An efficient modular approach for the assembly of S-linked glycopeptoids

Article abstract of DOI:10.1021/ol901524k

A short and convenient methodology for the synthesis of S-glycosylated peptoid models is described. The thioglycosylated building blocks were prepared from proper peracetylated sugars via glycosyl iodides in a one-pot fashion and directly employed in a su

Full text of DOI:10.1021/ol901524k

ORGANIC
LETTERS
2009
Vol. 11, No. 17
3898-3901
An Efficient Modular Approach for the
Assembly of S-Linked Glycopeptoids
Daniela Comegna* and Francesco De Riccardis
Dipartimento di Chimica, UniVersita` di Salerno, Via Ponte don Melillo,
84084 Fisciano (SA), Italy
dcomegna@unisa.it
Received July 3, 2009
ABSTRACT
A short and convenient methodology for the synthesis of S-glycosylated peptoid models is described. The thioglycosylated building blocks
were prepared from proper peracetylated sugars via glycosyl iodides in a one-pot fashion and directly employed in a submonomer solid-
phase stategy.
Cellular surfaces of all living organisms are coated by
glycans covalently attached to proteins, peptides, or lipids.
The saccharidic moiety plays an essential role in the
interaction with the environment and mediates many cell-cell
recognition processes, such as signaling, cell growth and
differentiation, immune response, and inflammation.1
events.2 Several multiantennary carbohydrate-based systems
have been created in the last two decades to serve as
biological probes. Remarkable examples are represented by
gold glyconanoparticles3 and quantum dots,4 glycodendrim-
ers,5 and glycoproteins.6 However, their synthetic access is
often very expensive and time-consuming. In this context,
the peptidomimetic backbone of peptoids, or N-substituted
oligoglycines,7 is an attractive scaffold for immobilization
of bioactive molecules, thanks to an easier preparation and
All these processes are based on associative interactions
between the proper saccharide sequences and their own
specific receptors (lectins). The affinity enhancement of
carbohydrate-protein interactions can be achieved by the
so-called “cluster effect” through the employment of mul-
tivalent glycoligands, whose applications are useful especially
when the protein targets are implicated in pathological
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Chem. 2009, 7, 2013–2025.
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J.; Fernande´s, A.; Penade´s, S. Angew. Chem., Int. Ed. 2001, 40, 2258–
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10.1021/ol901524k CCC: $40.75
Published on Web 08/05/2009
 2009 American Chemical Society

its ability to overcome pharmacokinetic instability and the
poor cellular uptake, typical of natural peptides. Furthermore,
the higher flexibility of the peptoid backbone facilitates the
receptor interaction. Due to these advantages, a growing
number of peptoid-based molecules are being investigated
in the search for new therapeutics.8
Scheme 2.
One-Pot Sequence for Thioglycoamine Formationa
In view of the widespread presence of glycopeptides in
Nature, the development of a fast and general synthetic
procedure toward glycosylated peptoids may represent an
important goal. To date, a few synthetic approaches to
N-linked,9 O-linked,10 and C-linked11 glycopeptoids have
appeared in the literature. Some alternative conjugation
methods have also been reported.12 To the best of our
knowledge, examples of S-linked glycopeptoids have not yet
been reported. Actually, the thioglycosidic linkage is known
to be more resistant toward the hydrolytic action of glyco-
sidases while maintaining biological properties of the
O-analogues.13 Indeed, this evidence has prompted the
development of several methods for use of the thioglycoside
bond in glycopeptide synthesis.14
a Yields reported in Table 1.
tion, except for isolation of the crude glycosyl iodide by
extractive workup. All the steps were operationally simple
Peptoids are generally obtained by a classical solid-phase
peptide synthesis15 (SPPS) or by the “sub-monomer” syn-
thetic strategy,16 relying on direct construction of the
oligomer on the solid support starting from bromoacetic acid
and suitable primary amine precursors (Scheme 1). In this
Table 1. Synthesis of Thioglycoamines via the Sequence
Reported in Scheme 2a
Scheme 1
.
Sub-monomer Peptoid Solid-Phase Strategy on a
Trityl Resin
a See the Supporting Information for experimental data. b Isolated overall
yields. c Last step took 6 h rather than 1 h.
paper, we propose an easy and straightforward synthetic route
to an array of thioglycosides appended to an ethylamino
linker.
By adapting a fast sequential procedure for the preparation
of thioglycosides,17 this method takes advantage of the in
situ generation of a glycosyl thiolate via a glycosyl iodide18
and its direct coupling with commercially available 2-bro-
moethylamine, as a hydrobromide salt, to give an N-
homocysteinyl linkage14a (Scheme 2).
Starting from commercially available per-O-acetylated
sugars 1 and 2 and easily prepared compounds 3, 419 and 5
(Table 1, entries 1-5), glycosylated building blocks 7-11
were prepared within 2 h without any intermediate purifica-
and did not require any special precaution. Only in the case
of the lactose precursor 6 (entry 6) were longer reaction times
required for the last step, and an inert atmosphere was strictly
necessary to prevent disulfide formation. In all cases, the
overall yields were satisfactory, and exclusive formation of
the 1,2-trans glycosides was observed.
In order to test the behavior of the readily obtained
glycosylated building blocks in a submonomer solid-phase
protocol, we decided to prepare some S-linked glycopeptoid
models (13-15, Figure 1).
Glycopeptoid 13 displays two ꢀ-D-galactose appendages.
This residue is frequently incorporated into multiantennary
constructs, owing to its specific interaction with human
Org. Lett., Vol. 11, No. 17, 2009
3899

to-tail macrocyclization for peptoids 13 and 14 under high
dilution conditions with the use of PyBOP (benzotriazol-1-
yl-oxytripyrrolidinophosphonium hexafluorophosphate) and
HOBt (1-hydroxybenzotriazole) in DMF.26 The correspond-
ing cyclic compounds were directly deacetylated with
ammonia in methanol to give compounds 17 and 18 in good
overall yields (Scheme 4).
Scheme 4
.
Macrocyclization Reaction and Global Deprotection
Figure 1. Linear S-linked glycopeptoids.
hepatic lectins20 or as epitope mimics of bacterial toxins.21
Compound 14 is a hybrid glycopeptoid decorated with both
L-fucose and D-galactose units. Multiligands containing both
sugars could be of biological interest due to their role in
adhesion mechanisms of the pathogen Pseudomonas aerugi-
nosa.22 Finally, the fully mannosylated peptoid 15 allows
an improved synthesis of a previously reported O-linked
counterpart23 used for interaction analysis with the model
lectin concavalin A.24 It may be included among the
mannoside clusters useful for their potential roles in prevent-
ing bacterial adhesion.25
The synthesis of compounds 13-15 (Figure 1) started after
loading bromoacetic acid onto a 2-chlorotrityl resin through
an ester linkage. The oligomerization was carried out in DMF
through cycles consisting of primary amine substitution and
N,N-diisopropylcarbodiimide (DIC)-mediated bromoacety-
lation (Scheme 1). Both reactions were accomplished in 30
min at room temperature and in very high yields as verified
by HPLC and mass spectrometry analysis of the crude
peptoids 13 and 14. In the case of fully mannosylated
hexamer 15, a partial deacetylation was observed. However,
the efficiency of the oligomerization was confirmed by the
HPLC profile and mass analysis of the crude mixture after
reacetylation. Feasible global deacetylation of the linear
glycopeptoids was demonstrated by treating hexamannosy-
lated peptoid 15 with ammonia in methanol to afford
compound 16 in high yield (Scheme 3).
Furthermore, since a more constrained structure may be
more efficient for some applications,8 we performed head-
1
The complexity of the rt H NMR spectra recorded for
the linear and cyclic oligomers 13-18 invoked the simul-
taneous presence of more than one conformer in slow
exchange on the NMR time scale.27
Scheme 3. Deprotection of Hexamannopeptoid 15
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3900
Org. Lett., Vol. 11, No. 17, 2009

In conclusion, we have developed a straightforward general
method for preparation of S-glycosylated peptoids and a high
yield method for their cyclization. The reported strategy relies
on the combination of a rapid synthesis of glycosylated
building blocks from inexpensive precursors and their direct
incorporation into a time-effective and high-yielding sub-
monomer solid-phase approach. The versatility of the method
has been demonstrated by the easy preparation of three
glycopeptoids with variable saccharide content. Due to the
therapeutic potential associated with the tuning of carbo-
hydrate-receptor interactions, the herein presented overall
strategy is expected to be a useful tool for sugar-based
drug discovery.
Acknowledgment. We acknowledge the financial support
of University of Salerno.
Supporting Information Available: Full experimental
details and characterization of all compounds are reported
as well as NMR spectra and HPLC chromathograms. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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