Synthesis of a 3-Thiomannoside

Article abstract of DOI:10.1021/acs.orglett.6b00428

An efficient and straightforward synthesis of a novel 3-thiomannoside derivative (1,2,4,6-tetra-O-acetyl-3-S-acetyl-3-thio-β-d-mannopyranoside) was developed starting from levoglucosenone. A xanthate-thiocarbonate exchange under acidic conditions was the key step for the new C-S bond. The product was obtained enantiospecifically in very good overall yield.

Full text of DOI:10.1021/acs.orglett.6b00428

Letter
pubs.acs.org/OrgLett
Synthesis of a 3‑Thiomannoside
María B. Comba, Alejandra G. Suarez, Ariel M. Sarotti, María I. Mangione,* Rolando A. Spanevello,*
́
and Enrique D. V. Giordano
Instituto de Química Rosario, Facultad de Ciencias Bioquímicas y Farmaceu
Suipacha 531, S2002LRK, Rosario, Argentina
́
ticas, Universidad Nacional de Rosario - CONICET,
S
* Supporting Information
ABSTRACT: An efficient and straightforward synthesis of a
novel 3-thiomannoside derivative (1,2,4,6-tetra-O-acetyl-3-S-
acetyl-3-thio-β-D-mannopyranoside) was developed starting
from levoglucosenone. A xanthate−thiocarbonate exchange
under acidic conditions was the key step for the new C−S
bond. The product was obtained enantiospecifically in very
good overall yield.
ulfur-containing carbohydrates or thiosugars possess
distinctive biological and physicochemical properties
thiosugar acceptor for the construction of thio-oligosaccharides.
In this regard the preparation of 1,2,4,6-tetra-O-acetyl-3-S-
acetyl-3-thio-β-D-mannopyranoside 1 has been achieved from
levoglucosenone 3 (1,6-anhydro-3,4-dideoxy-β-D-glycero-hex-3-
enopyranos-2-ulose), a biomass-derived starting material with a
convenient functionalized structure (Scheme 1).
S
which differ from their oxygenated counterparts. Many natural
functionalized thiosugars have shown to be useful tools to
probe carbohydrate−protein interactions within enzymes
systems and as prospective therapeutic agents.1,2 Examples of
these naturally occurring thiosugars include 5-thio-D-mannose,3
a potential mannosidase inhibitor, and glucosinolates (β-
thioglucoside-N-hydroxysulfates)4 which are known for their
bactericidal, fungicidal, nematocidal, and allelopathic properties
and have recently attracted intense research interest because of
their cancer chemoprotective attributes. Another important
member of this class of compounds is lincomycin, isolated from
fermentations of Streptomyces lincolnensis, which is an effective
antibiotic used against a wide range of pathogen, in particular
methicillin-resistant Staphylococcus aureus. Clindamycin, a
chlorinated semisynthetic derivative, is more active than the
parent compound and widely used in clinical treatments.5
Among the families of synthetic thiosugars with biological
activities, it can be mentioned that glycosyl S-nitrosothiols act
as nitric oxide donors,6 S-trityl glycosides as chemotheraphy
agents,7 5-thiosugars as enzyme inhibitors,8 3-thiosugars as
neuraminidase inhibitors,9 thio-linked analogs of Lewis A and B
as antigens,10−12 and thioanalogs of Amiloprilose are useful as
immunomodulators for treating autoimmnune disorders.13,14
Recently, thioglycosides derived from acceptor sugars such as 3-
thiogalactopyrano-, 4-thioglucopyrano-, and 4-thiomanno-
pyranosides have been developed as β-galactosidase inhib-
itors.15
Scheme 1. Retrosynthetic Strategy
This versatile chiral synthon 3 can be obtained by
conventional pyrolysis of cellulose-containing materials17 such
as waste paper, and also by microwave irradiation of
microcrystalline cellulose,18 hence, making it a sustainable
and green raw material for enantiospecific synthesis.
There are two main strategies described in literature for the
stereoselective preparation of thiosugars that can be considered
for the synthesis of the 3-thiomannoside derivative 1. One of
them implies the SN2 displacements of a sugar-derived triflate
precursor by thioacetate, thiobenzoate, or thiocyanate
anions.15,19 Comprehensive guidelines for this type of
The synthesis of thioglycosides requires the appropriate
preparation of a thiosugar acceptor which can be coupled with a
glycosyl donor.16 On the other hand, a sulfur atom can replace
any of the oxygen atoms present in a carbohydrate molecule.
Based on these precedents 3-thio and 4-thiosugars are
interesting synthetic targets, and efforts have been devoted
toward their construction.
In the present work, we describe an efficient and
Received: February 13, 2016
straightforward synthesis of a novel and properly protected
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00428
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Scheme 2. Synthesis of Disulfide 8
Scheme 3. Proposed Mechamism
nucleophilic displacement were recently published by Hale and
co-workers.20,21
These functionalities are then treated under basic hydrolytic
conditions to obtain a free thiol group. However, a serious
drawback of this method is the low yields achieved by the
nucleophilic substitution20−22 due to the concurrent elimi-
nation that occurs under the reaction conditions.
An alternative method to introduce a thiol functionality in a
carbohydrate skeleton is to take advantage of the structural
rigidity imposed by an episulfide derivative. These constrained
systems are useful synthons for the regio- and stereoselective
transformation of positions 2, 3, and 4 in a carbohydrate
framework.23 One of the most common procedures for the
preparation of episulfides involves several steps to achieve the
ring opening of an epoxide with thiourea or thiocyanate ions,
but such a reaction is not feasible for strained cyclic substrates
derived from 1,6-anhydro sugars. Furthermore, the nucleophilic
opening of the episulfide ring could also become trouble-
some.23a
Based on our ongoing research program on the generation of
high-added value products24 from biomass recycling,25 we
conceived a new synthetic approach to obtain thiomanno-
pyranoside 1 from levoglucosenone 3 as depicted in Scheme 2.
Xanthate 2 was obtained in a simple and efficient manner
from 3 and became a key intermediate in this strategy which
paves the way to a completely new protocol. Reduction of the
ketone 3 under Luche conditions afforded allylic alcohol 4 in a
chemo- and stereoselective way. Allylic xanthate 5 was obtained
when 4 was treated with carbon disulfide and methyl iodide in
the presence of sodium hydride. Cis-dihydroxylation of 5 with
catalytic amounts of osmium tetroxide and NMO as
stoichiometric oxidant gave the diol 2 in high overall yield.
Treatment of diol 2 with sulfuric acid in glacial acetic acid
afforded the thiocarbonate 6 as a single product.25 A Fischer
esterification occurs concomitantly during the process and is
the reason for the acetylated product. The structure of 6 was
assigned by NMR one- and two-dimensional experiments,
showing that the newly formed cis fused five membered ring
B
DOI: 10.1021/acs.orglett.6b00428
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Letter
had a β-face orientation, as expected by the configuration of the
C-2 oxygenated function. Mass spectrometry confirmed the
molecular formula proposed for compound 6. A plausible
mechanism for this transformation is depicted in Scheme 3.
The formation of the cyclic thiocarbonate 6 probably occurs
through the elimination of a water molecule at C-3 by the
anchimeric assistance of the adjacent xanthate group,
generating a cyclic intermediate. In this way, the five-membered
ring is formed. Moreover, water then attacks the carbocationic
species to yield the intermediate 9. Proton migration produces
the protonated species, which upon loss of a neutral molecule
of methanethiol affords cation 10. Deprotonation and
concurrent Fischer esterification produce compound 6.
Scheme 4. Synthesis of Thiomannopyranoside 1
In order to obtain the free thiol functionality it was necessary
to apply hydrolytic reaction conditions to achieve the ring
opening of 6. Alkaline hydrolysis26 of the cyclic thiocarbonate 6
also caused the removal of the acetate functionality and
afforded a polar compound 7. Initially we assumed that the
polarity was in consonance with a structure bearing a thiol and
two hydroxyl groups. In order to characterize compound 7, a
water-soluble product, an aliquot of the crude material was
precipitated from methyl tert-butyl ether as an off-white solid.
1
The H NMR spectrum in D2O (with water suppression)
1,6-anhydro bridge.28 This transformation was not a trivial one,
since it is well documented that there are difficulties
encountered for opening this type of anhydro bridge system.29
Based on these precedents, we decided to apply an acetolysis
procedure as a way to obtain the anomeric acetate. Thus, we
treated 11 with trimethylsilyl triflate in acetic anhydride and
surprisingly 1 was obtained as a unique product in very good
yield. The stereochemistry at the anomeric carbon was
established through nuclear Overhauser effect (NOE) experi-
ments (Figure 1). A 1.53% signal enhancement between H-3
and H-1 and a 1.27% signal enhancement between H-5 and H-
1 were clear proof of the β-anomeric configuration.
showed the absence of a methyl signal, confirming the
hydrolysis of the acetyl group at C-4. The 13C NMR spectrum
showed the absence of carbonyl carbons, corroborating also the
removal of the thiocarbonate and acetyl groups. However, a
high resolution mass spectrum revealed a mass peak
corresponding to the potassium cation of a disulfide structure
7. This outcome, although undesired, is known with thiols and
thiolates, since oxygen could easily oxidize them to disulfides
on standing in the air when a small amount of base is present.27
Hence, in the alkaline media used to hydrolyze thiocarbonate 6,
the thiolate anion was oxidized to disulfide 7 by the
atmospheric oxygen. Compound 7 was highly polar and
difficult to manipulate or dissolve in organic solvents. For
this reason, it was transformed into its tetra-acetyl derivative 8.
Usually, under these circumstances dithiothreitol (DTT) is
employed to reduce disulfides linkages, but in our case, this
reagent was ineffective at reducing either 7 or 8.
Others attempts to break the disulfide bond with NaBH4 or
LiCl/NaBH4 were also unsuccessful. Only after treating 8 with
19
a strong reducing agent such as LiAlH4
was the
corresponding free mercaptan obtained. Direct reduction of
the disulfide bond present in 7 with LiAlH4 was unsuccessful,
probably due to the insolubility of the tetra-anion formed.
Therefore, although an aliquot of each intermediate was fully
characterized, the crude disulfide 7 was acetylated, reduced, and
carried on to the next acetylation reaction without any
purification step. The triacetyl derivative 11 was obtained in
57% yield (Scheme 4).
Figure 1. NOE correlation of compound 1.
Finally, this synthetic protocol is based on the thiocarbonate
ring formation from a xanthate intermediate. The config-
urations of the new chiral centers were controlled by the
anhydro bridge. During the initial reduction of the ketone, the
bridge exerts a complete facial selectivity on C-2. The same
effect occurs during the hydroxylation at C-4. In the case of C-
3, its configuration was established by the xanthate group at the
adjacent C-2. Subsequent transformation did not affect the
mannopyranoside configuration of the chiral centers. Within
the thiosugars of interest for their biological activity, gluco-,
galacto-, and manno- configurations are the most impor-
tant.15,23,30,31 In this sense, thiomannopyranoside 1 offers
significant opportunities for use as a surrogate of mannose for
the construction of relevant glycomimetic molecules.
1
In the 300 MHz H NMR spectrum in CDCl3 of 11 we
observed the presence of three acetyl groups, two of them at
2.08 and 2.17 ppm consistent with acetate groups and a third
one at 2.35 ppm corresponding to the thioacetate group. The
75 MHz 13C NMR spectrum in CDCl3 showed three carbonyl
carbon signals at δ 170.1 and 170.2 ppm which was in
agreement with the chemical shift for two acetate carbonyl
groups. The other one at δ 194.0 ppm was characteristic of a
thioacetate functionality. These data were also supported by the
mass spectrometry result.
At this point, in order to obtain the desired 3-thiomanno-
pyranoside 1 it was necessary to achieve the ring opening of the
C
DOI: 10.1021/acs.orglett.6b00428
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derived starting material. The 3-thiomannopyranoside 1 was
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00428.
■
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Full experimental details and H NMR and 13C NMR
spectra (PDF)
1
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AUTHOR INFORMATION
Corresponding Authors
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Chem. 2010, 46, 129. (c) Giordano, E. D. PhD Thesis, National
University of Rosario-Argentine, 2014.
*E-mail: spanevello@iquir-conicet.gov.ar.
*E-mail: mangione@iquir-conicet.gov.ar.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by grants from Universidad
Nacional de Rosario, Consejo Nacional de Investigaciones
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