Synthesis of glycosyl disulfides containing an α-glycosidic linkage

Article abstract of DOI:10.1016/j.tetlet.2013.07.093

A wide range of symmetrical and unsymmetrical glycosyl disulfides is synthesized with focus on the use of α-glycosyl thiols. Oxidation of α-glycosyl thiols with iodine leads to symmetrical α,α- glycosyl disulfides, while unsymmetrical disulfides are readily synthesized from α- and β-glycosyl thiols under the action of DDQ. Thus, glycosyl disulfides containing at least one α-glycosidic linkage are made available.

Full text of DOI:10.1016/j.tetlet.2013.07.093

Tetrahedron Letters 54 (2013) 5348–5350
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of glycosyl disulfides containing an
a-glycosidic linkage
Raymond Smith a, Xiaojun Zeng b, Helge Müller-Bunz a, Xiangming Zhu a,b,
⇑
a Centre for Synthesis and Chemical Biology, UCD School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland
b College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua 321004, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
A wide range of symmetrical and unsymmetrical glycosyl disulfides is synthesized with focus on the use
Received 10 June 2013
Revised 10 July 2013
Accepted 19 July 2013
Available online 29 July 2013
of
fides, while unsymmetrical disulfides are readily synthesized from
action of DDQ. Thus, glycosyl disulfides containing at least one -glycosidic linkage are made available.
a
-glycosyl thiols. Oxidation of
a
-glycosyl thiols with iodine leads to symmetrical
a,a-glycosyl disul-
a
- and b-glycosyl thiols under the
a
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Glycosyl disulfide
Glycosyl thiol
DDQ
Synthesis
Thioglycosides have been the subject of significant interest in
the glycomimetic field due to their high stability and excellent
similarity to native glycosides.1 In comparison, glycosyl disulfides
have not been investigated thoroughly and there are only a few
reports on their chemical and biological applications. However,
as glycomimetics, glycosyl disulfides sometimes display better
binding interactions with protein receptors because of the in-
creased conformational flexibility of the resulting molecules.
For example, glycosyl disulfides exhibit potent inhibitory effects
against the common plant lectin, concanavalin A, while the corre-
sponding thiosugars showed no significant binding.2 Conceivably,
the three-bond interglycosidic linkage (–S–S–) could adjust the
molecular shape to the active conformation in a more flexible
manner, thereby influencing the biological activity. Glycosyl
disulfides have been shown to act as biologically active ligands
in human tumor cell lines.3 Also, unsymmetrical disulfides have
been employed as reductively activated prodrugs to improve
the pharmacokinetic properties of the anticancer drug, paclit-
axel.4 In addition to biological applications, glycosyl disulfides
have also been demonstrated to be efficient glycosyl donors for
the synthesis of O-glycosides.5
unsymmetrical disulfides was less straightforward and often
required activation of one of the sulfhydryl groups prior to the
coupling reaction. Szilágyi and co-workers employed glycosyl-
thio-phthalimides and -succinimides as glycosylsulfenyl donors
to couple with various thiols to make mixed disulfides.8 Another
similar procedure involved in situ generation of glycosylsulfenyl
benzotriazole intermediates which were then exposed to the
second thiol to produce unsymmetrical disulfides.9 The reactions
were carried out in one-pot fashion at low temperature furnish-
ing the mixed disulfides in high to excellent yields. Aversa et al.
have reported a mild procedure for the synthesis of unsymmet-
rical disulfides,10 in which
a range of sulfenic acids was
prepared in situ as the activated thiols. Prior to the above work,
methanethiosulfonate was also introduced to an anomeric thiol
and acted as an effective leaving group in the presence of
another glycosyl thiol giving rise to mixed disulfides in good
yields.11 It should be noted here that glycomethanethiosulfo-
nates were used earlier as glycosylating agents to construct
S–S-linked glycoproteins.12 Mixed glycosyl disulfides were also
synthesized directly from two different thiols under the action
of diethyl azodicarboxylate, in a one-pot fashion, in very good
yields.13 Despite the above progress on the synthesis of glycosyl
A number of procedures are available in the literature for the
synthesis of glycosyl disulfides. In general, symmetrical glycosyl
disulfides are readily prepared by oxidation of the corresponding
glycosyl thiols or thiol precursors. For example, galactosyl thiol
was converted into a disulfide in very high yield by treatment
with I2.6 GlcNAc thiol was oxidized by mCPBA to provide the
corresponding disulfide in high yield.7 The synthesis of
disulfides, careful inspection reveals that normal
a-glycosyl thi-
ols, such as -glucosyl thiol and -galactosyl thiol, have not
a
a
been used for the synthesis of disulfides (these thiols are
thought to be less reactive due to stereoelectronic effects). Also,
the synthesis of glycosyl disulfides through direct coupling of
two thiols is rare in the literature. Therefore, we decided to
explore the synthesis of glycosyl disulfides with a view to
increase product variety by using
the arsenal of direct coupling methods.
a-glycosyl thiols and expand
⇑
Corresponding author. Tel.: +353 17162386; fax: +353 17162501.
E-mail address: Xiangming.Zhu@ucd.ie (X. Zhu).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.093

R. Smith et al. / Tetrahedron Letters 54 (2013) 5348–5350
5349
Different glycosyl thiols were first prepared in order to carry out
the synthesis of glycosyl disulfides. -Glycosyl thiols 1 and 2 were
Next, we turned our attention to the investigation of the syn-
thesis of unsymmetrical disulfides with -glycosyl thiols as build-
a
a
synthesized from the corresponding benzylated 1,6-anhydrosugars
ing blocks. As mentioned above, in the literature, mixed disulfides
have been readily prepared from glycosyl thiols via glycosylsulfe-
nyl benzotriazole intermediates.9 Following this procedure, activa-
tion of thiol 1 with BtCl/BtH was conducted to generate in situ the
SBt intermediate, which was then treated with a solution of thiol
following a stereospecific procedure developed in our laboratory,14
and isolated exclusively as
a-anomers from the reaction mixture.
Thiol 1 was also converted into the acetylated 1-thiosugar 315 in
three steps, that is, Birch reduction, acetylation, and selective ano-
meric deacetylation. b-Glycosyl thiols 4–6 and
a-mannosyl thiol 7
416b in CH2Cl2, but unfortunately, no
a,b-linked disulfide was pro-
were readily prepared by standard literature procedures via reac-
tion of the corresponding fully acetylated glycosyl bromide with
thiourea and subsequent hydrolysis of the resulting thiouronium
salt with an alkali metal disulfide.16
With the glycosyl thiols in hand, their transformation into
disulfides was investigated, that is, the development of appropriate
conditions to form both symmetrical and unsymmetrical glycosyl
disulfides.
duced (Scheme 2). The reversed operation, that is, activation of
thiol 4 under the same conditions followed by the addition of thiol
1, did not furnish the desired product either. We speculated that
the free 6-OH group of thiol 1 might interfere with the reaction,
hence, 1 was converted into thiosugar 1118 as reported previously,
and then treated with 4, but again the reaction was found to be
unsuccessful. The products obtained in these reactions appeared
to be composed of b-thiosugars only, indicating that dimerization
of 4 predominated under the current conditions due, presumably,
to the higher nucleophilicity of b-glycosyl thiol. In comparison
As no previous examples of
in the literature, our first goal was to synthesize symmetrical
-disulfides with thiols 1–3 as the starting materials. Hence, 1
a,a-linked glycosyl disulfides exist
a,a
with a-thiols, b-thiols exhibit greater lone pair repulsion between
was treated with I2 in the presence of pyridine under standard con-
the anomeric sulfur and endocyclic oxygen, and such interactions
can cause the energy of the lone pair of the sulfur to be increased
and the lone pair thus becomes a better nucleophile.19 In compar-
ison, the orientation of these lone pairs relative to each other in
ditions.17 As expected, the reaction took place smoothly and gave
rise to
of thiol 2 with I2 under the same conditions led to the desired
-disulfide 9 in very good yield (77%). The acetyl-protected thiol
a,a-disulfide 8 in 70% yield (Scheme 1). Similarly, oxidation
a,a
a-anomers is such that any repulsion is minimized, resulting in
3 was also oxidized effectively with I2 to produce disulfide 10 in
them being poorer nucleophiles.
88% yield.
The setback with the Bt procedure led us to seek an alternative
method. Wang and co-workers have developed a new method for
the synthesis of unsymmetrical disulfides from simple aliphatic
and aromatic thiols using DDQ as the oxidant.20 This method is
particularly interesting due to its apparent selectivity for the exclu-
sive formation of unsymmetrical disulfides in spite of two different
thiols being present in the reaction mixture in equimolar ratio be-
fore addition of DDQ. We anticipated that this method might also
be applicable to the synthesis of mixed glycosyl disulfides. As a test
reaction, thiols 1 and 4 were first mixed together and then treated
with DDQ following Wang’s procedure.20 As expected, the desired
disulfide 12 was produced smoothly as indicated by TLC and was
isolated in 67% yield (Table 1, entry 1). Subsequently, a mixture
of thiols 2 and 4 was subjected to the same conditions, and the
OH
OH
BnO
BnO
OAc
O
O
O
BnO
BnO
AcO
AcO
BnO
1
BnO
2
AcO
SH
SH
SH
SH
3
OAc
OAc
OAc
AcO
AcO
O
O
O
AcO
AcO
AcO
AcO
SH
SH
NHAc
OAc
OAc
5
4
6
OAc
AcO
AcO
AcO
O
SH
7
unsymmetrical a,b-linked disulfide 13 was produced in good yield
(60%). Suitable crystals of 13 were obtained for X-ray analysis by
slow crystallization from dichloromethane and cyclohexane at
room temperature. The crystallographic data clearly show that a
disulfide linkage had formed (Fig. 1). To further exploit the DDQ
procedure for the synthesis of mixed glycosyl disulfides, reactions
of 2 with thiols 516a and 716a were also carried out in the presence
of DDQ. They proceeded satisfactorily and the desired disulfides 14
and 15 were isolated from the reaction mixtures in 62% and 64%
yields, respectively.
It should be mentioned here that the above reaction yields are
generally good but not excellent due to the formation of small
amounts of symmetrical b,b-disulfides, however, these are in line
with similar results obtained by Wang for secondary thiol starting
Figure 1. Prepared glycosyl thiols 1–7.
HO
O
BnO
BnO
BnO
OH
O
I2, py
S
BnO
BnO
S
OH
OBn
THF, 70%
BnO
SH
O
BnO
1
OBn
8
OH
BnO
BnO
O
BnO
BnO
OH
BnO
O
I2, py
S
S
OH
THF, 77%
BnO
SH
O
BnO
2
BnO
O
BtCl, BtH
CH2Cl2
OBn
1 or 4
9
SBt
AcO
AcO
AcO
O
Ref. 18
OAc
4 or 1
OAc
AcO
O
I2, py
S
AcO
AcO
S
OAc
OAc
O
BtCl, BtH
CH2Cl2
4
THF, 88%
BnO
BnO
AcO
By-products
SH
O
AcO
3
BnO
SH
OAc
10
11
Scheme 1. Synthesis of symmetrical disulfides 7 and 8.
Scheme 2. Attempted synthesis of a disulfide following Hunter’s procedure.9

5350
R. Smith et al. / Tetrahedron Letters 54 (2013) 5348–5350
Table 1
acetylated a-thiosugars might not be suitable for this coupling as
Synthesis of unsymmetrical glycosyl disulfides
the electron-withdrawing acetyl groups would further reduce the
reactivity of the anomeric sulfhydryl group, which would render
the homo-coupling of b-thiosugars more prominent. Indeed, when
Entry
1
Glycosyl thiols
Product
Yield (%)
67
1 + 4
HO
a
a
-thiol 3 was mixed with b-thiol 4 and treated with DDQ, the
,b-linked disulfide 18 was isolated in only 32% yield (entry 7) with
O
BnO
BnO
BnO
OAc
OAc
S
concomitant formation of the symmetrical b,b-disulfide as the
major product.
S
O
AcO
OAc
In summary, a series of symmetrical and unsymmetrical glyco-
12
syl disulfides containing normal
a-linkages has been synthesized
2
3
4
2 + 4
2 + 5
2 + 7
60
62
64
BnO OH
directly from the corresponding glycosyl thiols by oxidation with
either I2 or DDQ. All the disulfides were produced in generally good
yields, which dispelled our initial concerns regarding the relatively
low reactivity of a-glycosyl thiols. In particular, the DDQ-mediated
formation of unsymmetrical disulfides is very intriguing, and a
O
BnO
BnO
OAc
OAc
S
S
O
AcO
OAc
mechanistic study is in progress.
13
BnO OH
O
Acknowledgments
BnO
BnO
OAc
S
This work was supported by the University College Dublin and
the Natural Science Foundation of Zhejiang Province (R4110195).
R.S. is grateful for a demonstratorship from the UCD School of
Chemistry and Chemical Biology.
S
O
AcO
AcO
OAc
14
BnO OH
O
Supplementary data
BnO
BnO
S
S
OAc
OAc
Supplementary data (experimental procedure, characterization
data and X-ray crystallographic data of compound 13, as well as
copies of the 1H and 13C NMR of new compounds) associated with
this article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2013.07.093.
O
OAc
OAc
15
5
6
7
11 + 4
11 + 6
3 + 4
78
62
32
AcO
O
BnO
BnO
References and notes
BnO
OAc
OAc
S
S
O
O
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16
AcO
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a
-glycosidic linkage. To further demonstrate the effectiveness of
this method, we also investigated the use of the fully protected
thiol 11 as an -thiosugar building block. As expected, coupling
of -thiol 11 with b-thiol 4, under the same conditions as above
proceeded smoothly to give -linked disulfide 16 in a very good
yield (78%). Similarly, when 11 was exposed to b-GlcNAc thiol
21 in the presence of DDQ, the desired mixed disulfide 17 was pro-
duced readily in 62% yield. At this point, we speculated that fully
a
a
a
6
21. Paul, B.; Korytnyk, W. Carbohydr. Res. 1984, 126, 27–43.