A direct and stereospecific approach to the synthesis of α-glycosyl thiols

Article abstract of DOI:10.1039/b804536d

A new simple method for the synthesis of α-glycosyl thiols is described. Ring-opening of 1,6-anhydrosugars with commercially available bis(trimethylsilyl)sulfide under the action of catalytic amounts of TMSOTf smoothly afforded α-glycosyl thiols in very high yields and in a stereospecific way. The Royal Society of Chemistry 2008.

Full text of DOI:10.1039/b804536d

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www.rsc.org/obc | Organic & Biomolecular Chemistry
A direct and stereospecific approach to the synthesis of a-glycosyl thiols†
Ravindra T. Dere,a Yingxi Wanga and Xiangming Zhu*a,b
Received 19th March 2008, Accepted 16th April 2008
First published as an Advance Article on the web 30th April 2008
DOI: 10.1039/b804536d
A new simple method for the synthesis of a-glycosyl thiols is
described. Ring-opening of 1,6-anhydrosugars with commer-
cially available bis(trimethylsilyl)sulfide under the action of
catalytic amounts of TMSOTf smoothly afforded a-glycosyl
thiols in very high yields and in a stereospecific way.
To a great extent, the nonconventional approach for the
synthesis of thioglycosides became popular due to the chemical
stability of glycosyl thiols. Unlike sugar hemiacetals, glycosyl
thiols are quite stable, and the thioglycosyl anions do not
mutarotate even under basic conditions.10 As such, the anomeric
configuration of a glycosyl thiol can be maintained during the
formation of its corresponding thioglycoside products, rendering
the stereoselective synthesis of a- and b-glycosyl thiols extremely
important. The configurationally pure b-glycosyl thiols, such as
b-glucosyl thiol and b-galactosyl thiol, could be readily obtained
usually by treatment of a-glycosyl halides with thiourea followed
by hydrolysis with alkali metal disulfite.11
However, to our knowledge, in the literature no direct procedure
for the stereoselective preparation of normal a-glycosyl thiols
has been reported,12 although a-GlcNAc- and a-GalNAc-derived
anomeric thiols could be readily prepared from the corresponding
peracetylated sugars by virtue of their neighbouring acetamide
groups.13 Only b-glycosyl chlorides have been used occasionally to
prepare a-glycosyl thiols in a multi-step procedure,12a nevertheless,
the reproducibility of this procedure is very low due to the highly
reactive b-chlorides. Recently, Lawesson reagent has been reported
capable of directly converting reducing sugars or unprotected
sugars into the corresponding glycosyl thiols.14 However, in this
procedure configurationally unpure glycosyl thiols were often
produced.
Given the great value of thioglycosides in biological studies
and the wide occurrence of a-glycosidic linkages in various
glycoconjugates, there is a high demand for the development of
procedures for the stereoselective synthesis of a-glycosyl thiols that
can be used to construct a-thioglycosides. We have a long-standing
interest in the synthesis of sugar analogues of enhanced chemical
and enzymatic stability,15 particularly S-linked glycoconjugates
with a view to providing interesting structures for biological
studies. We report herein a direct and stereospecific approach for
the synthesis of a-glycosyl thiols.
The major challenge associated with the synthesis of a-glycosyl
thiols lies in the stereoselectivity. Although this type of compound
could conceivably be prepared by activation of normal glycosyl
donors without a neighbouring participating group in the presence
of a proper sulfur nucleophile, this process did not always lead
to the predominant formation of a-thiosugars. On the contrary,
sometimes b-products were produced as the major or only
products.16 Furthermore, in this way two or even more steps are
usually required in order to secure the thiols. Also, based on our
experience isolation of an isomerically pure glycosyl thiol from
an a/b-mixture would be very troublesome if both anomers were
produced in the glycosidation reactions.
The importance of carbohydrates and glycoconjugates in nu-
merous biochemical processes has stimulated the development
of glycomimetics as fundamental tools for biological research
and as potential agents for therapeutic intervention. In this
context, thioglycosides have attracted considerable attention due
to their resistance to chemical and enzymatic hydrolysis and their
similar solution conformation and biological activities compared
to native counterparts.1 As a consequence, many efforts have
been devoted in the past two decades towards synthesis of
thioglycosides, including thiosaccharides and S-glycoconjugates,
in order to provide valuable compounds for biological studies.2
For instance, an S-linked glycopeptide carrying two sugar moieties
has been synthesized recently in solution phase, which mimics the
peptide sequence Ala484-Ala490 in the Tamm-Horsfall protein
(THP). Apparently, this catabolically stable compound is of great
interest for further unraveling the biological role of THP.3 Also,
carbohydrate epitopes of conjugate vaccines have been modified to
contain S-linked residues and the resulting S-linked immunogens
generated an antigen-specific immune response that even exceeded
the response to the native oligosaccharides.4
Currently, glycosyl thiols or their precursors, such as anomeric
thioacetates, which can be S-deacetylated in situ to generate
the desired glycosyl thiols, are the key building blocks for the
construction of thioglycosides,2 although thioglycosides can also
be synthesized conventionally from normal glycosyl donors and
the corresponding sulfur-containing acceptors.5 By this non-
conventional approach, a variety of thioglycosides have been
synthesized as stable glycoside analogues and potential agents
for therapeutic intervention.2,6 For example, S-glycopeptides have
been synthesized recently by two independent groups, who both
utilized glycosyl thiols as sugar building blocks.6a,b In addition,
glycosyl thiols are also useful in the synthesis of many other
carbohydrate contexts, such as C-glycoside synthesis,7 glycosyl
sulfenamide and glycosyl sulfonamide synthesis,8 and glycosyl
disulfide synthesis.9
aCentre for Synthesis and Chemical Biology, UCD School of Chemistry and
Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland
bZhejiang Key Laboratory for Reactive Chemistry on Solid Surfaces, College
of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua 321004,
P R China. E-mail: Xiangming.Zhu@ucd.ie; Fax: +86 (0)353 17162501;
Tel: +86 (0)353 17162386
In the course of our studies on the synthesis of S-linked galac-
tosylceramides, we required a convenient access to a series of a-
glycosyl thiols, as shown in Scheme 1. At the very outset, attempts
† Electronic supplementary information (ESI) available: General proce-
dures for the synthesis of a-glycosyl thiols, 1H and 13C NMR spectra of all
products. See DOI: 10.1039/b804536d
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Table 1 Synthesis of a-glycosyl thiolsa
to use the above-mentioned b-glycosyl chloride-based procedure
for the synthesis of the a-glycosyl thiols met with difficulties in
the preparation of the required b-glycosyl chlorides. Hence, our
attention turned toward the present procedure. We envisioned that
1,6-anhydrosugars17 could serve perfectly as glycosylating agents
for the synthesis of a-glycosyl thiols because b-attack of 1,6-
anhydrosugars by any nucleophiles would not be possible if the
reactions undergo the SN2-type pathway. Also, we anticipated that
commercially available bis(trimethylsilyl)sulfide could be used 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 glycosidation conditions. To verify
these hypotheses, we performed exploratory experiments with 1,6-
anhydrogalactose 1 (Table 1). Treatment of 1 with a small excess
of bis(trimethylsilyl)sulfide in the presence of catalytic amounts
of TMSOTf at room temperature failed to provide any glycosyl
thiols. However, when the reaction mixture was heated to 50 ◦C,
6 was produced in very high yield as exclusively the a anomer
(Table 1, entry 1). The reaction was very clean as indicated by
TLC, and the anomeric configuration of the product could be
readily determined by NMR spectroscopy.
Entry Substrate
1
Product
Yield (%)b a/b ratio
88
90
78
85
92
a only
a only
a only
a only
a only
2
3
4
5
a All reactions were conducted under the same conditions; see text for
details. b Isolated yield following chromatography.
In summary, we have presented a highly stereoselective method
for the synthesis of a-glycosyl thiols by ring-opening of 1,6-
anhydrosugars with bis(trimethylsilyl)sulfide. All the a-glycosyl
thiols were isolated in high to excellent yields as exclusively the a
anomer. No trace of b-isomers was produced in the reactions. Thus
this one-step procedure provided a concise and efficient access to
a-glycosyl thiols, which could be used to synthesize various a-
S-linked glycoconjugates. Extended studies on the scope of the
reaction and application of the synthesized a-galactosyl thiols
towards the synthesis of a-S-galactosylceramides are currently
underway.
Scheme 1 Strategy for the synthesis of S-linked galactosylceramides.
Encouraged by this result, a range of properly protected
1,6-anhydrosugars were then prepared following the previous
procedure18 and subjected to the above ring-opening conditions
(Table 1). Each substrate (1 mmol) was treated under the same
conditions; it was dissolved in CH2Cl2 (10 mL) containing
bis(trimethylsilyl)sulfide (1.4 mmol). TMSOTf (0.4 mmol) was
added and the resulting mixture was heated at 50 ◦C until
TLC indicated complete consumption of the starting material.
The results, summarized in Table 1, indicate that under the
above reaction conditions, 1,6-anhydrosugars can be converted
effectively into a-glycosyl thiols in a stereospecific way. For
instance, the benzylated levoglucosan 2 could be ring-opened with
bis(trimethylsilyl)sulfide under the same reaction conditions to
give the desired a-glucosyl thiol 7 in 90% yield (Table 1, entry 2).
Similarly, configurationally pure thiol 8 could be produced from
the corresponding allylated levoglucosan 3 in very good yield.
Here it should be mentioned that levoglucosan derivatives have
been used previously to synthesize thioglycosides.19 In addition,
as shown in Table 1, excellent yields and a-selectivities were
also achieved for the conversion of 1,6-anhydrosugars 4 and 5
into glycosyl thiols 9 and 10, respectively. Also, in all the above
reactions, no disulfide formation was detected.
Acknowledgements
This work was supported by Research Frontier Program of Science
Foundation Ireland.
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The Royal Society of Chemistry 2008
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