20.9,
20.80, 20.78, 20.72, 20.69, 20.66, 20.65, 20.62, 20.58, 20.56. ESI-MS
m/z 1368.7 [M + Na]+. ESI-HRMS calcd for C68H80O28Na [M + Na]+
1367.4734; found 1367.4751.
General Procedure for the Synthesis of Thiols 34−43. To a
solution of the appropriate 1,6-anhydrosugars (1.0 mmol) and
bis(trimethylsilyl) sulfide (1.4 mmol) in CH2Cl2 (10 mL) was
added TMSOTf (0.4 mmol) at 0 °C. The mixture was then stirred at
50 °C until TLC indicated complete consumption of the starting
material (typically 4−6 h), then poured into aqueous NaHCO3, and
extracted with EtOAc. The organic layer was washed successively with
water and brine, dried over MgSO4, and concentrated in vacuo to give
a residue which was purified by flash column chromatography to afford
the corresponding α-glycosyl thiol.
1
+117 (c 0.2 CHCl3). H NMR (500 MHz, CDCl3): δ 7.35−7.25 (m,
5H), 6.00−5.88 (m, 2H), 5.71 (t, J = 5.5 Hz, 1H), 5.31 (m, 2H), 5.19
(m, 2H), 4.88 and 4.66 (AB peak, J = 10.5, 11.0 Hz, 2H), 4.40 (dd, J =
5.5, 12.0 Hz, 1H), 4.28 (dd, J = 5.5, 12.0 Hz, 1H), 4.17 (dd, J = 5.5,
12.5 Hz, 1H), 4.10 (dd, J = 5.5, 12.5 Hz, 1H), 4.05 (dt, J = 3.5, 10.0
Hz, 1H), 3.79−3.68 (overlapped m, 3H), 3.62 (dd, J = 5.5, 9.5 Hz,
1H), 3.49 (t, J = 9.5 Hz, 1H), 1.87 (d, J = 4.5 Hz, 1H). 13C NMR (150
MHz, CDCl3): δ 138.1, 135.1, 134.3, 128.50, 128.45, 128.1, 127.9,
127.8, 117.6, 116.7, 81.3, 79.1, 78.8, 77.0, 75.1, 74.4, 71.8, 71.5, 61.8;
ESI-MS m/z 389.1 [M + Na]+. ESI-HRMS calcd for C19H26NaO5S
[M + Na]+ 389.1399; found 389.1418.
2,3-Di-O-allyl-4-O-benzyl-1-thio-α-D-galactopyranose (38). Thiol
38 was obtained, after purification by flash column chromatography
(petroleum ether/EtOAc, 3:1), as a colorless syrup in 92% yield: [α]D
+76.2 (c 2.0 CHCl3); 1H NMR (500 MHz, CDCl3): δ 7.39−7.32 (m,
5H), 6.02−5.91 (m, 2H), 5.87 (t, J = 4.5 Hz, 1H), 5.36 (m, 2H), 5.22
(m, 2H), 4.98 and 4.96 (AB peak, J = 11.5 Hz, 2H), 4.33−4.17 (m,
4H), 4.20 (overlapped m, 1H), 4.12 (dd, J = 5.5, 10.0 Hz, 1H), 3.91
(br s, 1H), 3.76 (dd, J = 6.5, 11.5 Hz, 1H), 3.68 (dd, J = 2.5, 9.5 Hz,
1H), 3.56 (m, 1H), 1.83 (d, J = 4.0 Hz, 1H). 13C NMR (125 MHz,
CDCl3): δ 138.1, 134.9, 134.5, 128.6, 128.5, 128.0, 117.3, 116.6, 79.5,
78.3, 75.6, 74.49, 74.45, 72.2, 71.7, 71.6, 62.1. ESI-MS m/z 389.1 [M +
Na]+. ESI-HRMS calcd for C19H27O5S [M + H]+ 367.1579; found
367.1562.
3,4-Di-O-benzyl-1-thio-α-D-glucopyranose (39). Thiol 39 was
obtained, after purification by flash column chromatography
(petroleum ether/EtOAc, 3:1), as an amorphous solid in 86% yield:
[α]D +34.5 (c 1.0 CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.36−7.30
(m, 10H), 5.62 (t, J = 5.8 Hz, 1H), 4.91−4.80 (m, 3H), 4.69 (d, J =
10.8 Hz, 1H), 4.04 (dt, J = 9.2, 3.2 Hz, 1H), 3.88−3.83 (m, 1H),
3.80−3.78 (m, 2H), 3.70 (d, J = 9.0 Hz, 1H), 3.58 (t, J = 9.2 Hz, 1H),
2.35 (d, J = 6.0 Hz, 1H), 1.97 (d, J = 6.4 Hz, 1H). 13C NMR (100
MHz, CDCl3): δ 128.6, 128.5, 128.03, 128.0, 127.9, 82.0, 80.0, 76.9,
75.3, 74.8, 72.8, 71.6, 61.5. ESI-MS m/z 377.5 [M + H]+. ESI-HRMS
calcd for C20H24NaO5S [M + Na]+ 399.1242; found 399.1252.
2,4-Di-O-benzyl-1-thio-α-D-glucopyranose (40). Thiol 40 was
obtained, after purification by flash column chromatography
(petroleum ether/EtOAc, 3:2), as an amorphous solid in 90%
2,3,4-Tri-O-benzyl-1-thio-α-D-glucopyranose (34). Thiol 34
was obtained, after purification by flash column chromatography
(petroleum ether/EtOAc, 4:1), as a colorless syrup in 88% yield: [α]D
1
+95.1 (c 1.0 CHCl3). H NMR (400 MHz, CDCl3): δ 7.31−7.22 (m,
15H), 5.62 (t, J = 5.2, 4.8 Hz, 1H), 4.88 and 4.74 (AB peak, J = 10.8
Hz, 2H), 4.81 and 4.58 (AB peak, J = 11.0 Hz, 2H), 4.66 and 4.57 (AB
peak, J = 11.8 Hz, 2H), 4.02 (m, 1H), 3.82 (t, J = 9.2, 8.8 Hz, 1H),
3.68 (m, 3H), 3.48 (t, J = 10.0, 9.2 Hz, 1H), 1.84 (d, J = 4.8 Hz, 1H).
1
yield: [α]D +156.1 (c 1.2 CHCl3). H NMR (400 MHz, CDCl3): δ
10194
dx.doi.org/10.1021/jo202069y|J. Org. Chem. 2011, 76, 10187−10197

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7.37−7.29 (m, 10H), 5.70 (t, J = 5.2 Hz, 1H), 4.91 (d, J = 11.2 Hz,
1H), 4.70 (dd, J = 11.6, 8.8 Hz, 2H), 4.52 (d, J = 11.6 Hz, 1H), 4.05
(dt, J = 9.6, 3.2 Hz, 1H), 3.98 (t, J = 9.2 Hz, 1H), 3.80−3.72 (m, 2H),
3.58 (dd, J = 9.6, 5.6 Hz, 1H), 3.48 (t, J = 9.4 Hz, 1H), 2.70 (br s, 1H),
1.89 (d, J = 5.2 Hz, 1H), 1.78 (br s, 1H). 13C NMR (100 MHz,
CDCl3): δ 138.1, 137.1, 128.6, 128.5, 128.20, 128.18, 128.1, 127.9,
78.6, 78.0, 76.6, 74.6, 73.4, 72.0, 71.4, 61.7. ESI-MS m/z 399.2 [M +
Na]+. ESI-HRMS calcd for C20H24NaO5S [M + Na]+ 399.1242; found
399.1250.
Hz, 1H), 4.68 (dd, J = 11.2, 8.4 Hz, 2H), 4.24−4.20 (m, 1H), 4.04 (t,
J = 9.2 Hz, 1H), 3.90 (dd, J = 9.2, 5.2 Hz, 1H), 3.71−3.60 (m, 2H),
2.63 (dd, J = 9.6, 6.0 Hz, 1H), 1.96 (d, J = 4.8 Hz, 1H). 13C NMR
(100 MHz, CDCl3): δ 165.5, 137.3, 136.9, 133.0, 129.9, 129.7, 128.38,
128.35, 128.34, 128.1, 127.9, 127.87, 127.86, 78.3, 76.1, 75.2, 74.4,
73.9, 71.8, 71.7, 61.4. ESI-MS m/z 503.5 [M + Na]+. ESI-HRMS calcd
for C27H28NaO6S [M + Na]+ 503.1504; found 503.1485.
3-O-Acetyl-2,4-di-O-benzyl-1-thio-α-D-glucopyranose (46). Thiol
46 was obtained, after purification by flash column chromatography
(petroleum ether/EtOAc, 4:1), as a colorless syrup in 89% yield: [α]D
2,3-Di-O-benzyl-1-thio-α-D-glucopyranose (41). Thiol 41 was
obtained, after purification by flash column chromatography
(petroleum ether/EtOAc, 3:2), as an amorphous solid in 83% yield:
[α]D +43.4 (c 0.6 CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.38−7.31
(m, 10H), 5.74 (t, J = 4.8 Hz, 1H), 5.00 (d, J = 11.6 Hz, 1H), 4.74 (dd,
J = 18.0, 11.6 Hz, 2H), 4.62 (d, J = 11.6 Hz, 1H), 4.10−4.05 (m, 1H),
3.81−3.79 (m, 2H), 3.75 (dd, J = 9.2, 5.2 Hz, 1H), 3.71 (t, J = 9.0 Hz,
1H), 3.55 (t, J = 9.2 Hz, 1H), 2.36 (br s, 1H), 1.93 (d, J = 4.8 Hz, 1H),
1.84 (br s, 1H). 13C NMR (100 MHz, CDCl3): δ 138.4, 137.3, 128.6,
128.5, 128.1, 128.04, 128.01, 127.98, 127.95, 127.91, 80.8, 78.9, 78.7,
75.3, 72.1, 71.8, 70.0, 62.3. ESI-MS m/z 399.4 [M + Na]+. ESI-HRMS
calcd for C20H24NaO5S [M + Na]+ 399.1242; found 399.1249.
3-O-Benzyl-1-thio-α-D-glucopyranose (42). Thiol 42 was
obtained, after purification by flash column chromatography
(petroleum ether/EtOAc, 2:3), as an amorphous solid in 76% yield:
[α]D +92.3 (c 0.5 CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.38−7.30
(m, 5H), 5.64 (t, J = 5.8 Hz, 1H), 4.95 (d, J = 11.6 Hz, 1H), 4.82 (d,
J = 11.6 Hz, 1H), 4.00−3.96 (m, 1H), 3.98−3.82 (m, 3H), 3.62 (t, J =
8.6 Hz, 1H), 3.51 (t, J = 9.2 Hz, 1H), 2.51 (br s, 1H), 2.37 (d, J = 6.4
Hz, 1H), 1.97 (d, J = 6.8 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ
128.7, 128.1, 127.9, 82.1, 80.7, 75.1, 72.5, 71.6, 70.2, 62.2; ESI-MS m/z
309.3 [M + Na]+. ESI-HRMS calcd for C13H18NaO5S [M + Na]+
309.0773; found 309.0782.
1
+60.2 (c 0.4 CHCl3). H NMR (400 MHz, CDCl3): δ 7.34−7.30 (m,
10H), 5.70 (t, J = 4.8 Hz, 1H), 5.45 (t, J = 9.4 Hz, 1H), 4.68 and
4.50 (AB peak, J = 12.0 Hz, 2H), 4.62 (s, 2H), 4.15 (d-like, J = 9.6,
1H), 3.80 (br s, 2H), 3.69−3.60 (m, 2H), 2.07 (d, J = 4.4 Hz, 1H),
1.98 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 169.9, 137.7, 137.3,
128.59, 128.55, 128.13, 128.12, 128.10, 128.07, 78.4, 76.5, 75.4, 74.5,
73.2, 71.9, 71.7, 61.4, 21.0. MALDI-MS m/z 441.1 [M + Na]+.
MALDI-HRMS calcd for C22H26NaO6S [M + Na]+ 441.1348; found
441.1352.
2-O-Acetyl-3,4-di-O-benzyl-1-thio-α-D-glucopyranose (47). Thiol
47 was obtained, after purification by flash column chromatography
(petroleum ether/EtOAc, 4:1), as a colorless syrup in 78% yield: [α]D
1
+69.7 (c 0.6 CHCl3). H NMR (400 MHz, CDCl3): δ 7.36−7.25
(m, 10H), 5.86 (t, J = 5.8 Hz, 1H), 4.96 (dd, J = 10.5, 6.1 Hz, 1H),
4.87 (d, J = 8.8 Hz, 1H), 4.84 (d, J = 9.2 Hz, 1H), 4.79 (d, J = 11.6 Hz,
1H), 4.68 (d, J = 10.8 Hz, 1H), 4.11 (td, J = 9.6, 3.2 Hz, 1H), 3.93 (t,
J = 9.4 Hz, 1H), 3.81−3.79 (m, 1H), 3.78 (t, J = 4.0 Hz, 1H), 3.67−
3.62 (m, 2H), 2.03 (s, 3H), 1.80 (d, J = 6.0 Hz, 1H). 13C NMR (100
MHz, CDCl3): δ 169.9, 138.7, 137.7, 128.5, 128.4, 128.1, 128.0, 127.7,
127.6, 79.9, 77.1, 75.5, 75.2, 73.1, 72.0, 61.6, 20.9. ESI-MS m/z 441.4
[M + Na]+. ESI-HRMS calcd for C22H26NaO6S [M + Na]+ 441.1348;
found 441.1361.
2-O-Benzyl-1-thio-α-D-glucopyranose (43). Thiol 43 was
obtained, after purification by flash column chromatography
(petroleum ether/EtOAc, 2:3), as an amorphous solid in 83% yield:
[α]D +87.4 (c 0.5 CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.38−7.32
(m, 5H), 5.92 (t, J = 4.6 Hz, 1H), 4.77 (d, J = 11.2 Hz, 1H), 4.52 (d,
J = 11.2 Hz, 1H), 4.26 (t, J = 4.4 Hz, 1H), 4.12 (br s, 1H), 4.01−3.94
(m, 2H), 3.90−3.85 (m, 2H), 2.84 (s, 1H), 2.57 (br s, 1H), 2.22 (br s,
1H), 1.83 (d, J = 4.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 137.1,
128.6, 128.2, 128.2, 78.5, 75.3, 71.9, 70.1, 70.0, 69.2, 63.1. ESI-MS m/z
309.4 [M + Na]+. ESI-HRMS calcd for C13H18NaO5S [M + Na]+
309.0773; found 309.0760.
General Procedure for the Synthesis of Thiols 44−51. To a
solution of the appropriate 1,6-anhydrosugars (1.0 mmol) and
bis(trimethylsilyl) sulfide (1.4 mmol) in CH2Cl2 (10 mL) was
added TMSOTf (0.8 mmol) at 0 °C. The mixture was then stirred at
50 °C overnight (10−15 h), then poured into aqueous NaHCO3, and
extracted with EtOAc. The organic layer was washed successively with
water and brine, dried over MgSO4, and concentrated in vacuo to give
a residue which was purified by flash column chromatography to afford
the corresponding α-glycosyl thiol.
2-O-Benzoyl-3,4-di-O-benzyl-1-thio-α-D-glucopyranose
(48). Thiol 48 was obtained, after purification by flash column
chromatography (petroleum ether/EtOAc, 5:1), as an amorphous
1
solid in 77% yield: [α]D +10.5 (c 0.9 CHCl3). H NMR (400 MHz,
CDCl3): δ 7.89 (d, J = 8.4 Hz, 2H), 7.58 (t, J = 7.2 Hz, 1H), 7.43 (t,
J = 8.0 Hz, 2H), 7.38−7.29 (m, 5H), 7.11 (m, 5H), 5.80 (t, J = 4.8 Hz,
1H), 5.19 (t, J = 9.6 Hz, 1H), 4.83 (d, J = 11.2 Hz, 1H), 4.74−4.63 (m,
3H), 4.24−4.21 (m, 1H), 4.04 (t, J = 9.4 Hz, 1H), 3.90 (dd, J = 9.2, 5.2
Hz, 1H), 3.69−3.59 (m, 2H), 1.97 (d, J = 4.8 Hz, 1H). 13C NMR (100
MHz, CDCl3): δ 166.6, 138.0, 137.4, 123.7, 128.55, 130.0, 129.1,
128.6, 128.58, 128.55, 128.54, 128.3, 128.2, 128.1, 128.0, 127.7, 79.0,
78.9, 78.3, 75.4, 72.6, 71.0, 70.8, 61.1. MALDI-MS m/z 503.2 [M +
Na]+. MALDI-HRMS calcd for C27H28NaO6S [M + Na]+ 503.1504;
found 503.1513.
3,4-Di-O-benzyl-2-O-pivaloyl-1-thio-α-D-glucopyranose
(49). Thiol 49 was obtained, after purification by flash column
chromatography (petroleum ether/EtOAc, 5:1), as a colorless syrup in
83% yield: [α]D +78.9 (c 1.4 CHCl3). 1H NMR (400 MHz, CDCl3): δ
7.31−7.23 (m, 10H), 5.77 (t, J = 4.8 Hz, 1H), 4.94 (t, J = 9.6 Hz, 1H),
4.88 (d, J = 10.8 Hz, 1H), 4.66 (t, J = 12.4, 11.6 Hz, 2H), 4.57 (d, J =
11.6 Hz, 1H), 4.12 (d, J = 9.6 Hz, 1H), 3.90 (t, J = 9.0 Hz, 1H), 3.84
(dd, J = 9.2, 5.2 Hz, 1H), 3.62 (dd, J = 12.8, 1.2 Hz, 1H), 3.49 (dd, J =
12.8, 3.6 Hz, 1H), 1.95 (d, J = 4.4 Hz, 1H), 1.18 (s, 9H). 13C NMR
(100 MHz, CDCl3): δ 178.7, 138.3, 137.4, 128.5, 128.4, 128.2, 128.1,
127.6, 127.4, 79.0, 78.9, 78.7, 75.4, 72.5, 70.0, 61.1, 39.0, 27.2. MALDI-
MS m/z 483.2 [M + Na]+. MALDI-HRMS calcd for C25H32NaO6S
[M + Na]+ 483.1817; found 483.1822.
4-O-Acetyl-2,3-di-O-benzyl-1-thio-α-D-glucopyranose (44). Thiol
44 was obtained, after purification by flash column chromatography
(petroleum ether/EtOAc, 4:1), as a colorless syrup in 84% yield: [α]D
1
+29.0 (c 0.25 CHCl3). H NMR (300 MHz, CDCl3): δ 7.35−7.29
(m, 10H), 5.74 (t, J = 4.6 Hz, 1H), 4.92−4.86 (m, 2H), 4.74−4.62 (m,
3H), 4.10 (d, J = 10.8 Hz, 1H), 3.90−3.79 (m, 2H), 3.64−3.52
(m, 2H), 2.46 (dd, J = 9.3, 5.4 Hz, 1H), 1.99 (s, 3H), 1.92 (d, J =
4.5 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 171.1, 138.3, 137.2,
128.5, 128.3, 128.09, 128.06, 127.7, 127.6, 78.82, 78.76, 78.4, 75.4,
72.6, 70.7, 70.3, 61.1, 20.8. ESI-MS m/z 441.3 [M + Na]+. ESI-HRMS
calcd for C22H26NaO6S [M + Na]+ 441.1348; found 441.1369.
4-O-Benzoyl-2,3-di-O-benzyl-1-thio-α-D-glucopyranose
(45). Thiol 45 was obtained, after purification by flash column
chromatography (petroleum ether/EtOAc, 3:1), as an amorphous
2-Azido-3,4-di-O-benzyl-1-thio-α-D-glucopyranose (50). Thiol
50 was obtained, after purification by flash column chromatography
(petroleum ether/EtOAc, 3:1), as a colorless syrup in 86% yield: [α]D
1
+87.1 (c 0.5 CHCl3). H NMR (400 MHz, CDCl3): δ 7.36−7.30 (m,
10H), 5.66 (t, J = 5.0 Hz, 1H), 4.89 (d, J = 4.4 Hz, 2H), 4.85 (d, J =
2.8 Hz, 1H), 4.69 (d, J = 11.2 Hz, 1H), 4.09 (dt, J = 10.0, 3.2 Hz, 1H),
3.84−3.81 (m, 2H), 3.79−3.76 (m, 2H), 3.68 (d, J = 8.4 Hz, 1H),
3.64−3.61 (m, 1H), 1.96 (d, J = 5.6 Hz, 1H). 13C NMR (100 MHz,
CDCl3): δ 137.6, 137.4, 128.6, 128.5, 128.10, 128.07, 128.0, 127.9,
81.0, 78.5, 77.6, 75.7, 75.1, 72.6, 64.0, 61.4. ESI-MS m/z 400.2
1
solid in 66% yield: [α]D +19.0 (c 1.0 CHCl3). H NMR (400 MHz,
CDCl3): δ 8.00−7.98 (m, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.8
Hz, 2H), 7.38−7.31 (m, 5H), 7.16−7.11 (m, 5H), 5.79 (t, J = 5.0 Hz,
1H), 5.20−5.15 (m, 1H), 4.85 (d, J = 11.2 Hz, 1H), 4.75 (d, J = 11.6
10195
dx.doi.org/10.1021/jo202069y|J. Org. Chem. 2011, 76, 10187−10197

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Article
[M-H]−. ESI-HRMS calcd for C20H22O4N3S [M-H]− 400.1331; found
400.1318.
after purification by flash column chromatography (petroleum ether/
EtOAc, 3:1), as an amorphous solid in 72% yield: [α]D +48.5 (c 0.7
1
3,4-Di-O-acetyl-2-O-benzyl-1-thio-α-D-glucopyranose (51). Thiol
51 was obtained, after purification by flash column chromatography
(petroleum ether/EtOAc, 4:1), as an amorphous solid in 30% yield:
CHCl3). H NMR (400 MHz, CDCl3): δ 7.43−7.28 (m, 10H), 5.65
(t, J = 5.2 Hz, 1H), 5.19−4.99 (m, 5H), 4.62−4.55 (m, 3H), 4.26 (dd,
J = 12.4, 4.4 Hz, 1H), 4.17 (t, J = 9.0 Hz, 1H), 4.12 (dd, J = 14.4, 7.2
Hz, 1H), 4.05−4.00 (m, 2H), 3.75−3.66 (m, 3H), 3.63−3.59 (m, 1H),
3.50 (t, J = 9.6 Hz, 1H), 2.08 (s, 3H), 2.01 (s, 6H), 1.98 (s, 3H), 1.83
(d, J = 4.8 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 170.6, 170.1,
169.3, 169.2, 138.2, 136.8, 128.7, 128.40, 128.39, 128.36, 128.1, 127.8,
100.3, 79.7, 78.7, 78.1, 75.1, 74.6, 73.0, 72.6, 72.0, 71.7, 71.5, 68.3,
61.8, 61.7, 20.8, 20.59, 20.57, 20.5. ESI-MS m/z 729.6 [M + Na]+.
ESI-HRMS calcd for C34H42NaO14S [M + Na]+ 729.2193; found
729.2225.
1
[α]D +126.9 (c 0.3 CHCl3). H NMR (400 MHz, CDCl3): δ 7.35−
7.23 (m, 5H), 5.74 (t, J = 4.9 Hz, 1H), 5.42 (t, J = 9.6 Hz, 1H), 4.93
(t, J = 9.8 Hz, 1H), 4.67 and 4.52 (AB peak, J = 12.0 Hz, 2H), 4.19
(d-like, J = 10.0 Hz, 1H), 3.77 (dd, J = 9.6, 5.2 Hz, 1H), 3.70−3.56 (m,
2H), 2.06 (s, 3H), 2.04 (d, J = 4.4 Hz, 1H), 2.02 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 170.9, 170.0, 137.0, 128.6, 128.2, 127.9, 78.4,
76.0, 72.2, 71.1, 70.4, 68.8, 60.9, 20.8, 20.7. MALDI-MS m/z 393.1
[M + Na]+. MALDI-HRMS calcd for C17H22NaO7S [M + Na]+
393.0984; found 393.0985.
O-(2,3,4,6-Tetra-O-acetyl-α-D-glucopyranosyl)-(1→4)-O-
(2,3,6-tri-O-acetyl-β-D-glucopyranosyl)-(1→3)-2,4-di-O-benzyl-
1-thio-α-D-glucopyranose (56). Thiol 56 was obtained, after puri-
fication by flash column chromatography (petroleum ether/EtOAc,
2:1), as an amorphous solid in 65% yield: [α]D +22.0 (c 0.3 CHCl3).
1H NMR (400 MHz, CDCl3): δ 7.44 (m, 4H), 7.37−7.29 (m, 6H),
5.64 (t, J = 5.2 Hz, 1H), 5.38 (d, J = 4.0 Hz, 1H), 5.34−5.29 (m, 1H),
5.22 (t, J = 9.2 Hz, 1H), 5.16 (d, J = 8.0 Hz, 1H), 5.04 (dd, J = 10.0,
9.8 Hz, 2H), 4.95 (d, J = 9.6 Hz, 1H), 4.90−4.89 (m, 1H), 4.87 (dd,
J = 10.4, 4.0 Hz, 1H), 4.61−4.54 (m, 3H), 4.35 (dd, J = 12.0, 2.8 Hz,
1H), 4.24−4.18 (m, 2H), 4.17−4.11 (m, 2H), 4.06−4.05 (m, 1H),
4.00 (s, 1H), 3.96 (d, J = 8.8 Hz, 1H), 3.93−3.89 (m, 1H), 3.69−3.66
(m, 2H), 3.63−3.59 (m, 1H), 3.48 (t, J = 9.2 Hz, 1H), 2.08, 2.07, 2.06,
2.019, 2.016, 2.00, 1.99 (each s, each 3H), 1.84 (d, J = 4.8 Hz, 1H).
13C NMR (100 MHz, CDCl3): δ 170.44, 170.40, 170.1, 169.8, 169.6,
3,4-Di-O-benzoyl-2-O-benzyl-1-thio-α-D-galactopyranose
(52). Thiol 52 was obtained, after purification by flash column
chromatography (petroleum ether/EtOAc, 3:1), as an amorphous
1
solid in 69% yield: [α]D +50.0 (c 0.3 CHCl3). H NMR (400 MHz,
CDCl3): δ 8.03−8.01 (m, 1H), 7.92−7.91 (m, 2H), 7.86−7.82 (m,
2H), 7.64−7.59 (m, 1H), 7.52−7.43 (m, 3H), 7.34−7.27 (m, 6H),
5.97 (t, J = 4.6 Hz, 1H), 5.74 (d, J = 3.2 Hz, 1H), 5.67 (dd, J = 10.4,
3.2 Hz, 1H), 4.76 (d, J = 12.4 Hz, 1H), 4.65 (dd, J = 13.6, 6.8 Hz, 1H),
4.61 (d, J = 12.4 Hz, 1H), 4.36 (dd, J = 10.0, 5.2 Hz, 1H), 3.69 (dd, J =
12.0, 5.2 Hz, 1H), 3.58 (dd, J = 13.2, 6.8 Hz, 1H), 2.36 (t, J = 6.8 Hz,
1H), 2.07 (d, J = 4.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 166.6,
165.2, 137.0, 133.6, 133.3, 133.1, 129.9, 129.6, 129.4, 129.0, 128.59,
128.58, 128.40, 128.39, 128.3, 128.1, 128.0, 79.1, 77.2, 72.5, 72.1, 70.1,
69.9, 60.7. ESI-MS m/z 495.6 [M + H]+. ESI-HRMS calcd for
C27H26NaO7S [M + Na]+ 517.1297; found 517.1306.
General Procedure for the Synthesis of Thiols 53−58. To a
solution of the appropriate 1,6-anhydrosugars (1.0 mmol) and
bis(trimethylsilyl) sulfide (1.4 mmol) in CH2Cl2 (10 mL) was
added TMSOTf (0.6 mmol) at 0 °C. The mixture was then stirred at
50 °C overnight (>6 h), then poured into aqueous NaHCO3, and
extracted with EtOAc. The organic layer was washed successively with
water and brine, dried over MgSO4, and concentrated in vacuo to give
a residue which was purified by flash column chromatography to afford
the corresponding α-glycosyl thiol.
169.4, 138.3, 136.9 128.7, 128.5, 128.41, 128.37, 128.0, 127.8, 99.9,
95.6, 79.6, 78.9, 78.1, 77.1, 75.4, 75.1, 74.4, 72.8, 72.7, 72.1, 71.5, 70.0,
69.4, 68.5, 68.0, 63.0, 61.7, 61.5, 20.88, 20.81, 20.62, 20.61, 20.55,
20.54. ESI-MS m/z 1018.0 [M + Na]+. ESI-HRMS calcd for
C46H58NaO22S [M + Na]+ 1017.3038; found 1017.3019.
O-(2,3-Di-O-benzyl-α-D-glucopyranosyl)-(1→4)-2,3-di-O-
benzyl-1-thio-α-D-glucopyranose (57). Thiol 57 was obtained,
after purification by flash column chromatography (petroleum ether/
EtOAc, 2:3), as an amorphous solid in 74% yield: [α]D +24.4 (c 2.9
CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.32−7.25 (m, 12H), 7.23−
7.22 (m, 4H), 7.17−7.15 (m, 4H), 5.72 (m, 2H), 5.03 (d, J = 12.0 Hz,
1H), 4.93 (d, J = 11.2 Hz, 1H), 4.71 (d, J = 12.0 Hz, 1H), 4.64 (d, J =
11.6 Hz, 2H), 4.51−4.49 (m, 3H), 4.21 (d, J = 10.0 Hz, 1H), 4.09 (t,
J = 9.2 Hz, 1H), 3.98 (t, J = 8.6 Hz, 2H), 3.90 (d-like, J = 12.0 Hz,
1H), 3.81−3.79 (m, 2H), 3.75−3.71 (m, 3H), 3.46−3.39 (m, 3H),
2.41 (br s, 1H), 2.31 (br s, 1H), 1.95 (d, J = 4.8 Hz, 1H). 13C NMR
(100 MHz, CDCl3): δ 139.0, 138.7, 137.9, 137.4, 128.8, 128.7, 128.6,
128.5, 128.4, 128.3, 128.2, 128.0, 127.9, 127.8, 127.4, 126.6, 97.2, 81.8,
81.5, 79.6, 79.3, 78.8, 77.4, 75.5, 74.3, 73.4, 72.6, 71.6. ESI-MS m/z
741.5 [M + Na]+. ESI-HRMS calcd for C40H46NaO10S [M + Na]+
741.2709; found 741.2740.
O-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-(1→2)-3,4-di-
O-benzyl-1-thio-α-D-glucopyranose (53). Thiol 53 was obtained,
after purification by flash column chromatography (petroleum ether/
EtOAc, 2:1), as an amorphous solid in 58% yield: [α]D +47.9 (c 0.7
1
CHCl3). H NMR (400 MHz, CDCl3): δ 7.33−7.26 (m, 10H), 5.65
(t, J = 5.1 Hz, 1H), 5.14 (ddd, J = 12.1, 9.4, 7.0 Hz, 2H), 5.02 (d, J =
10.2 Hz, 1H), 4.97 (d, J = 10.6 Hz, 1H), 4.88 (dd, J = 16.2, 7.7 Hz,
2H), 4.65 (d, J = 11.6 Hz, 1H), 4.57 (d, J = 11.6 Hz, 1H), 4.13 (dd, J =
12.4, 3.6 Hz, 1H), 4.03 (d, J = 9.2 Hz, 1H), 3.88−3.82 (m, 3H), 3.77
(s, 2H), 3.71 (dd, J = 8.2, 5.5 Hz, 1H), 3.45 (d, J = 9.2 Hz, 1H), 2.07
(s, 3H), 1.99 (s, 3H), 1.98 (s, 3H), 1.97 (s, 3H), 1.95 (d, J = 4.9 Hz,
1H). 13C NMR (100 MHz, CDCl3): δ 170.6, 170.3, 169.5, 169.3,
139.0, 137.3, 128.4, 128.2, 128.1, 128.0, 127.3, 126.8, 100.8, 79.6, 78.7,
78.6, 76.7, 74.8, 73.1, 72.5, 72.1, 71.8, 71.3, 67.8, 61.5, 60.6, 20.72,
20.67, 20.60, 20.57. ESI-MS m/z 729.8 [M + Na]+. ESI-HRMS calcd
for C34H42NaO14S [M + Na]+ 729.2193; found 729.2204.
O-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-(1→4)-O-
[2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl-(1→6)]-O-(2,3-di-O-
benzyl-α-D-glucopyranosyl)-(1→4)-2,3-di-O-benzyl-1-thio-α-D-
glucopyranose (58). Thiol 58 was obtained, after purification by
flash column chromatography (petroleum ether/EtOAc, 1:1), as an
1
amorphous solid in 81% yield: [α]D +19.4 (c 0.7 CHCl3). H NMR
O-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-(1→2)-1-thio-
α-D-galactopyranose (54). Thiol 54 was obtained, after purification
by flash column chromatography (petroleum ether/EtOAc, 1:1), as an
(400 MHz, CDCl3): δ 7.33−7.16 (m, 20H), 5.74 (t, J = 5.0 Hz, 1H),
5.62 (d, J = 3.2 Hz, 1H), 5.54 (t, J = 9.8 Hz, 1H), 5.47 (t, J = 3.4 Hz,
1H), 5.18 (t, J = 9.4 Hz, 1H), 5.08 (t, J = 9.8 Hz, 3H), 5.03−4.96 (m,
2H), 4.93−4.85 (m, 3H), 4.73 (dd, J = 12.8, 8.8 Hz, 1H), 4.66 (dd, J =
13.6, 12.0 Hz, 2H), 4.59 (d, J = 7.6 Hz, 1H), 4.53 (t, J = 5.6 Hz, 2H),
4.28−4.25 (m, 1H), 4.26−4.24 (m, 1H), 4.24−4.21 (m, 1H), 4.17−
4.14 (m, 1H), 4.14 (m, 1H), 4.12−4.07 (m, 1H), 4.04 (dd, J = 10.4,
2.4 Hz, 1H), 3.99−3.94 (m, 2H), 3.86−3.83 (m, 1H), 3.82−3.75 (m,
2H), 3.77−3.75 (m, 1H), 3.74 (d, J = 4.4 Hz, 1H), 3.64−3.61 (m,
1H), 3.45−3.40 (m, 1H), 3.06 (d, J = 3.2 Hz, 1H), 2.41 (d, J = 2.8 Hz,
1H), 2.09, 2.08, 2.06, 2.03, 2.02, 2.01 (each s, each 3H), 1.99 (s, 6H),
1.95 (d, J = 4.8 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 170.71,
170.67, 170.2, 170.1, 170.0, 169.6, 169.5, 169.3, 138.7, 138.5, 137.7,
137.2, 128.5, 128.4, 128.3, 128.2, 128.0, 127.80, 127.77, 127.71,
127.68, 127.67, 127.2, 126.7, 100.8, 96.8, 95.6, 90.2, 81.3, 80.7, 79.4,
1
amorphous solid in 67% yield: [α]D +41.4 (c 0.5 CHCl3). H NMR
(500 MHz, CDCl3): δ 5.82 (t, J = 4.7 Hz, 1H), 5.21 (t, J = 7.5 Hz,
1H), 5.08 (t, J = 9.7 Hz, 1H), 5.03 (dd, J = 9.5, 8.0 Hz, 1H), 4.76 (d,
J = 7.5 Hz, 1H), 4.25 (dd, J = 12.5, 2.5 Hz, 1H), 4.19−4.17 (m, 2H),
4.16−4.14 (m, 1H), 4.10 (dd, J = 9.5, 5.0 Hz, 1H), 3.97−3.90 (m,
3H), 3.74−3.69 (m, 1H), 3.16 (br s, 1H), 2.60 (br s, 1H), 2.28 (br s,
1H), 2.10 (s, 3H), 2.07 (s, 3H), 2.03 (s, 3H), 2.01 (s, 3H), 1.93 (d, J =
4.5 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 170.6, 170.2, 169.7,
169.3, 102.1, 79.6, 77.7, 72.6, 71.6, 68.3, 61.8, 20.8, 20.7, 20.6, 20.5.
ESI-MS m/z 549.5 [M + Na]+. ESI-HRMS calcd for C20H30NaO14S
[M + Na]+ 549.1254; found 549.1255.
O-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-(1→3)-2,4-di-
O-benzyl-1-thio-α-D-glucopyranose (55). Thiol 55 was obtained,
10196
dx.doi.org/10.1021/jo202069y|J. Org. Chem. 2011, 76, 10187−10197

The Journal of Organic Chemistry
Article
78.5, 77.2, 75.0, 74.1, 73.3, 73.1, 72.7, 72.3, 72.1, 71.9, 71.4, 71.2, 70.4,
68.9, 68.4, 67.3, 61.9, 20.71, 20.69, 20.66, 20.63, 20.57, 20.56, 20.53.
ESI-MS m/z 1379.2 [M]+. ESI-HRMS calcd for C68H82O28NaS [M +
Na]+ 1401.4611; found 1401.4659.
(17) For some examples of the synthesis of β-glycosyl thiols, see:
(a) Fulton, D. A.; Stoddart, J. F. J. Org. Chem. 2001, 66, 8309−8319.
(b) Ibatullin, F. M.; Shabalin, K. A.; Janis, J. V.; Shavva, A. G.
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Tetrahedron Lett. 2003, 44, 7961−7964. (c) Xue, W.; Cheng, X.; Fan,
J.; Diao, H.; Wang, C.; Dong, L.; Luo, Y.; Chen, J.; Zhang, J.
Tetrahedron Lett. 2007, 48, 6092−6095. (d) Pei, Z.; Dong, H.;
ASSOCIATED CONTENT
■
Caraballo, R.; Ramstrom, O. Eur. J. Org. Chem. 2007, 4927−4934.
̈
S
* Supporting Information
(18) Dere, R. T.; Wang, Y.; Zhu, X. Org. Biomol. Chem. 2008, 6,
2061−2063.
1H NMR and 13C NMR spectra for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(19) Dere, R. T.; Kumar, A.; Kumar, V.; Zhu, X.; Schmidt, R. R.
J. Org. Chem. 2011, 76, 7539−7545.
(20) So far, only a few indirect procedures were reported for the
synthesis of α-glycosyl thiols. See: (a) Blanc-Muesser, M.; Vigne, L.;
Driguez, H. Tetrahedron Lett. 1990, 31, 3869−3870. (b) Gadelle, A.;
AUTHOR INFORMATION
Corresponding Author
*Tel +353 17162386; Fax +353 17162501; e-mail Xiangming.
Zhu@ucd.ie.
■
Defaye, J. Carbohydr. Res. 1990, 200, 497−498. (c) Ane,
Naud, S.; Lacone, V.; Vidot, S.; Fournial, A.; Kar, A.; Pipelier, M.;
Dubreuil, D. Tetrahedron 2006, 62, 4784−4794.
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A.; Josse, S.;
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ACKNOWLEDGMENTS
■
This work was supported by Research Frontier Program of
Science Foundation Ireland and the Natural Science
Foundation of Zhejiang Province (R4110195).
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