One-Pot Synthesis of Unprotected Anomeric Glycosyl Thiols in Water for Glycan Ligation Reactions with Highly Functionalized Sugars

Article abstract of DOI:10.1002/anie.201607228

Chemical synthesis of oligosaccharide conjugates is essential for studying the functional relevance of carbohydrates, and this task would be facilitated considerably if reliable methods for the anomeric ligation of unprotected sugars in water were available. Here, a method for the preparation of anomeric glycosyl thiols from complex unprotected mono-, di-, and oligosaccharides is presented. By exploiting the neighboring-group effect of the 2-acetamido-group, 1,2-oxazolines are generated and converted into 1-glycosyl thioesters through treatment with 1-thioacids. The unprotected anomeric glycosyl thiolates released in situ were conjugated to Michael acceptors, aliphatic halogenides, and aziridines to furnish versatile glycoconjugates. Conjugation of amino acids and proteins was accomplished using the thiol–ene reaction with terminal olefins. This method gives efficient access to anomeric glycosyl thiols and thiolates, which enables anomeric ligations of complex unprotected glycans in water.

Full text of DOI:10.1002/anie.201607228

Angewandte
Communications
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International Edition: DOI: 10.1002/anie.201607228
German Edition: DOI: 10.1002/ange.201607228
Carbohydrate Chemistry
One-Pot Synthesis of Unprotected Anomeric Glycosyl Thiols in Water
for Glycan Ligation Reactions with Highly Functionalized Sugars
Sebastian Kçhling, Matthias P. Exner, Saba Nojoumi, Jꢀrgen Schiller, Nediljko Budisa, and
Jçrg Rademann*
Abstract: Chemical synthesis of oligosaccharide conjugates is
essential for studying the functional relevance of carbohy-
drates, and this task would be facilitated considerably if reliable
methods for the anomeric ligation of unprotected sugars in
water were available. Here, a method for the preparation of
anomeric glycosyl thiols from complex unprotected mono-, di-,
and oligosaccharides is presented. By exploiting the neighbor-
ing-group effect of the 2-acetamido-group, 1,2-oxazolines are
generated and converted into 1-glycosyl thioesters through
treatment with 1-thioacids. The unprotected anomeric glycosyl
thiolates released in situ were conjugated to Michael acceptors,
aliphatic halogenides, and aziridines to furnish versatile
glycoconjugates. Conjugation of amino acids and proteins
was accomplished using the thiol–ene reaction with terminal
olefins. This method gives efficient access to anomeric glycosyl
thiols and thiolates, which enables anomeric ligations of
complex unprotected glycans in water.
alysts and accessible structures are limited.[4] Considering
purely chemical methods, glycosyl amines can be formed
without protecting groups with ammonium bicarbonate in
water,[5] however, their stability is limited strictly to basic
conditions. Anomeric glycosyl azides are significantly more
stable and are readily accessible from unprotected sugars, as
demonstrated by Shoda and co-workers.[6] Glycosyl azides
have been used successfully in copper-assisted dipolar cou-
pling reactions to furnish triazol-containing glycoconju-
gates,[7] although the glycosyl triazolyl linkage can be hydro-
lyzed by acids such as trifluoroacetic acid (TFA), a standard
reagent in the synthesis of (glyco)peptides.[8] In contrast,
thioglycosides are stable under both basic and acidic aqueous
conditions. They are thus useful linker entities in bioconju-
gates and for the solid-phase synthesis of oligosaccharides.[9]
In addition, they can be applied as glycosyl donors through
activation under oxidative or alkylating conditions.[10] During
our recent studies on the conjugation of glycosaminoglycans
(GAG),[8] the oligosaccharides of extracellular matrices, we
realized that glycosyl thiols are required in order to enable
more flexible ligation reactions and to obtain stable glyco-
conjugates.
Glycosyl thiols have been obtained from unprotected
glucose and hydrogen sulfide in anhydrous hydrogen fluoride,
although in low yield and without stereocontrol.[11] Law-
essonꢀs reagent has also been used for the thionation of simple
unprotected sugars,[12] however, considerable heating is
required, leading to anomeric mixtures in several examples.
Lawessonꢀs reagent is also not selective for aldehydes, but
thionates all carbonyl functionalities, including carboxylic
acids, amides, and esters, which are present in the majority of
bioactive glycans.[13] Since a broadly applicable and useful
method for the preparation of 1-glycosyl thiols from fully
unprotected mono- and oligosaccharides with acetamido,
carboxylate, hydroxy, and acetal functionalities has not been
available so far, it was our goal to develop such a method,
using unprotected 2-acetamido-2-desoxy-d-glucose (1) as
a model compound (Scheme 1). Recently, aryl and alkyl
thioglycosides, but not glycosyl thiols, were prepared from
simple unprotected sugars by using the specific anomeric
alkylation reagent 2-chloro-1,3-dimethylimidazolium chlo-
ride (DMC, 2) and a base.[14,15]
M
any biological functions of eukaryotic cells are mediated
by complex oligosaccharides attached to proteins or lipids,[1]
since interactions between cells and with the surrounding
extracellular matrix are governed by carbohydrate–protein
binding.[2] Therefore, synthetic access to glycoconjugates is
crucial for studying and understanding carbohydrate-depen-
dent biological processes. In classical carbohydrate chemistry,
glycoconjugates are mostly prepared through chemical gly-
cosylation reactions,[3] which require the use of fully protected
and highly reactive sugar donors and are thus not compatible
with the presence of water. As a result, chemical reactions
that allow the synthesis of glycoconjugates without protecting
groups and under aqueous or physiological conditions are in
high demand.
Several protecting-group-free approaches to carbohy-
drate conjugates have been applied so far. Enzymatic
conjugations are very useful, however, the available biocat-
[*] M. Sc. S. Kçhling, Prof. Dr. J. Rademann
Medicinal Chemistry, Institut fꢀr Pharmazie, Freie Universitꢁt Berlin
Kçnigin-Luise-Strasse 2+4, 14195 Berlin (Germany)
E-mail: joerg.rademann@fu-berlin.de
Homepage: http://www.fu-berlin.de/agrademann
M. Sc. S. Kçhling, Dr. J. Schiller, Prof. Dr. J. Rademann
Institut fꢀr Biophysik, Universitꢁt Leipzig
With the aim of producing 1-glycosyl thiols, we inves-
tigated these conditions with 1 and sulfur nucleophiles,
including sodium hydrogen sulfide, sodium sulfide, thiocar-
boxylates, thiourea, benzyl-thiols, trityl thiol, 2-cyanoethyl
thiol, and tert-butylthiol, but we did not obtain the desired
products. Instead, the sulfur nucleophiles reacted directly
with 2, furnishing 2-mercapto imidazolinium salts or the cyclic
Hꢁrtelstrasse 16–18, 04107 Leipzig (Germany)
Dr. M. P. Exner, S. Nojoumi, Prof. Dr. N. Budisa
Institut fꢀr Chemie, Technische Universitꢁt Berlin
Mꢀller-Breslau-Strasse 10, 10623 Berlin (Germany)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201607228.
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(entries 5,6) reacted to give the a-anomeric thioesters 10 and
11 owing to its axial 2-acetamide. N-acetyl-d-lactosamine,
that is, b-d-galactopyranosyl-(1!4)-2-acetamido-2-deoxy-b-
d-glucopyranose, was investigated as a disaccharide (entry 7)
and N,N’,N’’-tri-N-acetylchitotriose, a partial structure of the
polysaccharide chitin, was selected as
a trisaccharide
(entry 8). Both compounds furnished the pure thioesters 12
and 13, respectively, with yields of isolated product in the
same range as for monosaccharides (90 and 65%). Glyco-
saminoglycans (GAG) are especially interesting to the
glycobiology community since these polysaccharides form
the extracellular matrix (ECM) of higher organisms, which is
responsible for many biological functions through carbohy-
drate–protein interactions.[2a,18] Partial structures of hyalur-
onic acid (HA), the major GAG in the extracellular matrix,
were generated through a chemoenzymatic approach using
bovine testis hyaluronidase, according to a recently disclosed
method.[8] They comprise the disaccharide, b-d-glucopyranur-
Scheme 1. Protection-group-free conversion of saccharides into glyco-
syl thiols. Reaction conditions: a) NEt3, D2O/MeCN 2:1, 08C!RT,
90 min; thioacid 4 or 5 in MeCN, 5 min; b) NaOMe, MeOH, Dowex
H+-resin. DMC=2-chloro-1,3-dimethyl-imidazolium chloride.
onyl-(1!3)-d-2-acetamido-2-deoxy-glucopyranose
(HA-2
33, entry 9), the respective tetrasaccharide (HA-4, entries 10,
11, and 14), and the hexasaccharide (HA-6 34, entry 12). The
HA-octasaccharide 35 was obtained using a bacterial hyalur-
onidase from Streptococcus pyogenes and was dehydrated at
the terminal glucuronic acid residue to give a double bond in
the 4-position (DHA-8 35, entry 13). The partial structures of
HA were converted in to the pure b-thioesters 14, 15, 18, and
19 by using thiobenzoic acid, while in the reaction sequence of
HA-4 with thioacetic acid, traces of a diacetylated thioester
byproduct were observed, which reduced the yield of isolated
16 to 56%. For labeling of HA-4 with a fluorophore, the
thioacid of 5,6-carboxytetramethylrhodamine (TAMRA) was
prepared through acidic cleavage of the TAMRA triphenyl-
methyl thioester (36, see the Supporting Information) and
employed in the anomeric ligation reaction to provide
compound 19. In order to demonstrate that the anomeric
thioesters of oligosaccharides can be converted stereospecifi-
cally into the corresponding anomeric thiols, the benzoyl
thioester of HA-4 tetrasaccharide 15 was cleaved to the
anomeric 1-b-thio-glycosides 20 in 97% yield of isolated
product. Next, anomeric thiols of mono- and oligosaccharides
were investigated in anomeric ligation reactions (Scheme 2).
Glycosyl-1-thiolates of 8 and 20 were generated in situ and
reacted with acrylonitrile to furnish the Michael addition
products 21 and 22 in 73 and 95% yield, respectively.
2-thio-urea.[16] Nucleophilic attack on 2 could be avoided by
activating 1 with DMC and triethylamine, which furnished
oxazoline 3. While 3 was completely stable toward thiol
nucleophiles under basic conditions, we found that it reacts
smoothly with thioacetic acid 4 or thiobenzoic acid 5 to
stereoselectively furnish the 2-acetamido-glucosyl 1-b-thio-
esters 6 and 7. The conditions for these reactions were
carefully optimized for both thioacids with respect to the ratio
and concentration of reagents and the solvent. Full conver-
sion of the monosaccharide N-acetylglucosamine 1 into the
stable thioesters 6 or 7 was obtained for a thioacid/DMC/base
molar ratio of 2:1:3 in the case of thiobenzoic acid 5 (90%
yield of isolated product, vs. 75% for a ratio of 3:1:3) and
6:1:3 in the case of thioacetic acid 4. A 2:1 mixture of
deuterium oxide and acetonitrile was used as the solvent, thus
exploiting the reduced hydrolysis rate of DMC in deuterated
water[17] and ensuring the solubility of thiobenzoic acid. Our
experiments, however, did not indicate a significant difference
compared to water/acetonitrile mixtures (86 vs. 90% for 7).
Incorporation of the thioacetyl or thiobenzoyl residues
enabled the purification of products 6 and 7 in high yields
of 86 and 90%, respectively, by using flash chromatography or
HPLC (Table 1, entry 1 and 2). Thioesters 6 and 7 were both
converted into the b-2-acetamido-2-deoxy-d-glucopyranosyl
thiol 8 quantitatively upon treatment with either sodium
methoxide or sodium hydroxide as a base, followed by
neutralization (Table 1, entry 3). The odorless anomeric
glycosyl thiol 8 was stable for 24 h in aqueous basic solution
and did not show mutarotation caused by ring opening of the
hemithioacetal function. In contrast, a solution of 8 in water
was slightly acidic and 8 degraded slowly, with only 55% of
the initial 1-b-thiolaldose remaining after one day (see the
Supporting Information).
For attachment to surfaces and incorporation into artifi-
cial extracellular matrices, glycans with a spacer carrying
a reactive nucleophile are required. Glycans containing
a mercapto-terminated spacer (23–25) were obtained through
alkylation of glycosyl-1-thiolate 8 and 20 using the S-trityl-
protected mercaptopolyethylene glycol bromide 29. Forma-
tion of the disulfides of 8 and 20 could be prevented by using
a
catalytic amount of tris-(2-carboxyethyl)-phosphine
(TCEP). Removal of the S-trityl group in 23 furnished the
free thiol 24 when using trifluoroacetic acid (TFA) in
dichloromethane and triethylsilane as a trityl scavenger. The
tetrahyaluronyl thiol 20 was also ligated with a C2 spacer
containing a primary amine functionality by employing a ring-
opening/alkylation reaction of aziridine. Aziridine was gen-
erated in situ from 2-chloroethylamine and sodium hydroxide
The scope of the novel reaction was investigated with
a selection of mono- and oligosaccharides (Table 1). The
method worked smoothly with three N-acetyl-d-hexosamines,
yielding exclusively the 1,2-trans thioglycoside esters.
N-acetyl-galactosamine (entry 4) delivered the b-anome-
ric S-benzoylthioester 9. In contrast, N-acetyl-mannosamine
2
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Table 1: Anomeric glycosyl-1-thioacetates, 1-thiobenzoates, and 1-thiols from various mono-, di-, tri-, tetra-, hexa-, and octasaccharides.
Entry
Mono/Oligo-
saccharides
Product
Compound
number
Yield [%]
1
2
6 (Ac)
7 (Bz)
86
90
GlcNAc 1
3
4
GlcNAc-SBz 7
8
9
99
60
GalNAc
ManNAc
LacNAc
5
6
10 (Bz)
11 (Ac)
80
58
7
8
9
12
13
14
90
65
79
(GlcNAc)3
HA-2 33
HA-4
10
11
15 (Bz)
16 (Ac)
74
56
12
13
HA-6 34
17
18
63
60
DHA-8 35
14
15
HA-4
19
20
35
97
HA-4-SBz 15
as a base. The three-membered aziridine ring was opened by
the thiol nucleophile 20 to provide product 26 in 83% yield.
Finally, thiol–ene reactions of the glycosyl thiols were
investigated. Commercially available N-Fmoc-l-allyl-glycine
was employed as a starting material containing the required
terminal olefin. Irradiation of the photoinitiator 2-hydroxy-1-
[4-(2-hydroxyethoxy)phenyl]-2-methyl-1-propanone gener-
ated thiol radicals that added smoothly to the olefin to yield
the S-glycosylated amino acids 27 and 28, ready for used in
solid-phase peptide synthesis, in 70 and 59% yield, respec-
tively, after isolation.
lipase TTL from Thermoanaerobacter thermohydrosulfuricus,
which contains an N-pentenoyl lysine residue in position 221,
was used.[21] The non-canonical amino acid N-pentenoyl
lysine was incorporated into the protein using stop-codon
suppression. Upon applying thiol–ene conditions, quantita-
tive incorporation of the hyaluronan hexasaccharide was
accomplished, as indicated by HPLC-MS of the protein
(Scheme 3).
In summary, we have demonstrated a novel, high-yielding
and highly practical access to unprotected glycosyl thioesters
and glycosyl thiols from complex mono- and oligosaccharides.
The method involves the activation of unprotected 2-acetam-
ido sugars to anomeric 1,2-oxazolines. Smooth opening of the
For the direct attachment of the 1-thio-hexa-hyaluronane
30 (HA-6-SH) to a protein, the engineered thermostable
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Scheme 2. Anomeric ligation reactions with glycosyl-1-thiolates: a) NaOMe [for (c+d)]; b) NaOH [for (e)]; c) acrylonitrile, MeOH; d) TCEP cat.,
MeOH, 508C; e) 2-chloroethylamine hydrochloride, TCEP cat.; f) Dowex-H+, Fmoc-l-allyl-glycine, cat. 2-hydroxy-1-[4-(2-hydroxyethoxy)phenyl]-2-
methyl-1-propanone in MeOH or MeOH/H2O 4:1, hn; g) CH2Cl2/TFA/TES 10:10:1, 5 min. TCEP=tris(2-carboxyethyl)phosphine, TFA=trifluoro-
acetic acid, TES=triethylsilane.
Scheme 3. A) Protein conjugation of TTL221-PentK with hyaluronan hexasaccharide thiol 30. Reaction conditions: a) Vazzo44 in 0.25m PBS,
pH 6.0, hn,[19] 4 h. B,C) Mass spectrometry analysis before and after deconvolution. Calculated mass of product TTL221-PentK-S-HA-6 32:
31451 Da, found mass: 31450.9 Da (calculated mass of TTL221-PentK 31: 30280 Da, see the Supporting Information). The peak at 31013 Da
(ꢀ438 Da) belongs to TTL221-PentK-S-HA-6 32 minus the C-terminally cleaved tripeptide Tyr-Phe-Gln. Vazzo44=2,2’-Azobis[2-(2-imidazolin-2-
yl)propane] dihydrochloride.[20]
4
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glycosyl thiols, which are efficient reagents in anomeric
ligation reactions to provide spacer-extended glycosyl thiols
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proteins. This novel method will considerably facilitate access
to stable glycoconjugates and glycan- or GAG-based bioma-
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Acknowledgments
Support from the DFG TRR 67 (project A8) and SFB765
(project B9) is gratefully acknowledged. N.B. and M.P.E.
thank the Deutsche Forschungsgemeinschaft (DFG) for
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Keywords: bioorthogonal conjugation ·
carbohydrate chemistry · glycobiology · glycosyl thiols ·
oligosaccharides
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Published online: && &&, &&&&
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Communications
Carbohydrate Chemistry
S. Kçhling, M. P. Exner, S. Nojoumi,
J. Schiller, N. Budisa,
J. Rademann*
&&&& — &&&&
One-Pot Synthesis of Unprotected
Anomeric Glycosyl Thiols in Water for
Glycan Ligation Reactions with Highly
Functionalized Sugars
Sweet dreams are made of these: A direct
access to anomeric glycosyl thiols from
unprotected mono- and oligosaccharides
was developed. Sugar oxazolines were
opened smoothly with thioacids to form
odorless and storable glycosyl thioesters
as precursors for 1-thiol-sugars, thiolates
and, further functionalized glycosides,
including those with amino and thiol
spacers, S-glycosidic amino acids, and S-
linked glycoproteins.
6
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