A novel stereoselective synthesis of 1,2-trans-thioaldoses

Article abstract of DOI:10.1016/j.tetlet.2007.07.003

A mild and one-pot protocol for the efficient and stereoselective synthesis of 1,2-trans-aldosyl mercaptans is presented.

Full text of DOI:10.1016/j.tetlet.2007.07.003

Tetrahedron Letters 48 (2007) 6092–6095
A novel stereoselective synthesis of 1,2-trans-thioaldoses
Weihua Xue,* Xiaoyun Cheng, Jian Fan, Huajia Diao, Chunming Wang, Lei Dong,
Yi Luo, Jiangning Chen and Junfeng Zhang
State Key Laboratory of Pharmaceutical Biotechnology, Department of Biochemistry, Nanjing University, Nanjing 210093, China
Received 3 April 2007; revised 2 July 2007; accepted 3 July 2007
Available online 7 July 2007
Abstract—A mild and one-pot protocol for the efficient and stereoselective synthesis of 1,2-trans-aldosyl mercaptans is presented.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Carbohydrates are known to play a significant role in
many physiological processes such as cellular adhesion,
signalling and recognition that initiate immune
responses and induce cancer metastasis.1,2 It has been
reported that carbohydrates are also involved in the
similar or the same modes of action with many drugs3
so that they are recognized to have potential for the
treatment of diabetes and cancer.4,5 Carbohydrate
mimetics are often used to investigate these processes.
Thioalcohols are versatile synthetic intermediates and
are of great importance in many biological processes
because of their reducing properties and nucleophili-
cities.6,7 Consequently an appropriate approach is to
replace the oxygen atoms of the anomeric carbon with
sulfur to result in glycosylmeraptans that may give ana-
logues, which can serve as potential ligands binding
carbohydrate-specific receptors or serve as derivative
groups for glycoconjugation. Anomeric mercaptosugars
are of particular interest as precursors in preparation of
the widely used thioglycosides.8 Some research has
shown that thioaldoses are essential building blocks
for various carbohydrate derivatives such as oligosac-
charides,9 carbohydrate clusters,10 C-glycosides,11 glycos-
yl sulfenamides,12 glycosyl sulfonamides,13 glycosyl
disulfide,14 thionolactones15 and glycosylsulfenic acid.16
On the other hand, thioaldoses and their resulting glyco-
conjugates have received considerable attention due to
more effective resistance to both chemical and enzymatic
degradation than O-glycosides.17 Moreover, thioaldoses
have been reported to act as glycosyltransferase
inhibitors.18,19
The most frequently used method for the synthesis
of thiosaccharides involves the treatment of glycosyl
halides with a sulfur nucleophile such as thiourea, thio-
acetamide,20 N,N-dimethylthioformamide21 or KSAc,22
followed by mild hydrolysis or alcoholysis. Recently,
Davis reported23 that Lawesson’s reagent might be used
to directly synthesize glycosyl thiols from their corre-
sponding reducing sugars. Unfortunately, these syn-
thetic strategies suffer from drawbacks such as long
reaction time, use of expensive reagents, low yield and
tedious work-up. Especially, the use of Lawesson’s
reagent is somewhat restricted without good stereoselec-
tivity. Therefore, there is a need to develop a convenient
and practical method for the synthesis of mercapto-
aldoses. In this report we describe a stereoselective
one-pot preparation of 1,2-trans-thiosugars using so-
dium thiophosphate in methanol.
Sodium thiophosphate is known to be an effective
reagent for conversion from the halides to mercaptans.24
In the current study sodium thiophosphate was used as
the sulfur nucleophile to synthesize thioaldoses. Various
glycosyl halides were chosen to test our method. It was
observed that sodium thiophosphate (1.5 equiv per
halide) in methanol (20 ml) at room temperature produced
excellent yields of 1,2-trans-thiosugars within several
hours. Interestingly, the reactions occurred with nearly
complete inversion of anomeric configuration (Table
1). This reaction is presumably initiated by the forma-
tion of glycophosphorothioate intermediate, followed
by nucleophilic attack of methanol to give products
(Scheme 1). All products were characterized by 1H
NMR and 13C NMR spectroscopy. It is of pertinent
note that the reaction conditions are mild and 1,2-
trans-thiosaccharides are exclusively formed without
*
Corresponding author. E-mail: glycochemistry@yahoo.com
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.003

W. Xue et al. / Tetrahedron Letters 48 (2007) 6092–6095
Table 1. Synthesis of 1,2-trans-adosyl mercaptans from glycosyl halides
6093
Entry
Substrates
OBn
Products
Isolated yields (%)
OBn
O
O
BnO
BnO
BnO
BnO
1
93.7
SH
BnO
BnO
(a)
Cl
OPiv
PivO
PivO
OPiv
PivO
PivO
O
O
2
96.8
SH
PivO
(b)
OAc
PivO
Br
AcO
AcO
OAc
AcO
AcO
O
O
SH
N
3
91.8
O
O
N
O
Br
O
(c)
Br
SH
OBz
O
O
4
5
94.0
92.0
OBz
OBz
BzO
OBz
(d)
BzO
O
O
O
O
AcO
O
AcO
O
SH
AcO
AcO
(e)
Br
AcO
OAc
AcO
COOMe
SH
OAc
Cl
AcO
O
6
83.4
O
COOMe
AcNH
AcNH
AcO
AcO
(f)
OAc
OAc
AcO
AcO
AcO
OAc
OAc
O
O
O
O
7
95.2
O
O
AcO
SH
AcO
AcO
OAc
OAc
AcO
AcO
Br
(g)
OBz
OBz
BzO
BzO
BzO
OBz
OBz
O
O
O
O
8
9
88.2
96.5
O
BzO
O
BzO
BzO
SH
BzO
BzO
BzO
BzO
Br
O
(h)
OAc
OAc
OAc
OAc
O
AcO
AcO
O
AcO
O
O
O
AcO
SH
AcO
AcO
AcO
AcO
AcO
AcO
Br
(I)

6094
W. Xue et al. / Tetrahedron Letters 48 (2007) 6092–6095
O
Na
O
Na PO S
3
3
O
methanol
O
-
+
P
O
Br
Na
S
SH
Br
ONa
Scheme 1. Synthesis of aldosyl mercaptans.
the formation of 1,2-cis-a-glycosides or any undesired
byproducts. For general pyranosides, assignment of
the anomeric configuration is based on the JH-1,H-2
coupling constants (a-isomers, ꢀ2 Hz; b-isomers, 8–
10.5 Hz). Although there is no anomeric proton in a-sia-
lyl thiol, the anomeric configuration was inferred on
the basis of the JC-2,H-3ax coupling constants (a-isomer,
ꢀ8 Hz).25
O-benzoyl-b-D-thiolactose): 1H NMR 2.09 (d, 1H,
J1,SH = 9.9, SH), 4.69 (dd, 1H, J1,2 = 10.1, H-1), 5.48
(dd, 1H, J1,2 = 10.1 Hz, J2,3 = 3.4 Hz, H-2), 6.17
0
0
(t, 1H, J = 9.6 Hz, H-3), 5.55 (dd, 1H, J3 ;4 ¼ 7:2 Hz,
J2 ;3 ¼ 3:5 Hz, H-30), 4.25 (dd, 1H, J3,4 = 9.6 Hz,
J4,5 = 10.0 Hz, H-4), 5.69–5.78 (m, 2H, H-20, H-40),
3.86–3.99 (m, 2H, H-5, H-50), 4.44–4.58 (m, 2H,
H-6), d = 3.70–3.77 (m, 2H, H-60), 4.82 (d, 1H,
0
0
J1 ;2 ¼ 7:9 Hz, H-10), 7.07–8.04 (m, 35H, 7Ph). 13C
NMR 61.9(C-6), 61.4(C-60), 76.9(C-5), 70.8(C-50),
75.6(C-4), 66.9(C-40), 73.3(C-3), 71.4(C-30), 73.6(C-2),
69.5(C-20), 80.1(C-1), 101.4(C-10), 129.1–133.3 (7 · Ph),
163.4–166.8 (C@O). HRESIMS (m/z): Calcd for
C61H50O17SNa [M+Na]+: 1109.7984; found, 1109.7968.
0
0
In conclusion, we have demonstrated that commercially
available sodium thiophosphate is a novel reagent for
stereoselective thiolation of aldosyl halides to produce
1,2-trans-1-thioaldoses while leaving protecting groups
on sugar residues intact. Excellent yields, simple work-
up and mild reaction conditions make this method an
attractive addition to the present methodologies.
Acknowledgements
Typical experimental procedure: Sodium thiophosphate
dodecahydrate (3 mmol) was added to a solution of
D-aldosyl halides (2 mmol) in methanol (20 ml) under
argon. The resulting mixture was stirred at room tem-
perature for a period of 4–7 h until TLC indicated com-
plete conversion of halides. The reaction mixture was
poured into water and the products were extracted three
times with CH2Cl2. The combined extracts were washed
with brine, dried over Na2SO4, rotary evaporated and
the residue was recrystallized or purified by silica gel
column chromatography. Spectral data for selected
compounds: Compound b (2,3,4,6-tetra-O-pivaloyl-b-
The work was supported by State Key Laboratory of
Pharmaceutical Biotechnology in Nanjing University.
The authors wish to thank the reviewers for instructive
suggestions.
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0
J4,5 = 1.3, J5;6 ¼ 4:9 and J5,6 = 1.9, H-5), 4.17 (dd,
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176.3, 176.8, 177.1 and 178.0 (C@O). HRESIMS (m/z):
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