Synthesis of 6-sulfonatomethyl thioglycosides by nucleophilic substitution: Methods to prevent 1→6 anomeric group migration of thioglycoside 6-o-triflates

Article abstract of DOI:10.1002/ejoc.201300681

Introduction of a sulfonatomethyl moiety into the primary position of thioglycosides by nucleophilic displacement of the corresponding 6-O-triflate is described. The 1→6 migration of the anomeric group, which inevitably occurs through a bicyclic sulfonium ion intermediate, from conformationally flexible β-thioglycosides was prevented by using an α-thioglycoside or conformationally locked β-thioglycoside as the starting material. The thioglycoside 6-sulfonic acids showed excellent α-selectivity during synthesis of uronic acid containing heparinoid trisaccharides. Two routes to prepare C6-sulfonatomethyl thioglucosides by displacement of a 6-O-triflate moiety are reported. The undesired participation of the β-thio aglycon is prevented by changing the anomeric configuration or by locking the pyranose ring. The 6-sulfonatomethyl donors show excellent α-selectivities but significantly different reactivities during the synthesis of heparinoid trisaccharides. Copyright

Full text of DOI:10.1002/ejoc.201300681

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201300681
Synthesis of 6-Sulfonatomethyl Thioglycosides by Nucleophilic Substitution:
Methods to Prevent 1Ǟ6 Anomeric Group Migration of Thioglycoside 6-O-
Triflates
Mihály Herczeg,[a] Erika Mezo˝,[b] Dániel Eszenyi,[b] László Lázár,[a] Magdolna Csávás,[b]
Ilona Bereczki,[b] Sándor Antus,[a] and Anikó Borbás*[b]
Dedicated to Professor János Kuszmann on the occasion of his 80th birthday
Keywords: Carbohydrates / Sulfonic acids / Nucleophilic substitution / Sulfur / Glycosylation
Introduction of a sulfonatomethyl moiety into the primary po-
sition of thioglycosides by nucleophilic displacement of the
corresponding 6-O-triflate is described. The 1Ǟ6 migration
of the anomeric group, which inevitably occurs through a bi-
cyclic sulfonium ion intermediate, from conformationally
flexible β-thioglycosides was prevented by using an α-thio-
glycoside or conformationally locked β-thioglycoside as the
starting material. The thioglycoside 6-sulfonic acids showed
excellent α-selectivity during synthesis of uronic acid con-
taining heparinoid trisaccharides.
sulfonic acid derivatives, we decided to prepare heparinoid
pentasaccharides by systematic replacement of the sulfate
esters with a sodium sulfonatomethyl moiety. As this work
requires large-scale synthesis of the sulfonic acid containing
building blocks, we searched the literature for the most ef-
ficient procedures.
Introduction
Sulfated carbohydrates play key roles in numerous bio-
logical processes including viral cell recognition, cell–cell in-
teractions, blood clotting, inflammation, inhibition, and
promotion of tumor growth.[1] One approach to design
probes for studying these biological functions or to develop
leads for new antiviral, anticoagulant, or antitumor agents
is to prepare hydrolytically stable analogues of sulfated
carbohydrates by replacing the ester oxygen atom of the
sulfate moiety with a CH2 unit. Besides the synthesis of
sulfonic acid analogues of the sulfated Lewis X trisacchar-
ide,[2] glucose 6-sulfate,[3] the sulfated seminolipid,[4] and
heparin,[5] this approach has been used to produce stable
isosteric sulfonate analogues of biological phosphates such
as nucleotides[6] and mannose-6-phosphate.[7]
Recently, we found that isosteric sulfonic acid analogues
of the antithrombin-binding domain of heparin in which
two or three primary sulfate esters were replaced with a
sodium sulfonatomethyl group inhibited the blood coagula-
tion proteinase factor Xa; however, this occurred at dif-
ferent rates depending on the position of the sulfonato-
methyl moiety.[5b] To gain deeper insight into the structure–
activity relationship of the anticoagulant action of the
The synthesis of a carbohydrate sulfonate in which the
ester oxygen atom of the corresponding sulfate ester is re-
placed with a methylene group is generally accomplished
by addition of the methanesulfonate ester carbanion to a
carbonyl function,[2] by free radical addition of bisulfite to
a terminal olefin,[5] by Horner–Wadsworth–Emmons ole-
fination on a carbohydrate ulose,[4,5b,6b,7] or by reaction of
an α-lithiosulfonate ester with a primary carbohydrate iod-
ide[6a] or triflate.[3] Oxidation of thiols[8] or disulfides[9] is a
convenient method to obtain sulfonates that could be read-
ily extended to sulfonatomethyl derivatives.[10] Nucleophilic
substitution in which the leaving group is replaced by a sulf-
onatomethyl moiety[3] appears to be the most rapid and
facile route to the carbohydrate sulfonate esters. However,
previous reactions were limited to O-glycosides and suffered
from a significant disadvantage: reaction of a lithiated
methanesulfonate ester with a 6-iodocarbohydrate gave the
corresponding sulfonate in low yield,[3,6b] whereas with the
use of the more reactive carbohydrate-6-O-triflate, anchim-
eric assistance of the anomeric alkoxy group in the displace-
ment of the triflate was observed.[6a,11]
[a] Department of Organic Chemistry, University of Debrecen,
P. O. Box 20, 4010 Debrecen, Hungary
[b] Department of Pharmaceutical Chemistry,
Medical and Health Science Center, University of Debrecen,
P. O. Box 70, 4010 Debrecen, Hungary
Herein, we describe the efficient synthesis of 6-sulfonato-
methyl thioglycosides from the corresponding 6-O-triflates
by preventing the participation of the anomeric group.
Utilization of these sulfonic acid containing building blocks
E-mail: borbas.aniko@pharm.unideb.hu
Homepage: http://pharmchem.unideb.hu/borbas_a.htm
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300681.
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6-Sulfonatomethyl Thioglycosides by Nucleophilic Substitution
in the synthesis of heparinoid oligosaccharides is also pre- fore, we envisioned the synthesis of 6-sulfonatomethyl thio-
sented.
glycosides by using an α-thioglycoside with a flexible con-
formation (A) or a conformationally locked β-thioglycoside
(B) as the starting material (Figure 1).
Results and Discussion
The 6-sulfonatomethyl-containing methyl glucoside 3 can
be prepared in excellent yield by treating triflate 2 with the
lithiated sulfonate reagent prepared in situ from commer-
cially available ethyl methanesulfonate (Scheme 1).
Figure 1. Planned routes to thioglycoside 6-sulfonic acids through
6-O-triflate intermediates.
To check the viability of the α-thioglycoside approach,
compound 8 was initially prepared by our recently pub-
lished radical-mediated thiol-ene reaction.[15] Addition of
ethanethiol to 2-acetoxy-3,4,6-tri-O-acetyl-d-glucal (7)[16] in
toluene by irradiation at λmax = 365 nm in the presence of
2,2-dimethoxy-2-phenylacetophenone (DPAP) as a cleav-
age-type photoinitiator[17] provided exclusively α-thiogluc-
oside 8 in 80% yield after crystallization. Zemplén deacetyl-
ation followed by (2-naphthyl)methylenation gave 9, trans-
formation of which into 10 was achieved by benzylation
and subsequent regioselective cleavage of the 4,6-O-acetal
ring by using LiAlH4 and AlCl3.[18] Triflation of the pri-
mary free hydroxy group of the α-thioglucoside, the key
step in the whole procedure, took place quantitatively, and
subsequent nucleophilic displacement of the triflate moiety
with the α-lithiosulfonate ester afforded 6-sulfonatomethyl
thioglucoside derivative 11 in 74% yield for the two-step
procedure (Scheme 3).
Scheme 1. Introduction of the –CH2SO3Et moiety to methyl α-
glucoside 2 by nucleophilic substitution. NAP = 2-naphthylmethyl,
Bn = benzyl, Tf = trifluoromethanesulfonyl, Py = pyridine.
However, synthesis of thioglycoside 5 by the same route
failed. If compound 4 was treated with triflic anhydride, the
corresponding 6-O-triflate could not be isolated as a result
of, as we surmised, the immediate formation of sulfonium
ion 4c by intramolecular nucleophilic attack of the anom-
eric sulfur atom at C6.[12] Formation of a similar bicyclic
sulfonium ion from a C6-OH β-S-phenylmannoside upon
treatment with triflic anhydride was reported recently by
Codée et al.[13] Quenching the reaction with methanol re-
sulted in a 3:1 mixture of α- and β-methyl glucosides 6α/6β
(Scheme 2). The formation of the anomeric mixture impli-
cates oxocarbenium ion 4d rather than sulfonium ion 4c
as the reactive intermediate in the nucleophilic substitution
reaction.[13,14]
Scheme 3. Synthesis of the 6-sulfonatomethyl-containing α-thio-
glucoside 11. Np = naphthyl, pTSA = p-toluenesulfonic acid.
Scheme 2. 1Ǟ6 Anomeric group migration via sulfonium ion inter-
mediate upon triflate formation of 4.
To implement our second approach to thiogylcoside-6-
sulfonic acid, we planned to lock the C1 conformation by
4
According to the suggested mechanism depicted in introducing Ley’s diacetal protecting group[19] into the vici-
1
Scheme 2, adoption of the C4 conformation of the inter- nal 2,3-diol, which is known to ensure rigidity of the pyr-
mediate triflate and the syn relationship between C6 and anose ring.[20,21] Accordingly, phenyl 2,3-di-O-(2,3-dimeth-
the C1-thiol group (in 4b) are crucial for the migration of oxybutane-2,3-diyl)-1-thio-β-d-glucopyranoside
(13a)[22]
the anomeric group. Consequently, it could potentially be was prepared and transformed through the 6-O-tri-
4
prevented either by locking the C1 ring conformation or phenylmethyl derivative into the needed 6-hydroxy com-
by inverting the anomeric configuration from β to α. There- pound 14. Triflation followed by nucleophilic substitution
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A. Borbás et al.
SHORT COMMUNICATION
resulted in desired 15 in 63% yield, and this proves that the acceptor 16 provided desired trisaccharide 17 in 61% yield.
acetal protecting group helped to minimize the competing Changing the promoter system from NIS/TfOH to NIS/Ag-
intramolecular nucleophilic attack of the anomeric β-thiol OTf and decreasing the temperature resulted in a more ef-
group (Scheme 4).
ficient glycosylation procedure that furnished 17 in 79%
yield. The NIS/TfOH-mediated reaction of acceptor 16 and
disarmed donor 15 afforded corresponding trisaccharide 18
in only 38% yield. By applying the NIS/AgOTf promoter
system, a higher temperature and a longer reaction time led
to efficient condensation; however, the isolated yield of 18
remained below 60%. We assume that the disarmed charac-
ter of donor 15 as a result of its rigidity imposed by the
diacetal protecting group[24] is disadvantageous if it is cou-
pled with iduronic acid containing acceptor 16 of inherent
low reactivity.
Conclusions
Two approaches were elaborated to prevent the participa-
tion of the anomeric group during synthesis of 6-sulfonato-
methyl thioglycosides by nucleophilic substitution. It was
found that either a trans relationship between C6 and the
anomeric group in α-thioglucoside 10 or a rigid conforma-
tion of β-thioglucoside diacetal 14 excluded efficiently the
undesired intramolecular reaction of the corresponding 6-
O-triflate. Obtained thioglycoside sulfonic acids 11 and 15
proved to be α-selective glycosyl donors to provide hepa-
rinoid trisaccharides. However, an important difference in
efficacy of both generated building blocks was observed,
and armed donor 11 was superior to disarmed donor 15
during reaction with a uronic acid containing acceptor of
Scheme 4. Nucleophilic displacement on conformationally locked
β-thioglucoside 14. DMAP = 4-(dimethylamino)pyridine, Tr = tri-
phenylmethyl.
To test the applicability of the obtained 6-sulfonato-
methyl thioglycosides in the synthesis of heparinoid oligo-
saccharides, 11 and 15 were treated with l-iduronic acid
containing disaccharide acceptor 16. Although couplings
with both donors led to stereoselective formation of the re-
quired α-linkage, the yields of the procedures were substan-
tially different (Table 1). The N-iodosuccinimide (NIS)/
TfOH-promoted condensation of armed[23] donor 11 and
Table 1. Synthesis of uronic acid containing heparinoid trisac- low reactivity.
charides from acceptor 16 by using donors 11 and 15.
We believe that the developed methods that allow easy
introduction of various substituents into the primary posi-
tion of thioglycosides would be useful in the synthesis of
biologically important saccharide mimetics such as 6-de-
oxy-6-fluoro-[25] or 6-deoxy-6-phoshonatomethyl deriva-
tives.[7,26]
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, characterization data, and 1H and
13C NMR spectra of 3, 4, 6, 9–11, and 13–18.
Acknowledgments
The project was financed by the European Union and the Euro-
pean Social Fund through the TÁMOP 4.2.4.A/1-11-1-2012-0001
Project (National Excellence Program). Financial support of the
Hungarian Research Fund (OTKA K 105459) is also acknowl-
edged.
Donor
Promoter
T [°C]
Time
[h]
Product, yield
[%]
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Received: May 9, 2013
Published Online: July 23, 2013
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