Free-radical hydrothiolation of glycals: A thiol-ene-based synthesis of S-disaccharides

Article abstract of DOI:10.1016/j.tetlet.2011.11.140

A method for the synthesis of a new family of 1-deoxy S-disaccharides has been established via free-radical hydrothiolation of glycals by sugar thiols (thiol-ene coupling). The photoinduced coupling between four tri-O-acetyl-d-glycals and three different sugar thiols reveals that the reaction efficiency and stereoselectivity are highly dependent on the stereochemistry of the OAc groups at C3 and C4 of the glycal.

Full text of DOI:10.1016/j.tetlet.2011.11.140

Tetrahedron Letters 53 (2012) 702–704
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Free-radical hydrothiolation of glycals: a thiol-ene-based synthesis
of S-disaccharides
Samuele Staderini a, Angela Chambery b, Alberto Marra a, , Alessandro Dondoni b,
⇑
⇑
a Dipartimento di Chimica, Laboratorio di Chimica Organica, Università di Ferrara, Via L. Borsari 46, 44100 Ferrara, Italy
b Dipartimento di Scienze della Vita, II Università di Napoli, Via Vivaldi 43, 81100 Caserta, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A method for the synthesis of a new family of 1-deoxy S-disaccharides has been established via free-
Received 8 November 2011
Revised 28 November 2011
Accepted 30 November 2011
Available online 7 December 2011
radical hydrothiolation of glycals by sugar thiols (thiol-ene coupling). The photoinduced coupling
between four tri-O-acetyl-D-glycals and three different sugar thiols reveals that the reaction efficiency
and stereoselectivity are highly dependent on the stereochemistry of the OAc groups at C3 and C4 of
the glycal.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Allal
Galactal
Glucal
Gulal
Sugar thiols
Glycans and their conjugates deeply influence many fundamen-
tal biological processes in living organisms.1 They mediate a vari-
ety of events, including inflammation, immunological response,
fertilization, cancer metastasis, and viral and bacterial infection.2
Hence, there is an urgent need to provide usable quantities of
natural carbohydrates with a well defined structure and composi-
tion to be used in studies of those phenomena at molecular levels.
There is, however, substantial difficulty to obtain complex natural
O-linked oligosaccharides in a pure and homogeneous form from
natural sources because of the presence of mixtures of glycosylated
species (glycoforms). Moreover, these compounds display an
intrinsic instability toward chemical and enzymatic degradation
due to the readily hydrolizable exocylic carbon–oxygen bond.
Therefore, synthetic efforts have been directed toward the supply
of carbon- and sulfur-linked isosteres, that is, compounds bearing
a methylene group or a sulfur atom in place of the oxygen atom
of the glycosidic bond that is present in natural products. Thus,
simple C-disaccharides3 and S-disaccharides4 have been prepared
because these products can be used as probes of recognition spec-
ificity and may provide important insight into the mechanism of
glycoside elaboration by carbohydrate processing enzymes. In
turn, these glycomimetics may become effective inhibitors of those
enzymes and therefore evolve into lead compounds of pharmaceu-
tical relevance. It has to be noted, however, that for biological stud-
ies, S-oligosaccharides may be more suitable than C-analogues
because the sulfur derivatives, despite some differences in C–S
and C–O bond lengths, as well as in C–S–C and C–O–C bond an-
gles,5 represent the smallest step away from natural O-glycosides
in the backbone space.6 While several chemical syntheses of
S-disaccharides have been established over the second half of last
century,4 the free-radical thiol-ene coupling (TEC) between alkenyl
sugars and sugar thiols was reported7 for the first time by our
group in 2009. Under optimized conditions (irradiation time,
reagent ratio, and solvent) TEC afforded S-linked disaccharides in
elevated yields. Given our ongoing research in the use of TEC in
glycochemistry8 as a very efficient metal-free click process,9 we
would like to report here on a new TEC-based approach to
S-disaccharides by using glycals as ene partners. Protected glycals
are well known precursors to functionalized carbohydrates due to
the occurrence of a variety of addition reactions to the endocyclic
carbon–carbon double bond.10 Epoxidation is probably the most
important of these addition reactions11 because the so-called gly-
cal epoxides that are formed are precursors to O- and C-glycosides
and glycoconjugates. Other reactions, however, such as azidation
reactions12 bear substantial importance because of the easy
transformation of the 2-azido substituted products into 2-amino
derivatives. Quite surprisingly, to the best of our knowledge there
is only a single example that has been reported in 1970 on the
free-radical hydrothiolation of a glycal.13 This consists of the ther-
mal addition of thiolacetic acid to
D-glucal triacetate in the
presence of the free-radical initiator cumene hydroperoxide. The
reaction afforded a mixture of two diastereomers in 70:30 ratio
with the major product featuring the axial SAc group and the
⇑
Corresponding authors. Tel.: +39 0532 455176; fax: +39 0532 240709 (A.D.).
E-mail address: adn@unife.it (A. Dondoni).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.140

S. Staderini et al. / Tetrahedron Letters 53 (2012) 702–704
703
minor one having the same group equatorial. The product distribu-
AcO
SR
AcO
O
O
tion was interpreted on the basis of the different stability of glyco-
syl radical intermediates. We were, thus, spurred to investigate in
more detail the substrate scope and stereochemical outcome of the
photoinduced addition of sugar thiols to isomeric glycals en route
to 1-deoxy S-disaccharides and the relevant results are reported
below.
(AcO)2
(AcO)2
SR
AGRax
AGReq
Figure 1. Anomeric glycosyl radical (AGR) intermediates formed by addition of a
thiyl radical to glycals.
We first investigated the model reaction between 3,4,6-tri-O-
acetyl-D-glucal 1a and peracetylated 1-thio-b-D-glucopyranose 2a
(Table 1) under previously established standard conditions for
S-disaccharide synthesis via TEC,7 that is, irradiation at wavelength
close to visible light (kmax 365 nm) in the presence of catalytic
2,2-dimethoxy-2-phenylacetophenone (DPAP) as radical initiator.
The reaction was carried out at room temperature in a glass vial
without any caution to exclude air and moisture. After some
experimentation optimized reaction conditions were established.
These entailed using 6 equiv of 2a, 1 h irradiation and 20:1
EtOH–CH2Cl2 as the solvent. Under these conditions the glucal 1a
was totally consumed (100% conversion) to give a mixture of
products 3a and 4a in 80% isolated overall yield and 57:43 ratio.
The use of a lower excess of 2a (4 equiv) or a shorter irradiation
time (30 min) resulted in a partial conversion of glucal 1a (73%
and 33%, respectively) with consequent significant lower overall
yield of 3a and 4a (53% and 33%, respectively). These products
were formed in about 1:1 ratio also under these conditions. Hence,
the reaction was essentially lacking in stereoselectivity while it
appeared to be totally regioselective with the thiyl radical
generated from thiol 2a attacking exclusively the C2 carbon of
the glucal 1a. In agreement with that suggested for the addition
of thiolacetic acid to 1a,13 these results are consistent with the
initial formation of two anomeric glycosyl radical (AGR)
intermediates stabilized by the adjacent oxygen atom, namely
AGRax in which the RS group is axial and AGReq in which the same
group is equatorial (Fig. 1). In the present case these intermediates
must have comparable energies with the consequence that the
products 16 and 17 are formed in essentially equal amounts.
It was soon realized that the relative amounts of AGRax and
AGReq depended considerably on the stereochemistry of the OAc
groups at C3 and C4 in the starting glycal. Accordingly, the addition
of the sugar thiol 2a to the D-galactal triacetate 1b under the above
standard conditions afforded a mixture of diastereomeric sulfides
3b and 4b in good yield and with a net excess of the latter display-
ing the equatorially linked RS group (Table 1). This is consistent
with the preferential formation of AGReq over AGRax due to the
shielding exerted by the axial OAc group at C4 in 1b. This stereo-
chemical outcome was completely reversed in the hydrothiolation
of D-allal triacetate 1c by 2a as this reaction afforded exclusively
the axially substituted sulfide 3c although in only fair yield (Table
1). Thus, it appears that in this case the axial OAc group at C3 of 1c
induces the exclusive formation of the AGRax radical intermediate
via an addition of the thiyl radical to the double bond anti to the
alkoxy group at C-3 of the glycal to give a 2,3-trans-diaxial substi-
tuted product.
Table 1
Hydrothiolation of glycals 1a
OAc
AcO
OAc
O
OAc
O
AcO
O
S
hν (365 nm)
OAc
OAc
O
AcO
S
OAc
OAc
AcO
AcO
(AcO)2
O
O
SH
(AcO)2
+
+
O
Ph
(AcO)2
AcO
AcO
Ph
OAc
MeO OMe
DPAP
1
2a
3
4
a
Glycal
Conversion (%)
100
Product(s)
Yieldb (%)
3:4 ratioc
OAc
OAc
AcO
AcO
AcO
O
OAc
OAc
O
O
AcO
S
AcO
AcO
OAc
OAc
O
AcO
AcO
AcO
80
57:43
37:63
100:0
100:0
S
AcO
O
OAc
1a
3a
4a
OAc
O
OAc
O
OAc
AcO
AcO
AcO
AcO
AcO
AcO
OAc
OAc
AcO
O
S
OAc
OAc
O
100
40
59
38
20
S
AcO
O
AcO
OAc
1b
OAc
3b
AcO
4b
OAc
OAc
OAc
O
O
AcO
AcO
S
AcO
O
—
—
AcO
AcO
3c
1c
OAc
OAc
AcO
AcO
AcO
AcO
OAc
OAc
O
O
S
O
35
AcO
AcO
1d
3d
a
b
c
Reaction conditions: 6 equiv of 2a, 0.6 equiv of DPAP, 20:1 EtOH–CH2Cl2, 1 h.
Overall yield of products isolated by column chromatography on silica gel.
Ratio determined by 1H NMR.

704
S. Staderini et al. / Tetrahedron Letters 53 (2012) 702–704
Table 2
Hydrothiolation of glucal 1a and galactal 1b by different sugar thiolsa
Glycal
Thiol
Products
Conversion (%)
100
Yieldb (%)
100
5:6 ratioc
54:46
OAc
O
OAc
O
OAc
AcO
AcO
AcO
AcO
AcO
O
S
AcO
AcO
O
SH
AcO
S
AcO
OAc
O
AcO
AcO
2b
OAc
AcO
AcO
O
AcO
AcO
1a
OAc
5a
6a
OAc
O
OAc
O
OAc
OAc
AcO
AcHN
O
S
OAc
OAc
O
AcO
AcO
AcO
AcO
AcO
S
AcO
AcO
SH
OAc
OAc
O
AcO
AcO
100
100
100
82
100
100
74:26
38:62
50:50
AcHN
O
AcHN
OAc
2c
1a
5b
AcO
6b
OAc
O
OAc
O
AcO
AcO
OAc
O
AcO
AcO
AcO
AcO
AcO
AcO
O
SH
S
OAc
O
AcO
AcO
OAc
S
O
AcO
AcO
6c
2b
AcO
1b
OAc
5c
OAc
O
OAc
O
OAc
O
OAc
AcO
AcO
AcO
AcO
AcO
AcO
AcHN
OAc
OAc
AcO
AcO
O
S
SH
OAc
OAc
O
AcHN
S
AcHN
O
AcO
2c
OAc
1b
5d
6d
a
b
c
Reaction conditions: 6 equiv of 2a, 0.6 equiv of DPAP, 20:1 EtOH–CH2Cl2, 1 h.
Overall yield of products isolated by column chromatography on silica gel.
Ratio determined by 1H NMR.
An identical stereoselectivity was observed in the reaction of 2a
Supplementary data
with D-gulal triacetate 1d to give diastereoisomer 3d despite the
presence of the axial OAc group at C4 (Table 1). This, however, af-
fected the kinetics of the process as shown by the incomplete con-
version of glycal 1d and the low yield of isolated S-disaccharide 3d.
Next, the substrate scope of the reaction was investigated by
considering the addition of two more thiols 2b and 2c to glucal
1a and galactal 1b (Table 2). The choice of thiol 2c relied on the fact
that the 2-acetamidoglucosyl moiety (GlcNAc) is a key structural
motif that is present in numerous biologically active carbohy-
drates. Moreover the presence of the NHAc group might serve to
validate the stability of this important functionality under the con-
ditions of TEC. Thus, it was with our great delight that the photo-
induced hydrothiolation of 1a and 1b by thiols 2b and 2c under
the above optimized conditions occurred with essentially quantita-
tive conversion of the glycals to give the corresponding pairs of
diastereoisomers 5a–6a, 5b–6b, 5c–6c ,and 5d–6d in very high iso-
lated yields. All reactions, however, were scarcely stereoselective
as the two S-disaccharides 5 and 6 were formed in comparable
or even equal amounts. Thus, it appears that the substitution pat-
tern in the thiol exerts scarce or no effect on the stereochemical
course of the reaction.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.11.140.
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In conclusion, it has been demonstrated for the first time that
glycals can undergo a photoinduced addition of glycosylthiyl radi-
cals with total regioselectivity to give 1-deoxy S-disaccharides in
good to excellent yields. While the addition of three different sugar
thiols to
stereoisomers in comparable amounts, the additions of a sugar
thiol to -allal and -gulal are totally stereoselective as they both
afford a single product although in low yields.
D-glucal and D-galactal leads to pairs of S-disaccharide dia-
D
D
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