Tri-isopropylsilyl thioglycosides as masked glycosyl thiol nucleophiles for the synthesis of S-linked glycosides and glyco-conjugates

Article abstract of DOI:10.1039/c4ob00741g

Tri-isopropylsilyl thio-glycosides (TIPS S-glycosides) were synthesized through base promoted S_N2 substitution of glycosyl halides with TIPS-SH or by Lewis acid promoted glycosylation of TIPS-SH with glycosyl acetates or p-methoxyphenyl glycosi

Full text of DOI:10.1039/c4ob00741g

Organic &
Biomolecular Chemistry
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Tri-isopropylsilyl thioglycosides as masked
glycosyl thiol nucleophiles for the synthesis of
S-linked glycosides and glyco-conjugates†
Cite this: Org. Biomol. Chem., 2014,
12, 4816
Received 8th April 2014,
Accepted 8th May 2014
S. Mandal and U. J. Nilsson*
DOI: 10.1039/c4ob00741g
www.rsc.org/obc
Tri-isopropylsilyl thio-glycosides (TIPS S-glycosides) were syn- side aglycon part typically influence the reactivity and reaction
thesized through base promoted SN2 substitution of glycosyl outcome, that is why methods for easy diversification of the
halides with TIPS-SH or by Lewis acid promoted glycosylation of thio-glycoside aglycon are of interest. Thioglycoside synthesis
TIPS-SH with glycosyl acetates or p-methoxyphenyl glycosides. is usually performed by SN2 displacement of a glycosyl halide
Various thioglycoside derivatives were obtained in high yields by by a thiol(ate) or by Lewis acid-catalysed glycosylation of a thiol
one-pot fluoride-mediated de-silylation and thiol alkylation with with glycosyl acetates or phenyl O-glycosides.4,5 Additional
alkyl halides or Michael acceptors of one common TIPS methods include in situ aminolysis and alkylation of thio-
S-glycoside.
acetates,19,20 Michael type addition of 1-thiolates to carbo-
hydrate enones,21 coupling of glycals and thiols in Ferrier-type
reactions,22 thiol–ene click reactions,21 ring opening of carbo-
hydrate epoxides with thiols,23 the use of Lawesson’s reagent
with hemiacetals,24 formation of α-thio-glycosidic linkages
from 1,6-anhydro derivatives with bis-(trimethylsilyl) sulfide,25
formation of β-thioglycosidic linkages by the use of Na2S and
CS2,4 and Michael type reactions involving a thiirane inter-
mediate.4 In case a collection of thio-glycosides carrying
diverse aglycon structures is needed, the majority of these
methods would require that a separate (glycosylation) reaction
with a thiol was undertaken for each member of the collection.
Triisopropylsilyl sulfides are remarkably stable,26 yet mildly de-
silylated and alkylated in the presence of fluoride sources.27–29
Triisopropylsilyl thio-glycosides are known and their de-silyla-
tion has been demonstrated,30 but have not been evaluated as
masked glycosyl thiolate nucleophiles for in situ activation and
reaction with electrophiles. Herein, we report on a novel,
rapid, and effective synthetic method towards different thio-
glycosides in one step within 5 min by reacting electrophiles
with readily accessible tri-isopropylsilyl thio-glycosides as
common precursors in the presence of tetrabutylammonium
fluoride.
Development of glycomimetics is an important area of
research due to their potential as biological tools and in
pharmaceutical applications.1,2 A large and important class of
glycomimetics includes stable analogues in which one or more
oxygen atoms, i.e. glycosidic oxygens, have been replaced by
e.g. sulfur3,4 or other heteroatoms,5 leading to structures more
tolerable towards enzymatic and acidic hydrolysis and thus
with enhanced stability in biological environments. Hence, the
enhanced hydrolytic stability of thioglycosides3,4 makes them
particularly useful as tools in investigation of glycoconjugate
functions. Examples include thioglycosides as key mediators
for cellular surface recognition and enzyme inhibitors,6 and
thioglycosides binding to many lectins,7 e.g. the unnatural dis-
accharide thiodigalactoside binding to galectins with about
the same affinity as LacNAc.8 Indeed, thiodigalactoside shows
promising immune-promoting properties against tumor cells9
and its derivatives have been shown to attenuate tumor moti-
lity,10 macrophage differentiation,11 fibrosis progression,12
hepatitis,13 and pancreatic islet cell apoptosis.14
Furthermore, thioglycosides are being used as versatile
donors and thus key precursors in oligosaccharide synthesis,
synthesis of glycodendrimers,15,16 sulfur containing glyco-
lipids,4 and S-linked protein glycoconjugates.17,18 In such a
use of thioglycosides, the chemical properties of the thioglyco-
Boron trifluoride etherate-catalysed glycosylation of tri-iso-
propylsilylthiol (TIPSSH) with anomeric acetates or p-methoxy
phenyl glycosides, as well as SN2 displacement of anomeric
bromides with TIPSSH in the presence of a base, K2CO3,
resulted in stereoselective formation of TIPS thio-glycosides
(Scheme 1). Evaluation of reaction conditions for the Lewis
acid-mediated activation of glycosyl acetates and p-methoxy-
phenyl β-glycosides revealed that dichloromethane was a
solvent superior to toluene, diethyl ether, and acetonitrile for
Centre for Analysis and Synthesis, Department of Chemistry, Lund University,
POB 124, SE-22100 Lund, Sweden. E-mail: ulf.nilsson@chem.lu.se
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, characterization data and copies of 1H and 13C NMR of all compounds
and COSY and HMQC for selected compounds. See DOI: 10.1039/c4ob00741g
4816 | Org. Biomol. Chem., 2014, 12, 4816–4819
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Cleavage and in situ alkylation of STIPS sulfides have been
demonstrated to be efficient with fluoride sources.27 Hence,
the S–Si bond of the TIPS thioglycosides (2, 7, 9, and 11) was
found to be easily transformed into various thioglycosides by
activation with fluoride ions in the presence of an electrophile
(Michael acceptor, alkyl halide, acid chloride, or glycosyl
bromide) in a high-yielding and stereoselective reaction at RT
in 5 min on both small and large (gram) scales (Scheme 2).
Michael acceptors are known to be highly efficient electro-
philes in reaction with thiol(ate) nucleophiles, which proved to
also be the case with the conditions for de-silylating and acti-
vating TIPS thioglycosides with TBAF (Table 1). Michael
additions to methyl propiolate afforded the more stable
E-isomer exclusively (compounds 17, 18, and 19; Table 1)
according to NMR analysis. Hence, the method is of potential
value for the construction of hydrolytically stable glycomi-
metics via thiolate Michael additions.
Neoglycopeptides and proteins are important research tools
in glycobiology and S-glycosylated cysteine derivatives are
useful building blocks for such structures. Reaction of N-Boc-
Scheme 2 General scheme for cleavage and in situ alkylation of STIPS
glycosides.
Table 1 One-pot de-silylation and glycosyl thiol alkylation with
Michael acceptorsa
Cpd
Electrophile
Thioglycoside product
Yield (%)
91
2
Scheme 1 Synthesis of tri-isopropylsilyl thio-glycosides: Method A:
BF3·Et2O, TIPSSH, dry toluene. Method B: BF3·Et2O, TIPSSH, dry DCM.
Method C: K2CO3, TIPSSH, dry acetone.
2
7
9
93
95
94
activation of glycosyl acetates (4, 6a, 8a, 10a), while toluene31
was the best solvent with p-methoxyphenyl β-galactoside as a
donor (1). Furthermore, boron trifluoride etherate proved to be
the best choice of Lewis acid over TMSOTf. Among different
conditions investigated for the displacement of glycosyl bro-
mides (5, 6b, 8b, 10b, 12, 13) under basic conditions, NaH in
DMF, Cs2CO3 in DMF, and K2CO3 in acetone, the best results
were obtained with K2CO3 in acetone. While reasonable yields
were obtained by boron trifluoride etherate activation of glyco-
syl acetates (4, 6a, 8a, 10a) and p-methoxyphenyl β-galactoside
1, the best yields for formation of TIPS thio-glycosides were
obtained using glycosyl bromides (5, 6b, 12,32 13 33) in the
presence of a base. For mannose and rhamnose the best yields
were achieved with Lewis acid-promoted activation of anome-
ric acetates (8a and 10a).
a STIPS glycoside (1 eq.), Michael acceptor (1.3 eq.), MeCN (26 mL
mmol−1 STIPS glycoside), TBAF (1.2 eq., 1.0 M in THF), 5 min.
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protected β-iodo-L-alanine ester derivatives with TIPS thio-gly-
cosides in the presence of TBAF in acetonitrile at RT for 5 min
furnished the corresponding L-cysteine derivatives 20–24 in
excellent yields (Table 2). Hence, the method provides an
efficient one step protocol with minimal formation of e.g.
eliminated by-products.
Table 3 One-pot de-silylation and glycosyl thiol alkylation with alkyl,
acyl, and glycosyl halidesa
Cpd
Electrophile
Thioglycoside product
Yield (%)
97
2
To further explore the method, TIPS thio-β-glycosides were
evaluated as masked sulfur nucleophiles with alkyl, acid, and
glycosyl halides, including substituted galactosyl bromides
(1232 and 1333), under the same reaction conditions as
described above (Table 3). All reactions proceeded smoothly to
furnish the corresponding alkyl β-thioglycosides 25, 27–28,
and 30, glycosyl thio-benzoates 26 and 29, and thiodigalacto-
sides 31–33 in excellent yields. In particular, the examples
involving synthesis of thiodigalactoside derivatives 31–33 are
illustrative of the high efficiency of the STIPS glycosides in the
synthesis of thioglycosides as other methods for synthesis of
thiodiglycosides including those using glycosyl thiouronium
intermediates as masked glycosyl thiolate nucleophiles provide
significantly less clean reactions and substantially lower yields
in our hands and in published work by others.34–36 Further-
2
2
BzCl
96
98
2
7
BnBr
BzCl
98
97
Table 2 One-pot de-silylation and glycosyl thiol alkylation with
β-iodo-L-alanine estersa
Cpd Electrophile
Thioglycoside product
Yield (%)
91
2
11
2
98
88
2
7
9
93
94
93
5
14
15
1232
95
93
1333
11
94
a STIPS glycoside (1 eq.), alkyl (1.3 eq.), acyl (1.3 eq.), or glycosyl halide
(1 eq.), MeCN (26 mL mmol−1 STIPS glycoside), TBAF (1.2 eq., 1.0 M in
THF), 5 min.
a STIPS glycoside (1 eq.), β-iodo-L-alanine ester (1.2 eq.), MeCN (26 mL
mmol−1 STIPS glycoside), TBAF (1.2 eq., 1.0 M in THF), 5 min.
4818 | Org. Biomol. Chem., 2014, 12, 4816–4819
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more, formation of glycosyl thiouronium intermediates com-
monly requires reaction at higher temperatures with thiourea
S. J. Forbes, N. Hirani, J. Gauldie and T. Sethi, Am. J. Respir.
Crit. Care Med., 2012, 185, 537–546.
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N. Arsenijevic, U. Nilsson, H. Leffler and M. L. Lukic, Hepa-
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14 T. Saksida, I. Nikolic, M. Vujicic, U. J. Nilsson, H. Leffler,
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Conclusions
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Acknowledgements
The authors thank The Swedish Research Council (grant no. 20 U. J. Nilsson, E. J.-L. Fournier and O. Hindsgaul, Bioorg.
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