Synthesis of glycopeptoid sulfonamides diversifying N-glycopeptide linkage region mimics

Article abstract of DOI:10.1039/c4ra01009d

Replacing the planar carboxamides with tetrahedral sulfonamides in the glycopeptoid backbone, glycopeptoid sulfonamides were synthesized as N-glycopeptide mimics with diverse structures using β-peptoid, chiral amino acids and β-amide or β-sulfonamide linked amino acids with different functional groups. The sulfonamide group exists in different conformations and participates in C-H...O interactions.

Full text of DOI:10.1039/c4ra01009d

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Synthesis of Glycopeptoid Sulfonamides Diversifying
N-glycopeptide Linkage Region Mimic
Anadi Singhamahapatra,a* Laxminarayan Sahoo,a Babu Vargheseb and Duraikkannu
Loganathana†
a Department of Chemistry, Indian Institute of Technology Madras, Chennai – 600036, India
Email: singhaindia@gmail.com
b Sophisticated Analytical Instrumentation Facility, Indian Institute of Technology Madras, Chennai- 600036, India
 Correspondence: Anadi Singhamahapatra, Department of Chemistry, Indian Institute of
Technology Madras, Chennai – 600036, India; Tel.: +91-44-22575221, +91-9884242732; Fax:
091-44-22570509; E-mail: singhaindia@gmail.com
ƚ
Deceased on 9th February, 2013
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Graphical Abstract
Replacing planar carboxamides with tetrahedral sulfonamides, glycopeptoid sulfonamides were
synthesized with diverse conformations and ability to participate in non-covalent interactions.
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Abstract
Replacing the planar carboxamides with tetrahedral sulfonamides in the glycopeptoid backbone,
glycopeptoid sulfonamides were synthesized as N-glycopeptide mimic with diverse structures using
β-peptoid, chiral amino acids and β-amide or β-sulfonamide linked amino acids with different
functional groups. The sulfonamide group exists in different conformations and participates in C-H…O
interactions.
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Glycosylation of proteins acts as a decisive factor in a range of biological processes including cell-cell
recognition, cell growth regulation, cell differentiation, immunological response, metastasis and
bacterial and viral infection.1 As the natural glycoproteins suffer from poor proteolytic stability, low
bioavailability and microheterogeneity, glycopeptide mimics were developed for targeted medical
applications. Glycopeptoids are recent inclusion to this list.2 Including synthesis of clickable
glycopeptoid reported from our group3 in recent literature, there are several reports on synthesis of
glycopeptoids with diverse linkages and modifications in the peptoid backbone with rapidly growing
interest in this area of research.4 Sulfonamides are known as transition state analogs for the hydrolysis
of amide bonds in peptide. Considering their importance in medicinal chemistry,5 sulfonamides are used
as replacement of carboxamides in peptidomimetics.6 The present work includes synthesis of
glycopeptoid sulfonamide building blocks by replacing the carboxamide group with sulfonamide in the
peptoid backbone. The tetrahedral geometry of the sulfonamide group compared to planar carboxamides
and the relatively low energy for the rotation around S-N bond may introduce unnatural conformations
in the peptide backbone useful for their specific biological activities (Figure 1).
Figure 1 Comparative conformation of glycopeptide, glycopeptoid and glycopeptoid sulfonamide
Due to the absence of NH protons, amide groups in peptoid cannot participate as hydrogen bond donor
but they can act as hydrogen bond acceptor. Compared to amides, sulfonamides having two oxygen
atoms have better probability to act as hydrogen bond acceptor. Thus, this present work was initiated
with the objective to diversify the conformation of peptoid backbone using more flexible sulfonamides
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with enhanced ability to participate in non-covalent interactions with other biomolecules for biomedical
applications.
Propargyl amine was alkylated with tert-butyl bromoacetate (1 equiv.) in presence of K2CO3 (2 equiv.)
as the base followed by reaction of the secondary amine synthesized with 2-chloroethanesulfonyl
chloride (1.2 equiv.) in presence of diisopropylethylamine (2 equiv.) as the base (Scheme 1) to give
N-propargylated vinylsulfonamide (1). The synthesis of other isomer of N-propargylated
vinylsulfonamide (2) was done by Michael addition of propargyl amine on tert-butyl acrylate followed
by reaction with 2-chloroethanesulfonyl chloride (1.2 equiv.) in presence of diisopropylethylamine (2
equiv.) as the base (Scheme 1).
Scheme 1 Synthesis of glycopeptoid sulfonamides (9-18)
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Compound 1 and 2 were converted to the N-phthalimide protected derivatives 3 and 4 respectively by
Michael addition of phthalimide (1 equiv.) in presence of potassium phthalimide (20 mol%) as the base
(Scheme 1). The N-propargylated sulfonamides (1-4) were reacted with per-O-acetylated β-D-
glycopyranosyl azides7 derived from D-glucose (5), 2-acetamido-2-deoxy-D-glucose (6), D-galactose (7)
and D-xylose (8) in presence of Cu(I) as the catalyst8 (Scheme 1) which was generated in situ by
reaction of copper sulfate (20 mol%) and sodium ascorbate (40 mol%) to give a series of triazole-linked
glycopeptoid sulfonamides with systematic variation in the glycan and the peptoid part (Table 1).
Analytically pure sample of all the compounds were obtained in excellent yields after column
purification.
Table 1 Synthesis of glycopeptoid sulfonamides (9-18)
Sl. No.
1
Azide
Alkyne
Product
Yield (%)
90
5
1
2
3
92
95
5
5
2
3
4
92
5
4
6

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5
6
85
80
6
6
3
4
7
8
94
92
87
90
7
7
8
8
3
4
3
4
9
10
The structural diversity was further explored with synthesis of triazole-linked glycopeptoid
sulfonamides (31-34) with chiral amino acids such as L-valine (19), L-pheylalanine (20), D-pheylalanine
(21) and L-isoleucine (22). The acid group of the amino acids (19-22) was protected as methyl ester by
reaction with methanol and thionyl chloride (2 equiv.) followed by conversion of the amine to methane
sulfonamide by reaction with methanesulfonyl chloride (1.2 equiv.) in presence of
diisopropylethylamine (2 equiv.) as the base (Scheme 2). N-alkylation of methane sulfonamides of
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amino acids (23-26) using propargyl bromide (1.2 equiv.) in presence of potassium carbonate (2 equiv.)
as the base gave the N-propargylated sulfonamides of amino acids (27-30). These alkyne functionalized
peptoid sulfonamides derived from amino acids (27-30) were reacted with 2,3,4,6-tetra-O-acetylated-β-
D-glucopyranosyl azide (5) in prsence of Cu(I) as the catalyst to give triazole-linked N-glycopeptoid
sulfonamides (31-34) in excellent yields after column purification (Scheme 2).
Scheme 2 Synthesis of triazole-linked N-glycopeptoid sulfonamides with chiral amino acids (31-34)
The versatility of this methodology was further extended to synthesis of glycopeptoid sulfonamides with
β-amide (37) and β-sulfonamide (40) linked L-valine (Scheme 3).
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Scheme 3 Synthesis of glycopeptoid sulfonamides with β-amide and β-sulfonamide linked L-valine (37
& 40)
The amino group of the methyl ester protected amino acid was converted to either acrylamide (35) or
vinyl sulphonamide (38) by reaction with acryloyl chloride or 2-chloroethanesulfonyl chloride
respectively (Scheme 3). Michael addition of propargyl amine to acrylamide (35) or vinyl sulfonamide
(38) followed by reaction with methalesulfonyl chloride (1.2 equiv.) in presence of
diisopropylethylamine (2 equiv.) as the base gave compound 36 and 39 respectively. Cu(I) catalyzed
click reaction of N-propargylated sulfonamides (36 and 39) with per-O-acetylated glucopyranosyl azide
(5) gave triazole-linked glycopeptoid sulfonamides with β-amide (37) and β-sulfonamide (40) linked L-
valine (Scheme 3).
X-ray structural study of N-propargylated sulfoamides (3, 4, 28 and 29) showed in all the molecules the
nitrogen atom of sulfonamide has almost planner geometry and the sulfur atom has tetrahedral geometry
(Figure 2).
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Figure 2 Crystal structures of N-propargylated sulfonamides (3, 4, 28 and 29)
The torsion angle (ω) of the sulfonamide backbone have values -103.60˚, 75.25˚, 89.85˚ and -90.23˚
respectively for compound 3, 4, 28 and 29 (Figure 3). The presence of an extra methylene group in
compound 4 introduces extra torsion angle (N2-C14-C15-C16) with the value of -177.34˚. For
sulfonamides derived from chiral amino acids (28 and 29), the side chain of the amino acid (benzyl
group) and the propargyl substituent on sulfonamide nitrogen has torsion angle -65.15˚ and 64.80˚
respectively for compound 28 and 29. In addition to their diversity in conformation, these molecules
differ in their ability to participate in non-covalent interactions. Due to absence of NH proton the
sulfonamide group cannot participate in regular hydrogen bonds but the oxygen atoms of the
sulfonamide participate in C-H…O interactions. In compound 3 one oxygen atom of sulfonamide
participate in C-H…O interaction with aromatic C-H proton of N-phthalimide group whereas the other
oxygen participate in two C-H…O interactions with two C-H protons of tert-butyl groups. One of the
sulfonamide oxygens in compound 4 participates in C-H…O interaction with alkyne proton of the
propargyl group. In the crystal structure of compound 28 and 29, one oxygen of the sulfonamide
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participates in C-H…O interaction with the alkyne proton of the propargyl group whereas the other
oxygen participates in C-H…O interaction with one of the methylene protons of the propargyl group
(Figure 3).
Figure 3 Comparative torsion angles and C-H…O interactions in the crystal structures of
N-propargylated sulfonamides (3, 4, 28 and 29)
To summarize, a series of triazole-linked glycopeptoid sulfonamides were synthesized with diverse
structures involving simple synthetic methodology using Cu(I) catalyzed click reaction with high yield.
1
Unlike carboxamide based peptoids, the H and 13C NMR spectra of these sulfonamide containing
peptoids did not show the existence of cis-trans isomers. The triazole protons in all the compounds
1
appeared as singlet in H NMR spectrum. The X-ray structural study of N-propargylated sulfonamides
(3, 4, 28 and 29) showed variation of torsion angles with small modifications in the structure which
proves the conformational flexibility of peptoid sulfonamide backbone. The oxygen atoms of the
sulfonamide group participated in C-H…O interactions which vary significantly with changes in the
structure. In addition to that the triazole rings which are in close proximity of sulfonamides in triazole-
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linked glycopeptoid sulfonamides, may also participate in non-covalent interactions (H-bonds and
C-H...O interactions). The ability to participate in these types of interactions will help the molecules to
interact with target biomolecules for bio-medical applications. The tert-butyl ester and phthalimide
protected glycopeptoid sulfonamides (11-18) can be used for synthesis of large peptides following
selective deprotection of the ester or N-phthalimide groups. These methodologies can be further
extended for the synthesis of larger glycopeptoid sulfonamides which may introduce unusual
conformation in the peptide backbone and improve their pharmacokinetic properties. Thus in
conclusion, it can be said that a plethora of sequence space using glycopeptoid sulfonamides with
myriad structures, varied conformations and huge potential to be used for medical application are yet to
be explored in the area of peptidomimetics.
Acknowledgment:
The authors thank Indian Institute of Technology Madras for instrumental facilities. AS is thankful to
the Council of Scientific and Industrial Research (CSIR), New Delhi for the award of Senior Research
Fellowship. LNS is thankful to University Grants Commission (UGC), New Delhi for the award of
Senior Research Fellowship. The authors are thankful to Prof. S. Sankararaman, Department of
Chemistry, Indian Institute of Technology Madras and Dr. Satyanarayan Sahoo, Department of
Chemistry, Berhampur University for their valuable inputs during the manuscript preparation.
Notes and references
a Department of Chemistry, Indian Institute of Technology Madras, Chennai-600036, India. Tel.: +91-
44-22575221, +91-9884242732; Fax: 091-44-22570509; Email: singhaindia@gmail.com
b Sophisticated Analytical Instrumentation Facility, Indian Institute of Technology Madras, Chennai-
600036, India
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† Deceased on 9th February, 2013
Electronic Supplementary Information (ESI) available: [Experimental procedure, spectral data (1H
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