Carboxamide versus sulfonamide in peptide backbone folding: A case study with a hetero foldamer

Article abstract of DOI:10.1021/ol4002762

Strikingly dissimilar hydrogen-bonding patterns have been observed for two sets of closely similar hetero foldamers containing carboxamide and sulfonamides at regular intervals. Although both foldamers maintain conformational ordering, the hydrogen-bondin

Full text of DOI:10.1021/ol4002762

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Carboxamide versus Sulfonamide in
Peptide Backbone Folding: A Case Study
with a Hetero Foldamer
Veera V. E. Ramesh,† Sangram S. Kale,† Amol S. Kotmale,‡ Rupesh L. Gawade,§
Vedavati G. Puranik,§ P. R. Rajamohanan,‡ and Gangadhar J. Sanjayan*,†
Division of Organic Chemistry, Central NMR Facility, and Center for Materials
Characterization, National Chemical Laboratory, Dr. Homi Bhabha Road,
Pune 411 008, India
gj.sanjayan@ncl.res.in
Received January 30, 2013
ABSTRACT
Strikingly dissimilar hydrogen-bonding patterns have been observed for two sets of closely similar hetero foldamers containing carboxamide and
sulfonamides at regular intervals. Although both foldamers maintain conformational ordering, the hydrogen-bonding pattern and backbone
helical handedness differ diametrically.
Sulfonamides are an important class of compounds
which are widely used in the design of diverse classes of
drug candidates.1 In view of their biomedical importance,
sulfonamide building blocks have been incorporated into
many peptides.2 Although both come under the class of
amides, carboxamide and sulfonamide have strikingly
different hydrogen-bonding and geometrical preferences:
(i) as compared to carboxamide NH, the sulfonamide NH
is more acidic, resulting in its better participation in
H-bonding events; (ii) sulfonamide has two H-bonding
acceptor oxygens; (iii) the sulfonamides have a favored
dihedral angle, ω e 90°, as opposed to carboxamides
which usually favor a planar conformation with ω e
180°; and (iv) the bond length SÀN in sulfonamide is
greater than CÀN in carboxamide, thus sulfonamide has
low SÀN rotation barrier as compared to carboxamide.3
Intrigued by their distinctly different conformational
propensities, we were interested in investigating the effect
on swapping carboxamide with sulfonamide in foldamers.
In order to realize this goal, we designed two sets of hetero
foldamers4 featuring regularly repeating R,β,R-tripeptide
building blocks of the structure Pro-Xaa-Aib (Figure 1).
Whereas 1, 3, and 5 feature anthranilic acid (Xaa = Ant,
† Division of Organic Chemistry.
‡ Central NMR Facility.
(3) Radkiewicz, J. L.; McAllister, M. A.; Goldstein, E.; Houk, K. N.
J. Org. Chem. 1998, 63, 1419.
§ Center for Materials Characterization.
(1) (a) Supuran, C. T.; Scozzafava, A. Med. Res. Rev. 2003, 23, 535.
(b) Maren, T. H. Annu. Rev. Pharmacol. Toxicol. 1976, 16, 309.
(2) (a) Gennari, C.; Salom, B.; Potenza, D.; Williams, A. Angew.
Chem., Int. Ed. Engl. 1994, 33, 2067. (b) Gennari, C.; Salom, B.; Potenza,
D.; Longari, C.; Fioravanzo, E.; Carugo, O.; Sardone, N. Chem.;Eur.
J. 1996, 2, 644. (c) Liskamp, R. M. J.; Kruijtzer, J. A. W. Mol. Diversity
2004, 8, 79. (d) Langenhan, J. M.; Fisk, J. D.; Gellman, S. H. Org. Lett.
2001, 3, 2559. (e) Liskamp, R. M. J.; Rijkers, D. T. S.; Kruijtzer, J. A. W.;
Kemmink, J. ChemBioChem 2011, 12, 1626. (f) Turcotte, S.; Gervais,
S. H. B.; Lubell, W. D. Org. Lett. 2012, 14, 1318.
(4) (a) Seth Horne, W.; Gellman, S. H. Acc. Chem. Res. 2008, 41,
1399. (b) Martinek, T. A.; Fulop, F. Chem. Soc. Rev. 2012, 41, 687. (c)
Pilsl, L. K. A.; Reiser, O. Amino Acids 2011, 41, 709. (d) Vasudev, P. G.;
Chatterjee, S.; Shamala, N.; Balaram, P. Chem. Rev. 2011, 111, 657. (e)
Guichard, G.; Huc, I. Chem. Commun. 2011, 47, 5933. (f) Roy, A.;
Prabhakaran, P.; Baruah, P. K.; Sanjayan, G J. Chem. Commun. 2011,
47, 11593. (g) Prabhakaran, P.; Priya, G.; Sanjayan, G. J. Angew. Chem.,
Int. Ed. 2012, 51, 4006. (h) Nagel, L.; Plattner, C.; Budke, C.; Majer, Z.;
DeVries, A. L.; Berkemeier, T.; Koop, T.; Sewald, N. Amino Acids 2011,
41, 719.
r
10.1021/ol4002762
XXXX American Chemical Society

an aromatic β-amino carboxylic acid) as the central residue
of the tripeptide building block, 2, 4, and 6 feature
2-aminobenzenesulfonic acid (SAnt, an aromatic β-amino
sulfonic acid) as the central residue in the tripeptide
building blocks.
as well as in their higher analogues (1b and 3a feature only
C6 H-bonding, whereas their sulfonamide analogues 2a
and 4a feature C11 H-bonding). Oligomers 3a and 4a
assume helical architecture containing different H-bonded
networks, and the onset of helix formation can be seen from
the tripeptide stage itself.
Figure 2. PyMOL-rendered crystal structures of carboxamide
oligomers 1b and 3a and sulfonamide oligomers 2a and 4a.
Hydrogens, other than the polar amide hydrogens, have been
removed for clarity.
Analysis of the torsion angles and hydrogen-bonding
parameters of all of the crystal structures reveals the
following characteristic features, as detailed in Tables 1
and 2, respectively. In the (Pro-Ant-Aib) oligomers 1b and
3a, proline adopts preferential torsional angles φ and ψ
around(60° and(35°, while in the case of (Pro-SAnt-Aib)
oligomers 2a and 4a, the Pro φ and ψ values are (80° and
(10°, respectively (Table 1). The Ant φ ranges from a
minimum value of 160.4° (3a) to a maximum value of
S
169.3° (1b); on the other hand, Ant φ ranges from a
Figure 1. Designed R,β,R-hetero foldamers featuring carboxamide
minimum value of À133.9° (4a) to a maximum value of
À143.3° (2a). However, significant differences in ψ value
of Ant (À154.6 to À166.8°) and SAnt (64.3 to 70.8°) have
been noted. It is noteworthy that, among all torsion angles,
(Pro-Ant-Aib) and sulfonamide (Pro-SAnt-Aib) building blocks.
Investigation of crystal data unambiguously revealed
that the Pro-Ant-Aib oligomers 1b and 3a display six-
membered intra-residual hydrogen bonding (C6
H-bonding) within the Ant rings (Figure 2). In stark
contrast, their sulfonamide counterparts 2a and 4a dis-
play an inter-residual 11-membered ring intramolecular
H-bonding (C11 H-bonding). The nature of these
H-bonded interactions is persistent in the shorter segments
S
the amide dihedral angle ω of Ant and Ant differs the
most. In the (Pro-Ant-Aib) oligomers, Ant displays ω
values about 178°. In stark contrast, SAnt displays ω value
ranging from 58.3° (4a) to 86.4° (2a). A closer look at the ω
(5) Parkin, A.; Collins, A.; Gilmore, C. J.; Wilson, C. C. Acta
Crystallogr., Sect. B 2008, 64, 66.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Backbone Torsion Angles Observed in Crystals 1b, 2a, 3a, and 4a
torsion (deg)
Pro
Ant/SAnt
Aib
compd no.
1b
type of amide
carboxamide
φ
ψ
φ
θ
ψ
ω
φ
ψ
(NH...OdC)
À61.8(4) À34.2(4)
À65.5(4) À41.6(4)
À67.1(4) À32.3(4)
169.3(3) À3.0(4) À155.9(3) À178.6(3)
49.7(4)
46.6(4) 45.5(4)
8.72
À40.70
9.84
1st seg
165.8(3)
160.4(3)
0.9(5)
166.8(3)
179.0(3)
3a
2a
carboxamide
sulfonamide
2nd seg
1.7(5) À154.6(3)
177.7(3) À59.5(4)
À89.9(3)
À87.9(3)
À0.9(3) À143.3(2)
À6.9(4) À138.8(3)
2.0(3)
4.5(4)
4.1(4)
64.3(2)
68.0(2)
70.8(3)
86.4(2)
58.3(2)
65.5(3)
3.13
1st seg
41.7(3) 71.3(3)
À83.84
À116.78
4a
sulfonamide
2nd seg
À69.9(3) À21.3(4) À133.9(3)
69.4(3) À62.6(3)
Table 2. Backbone Hydrogen-Bonding Parameters Observed in Crystals 1b, 2a, 3a, and 4a
hydrogen-bonding parameters
1st segment
angles (deg)
2nd segment
angles (deg)
˚
distances (A)
˚
distances (A)
compd
no.
type of
amide
(O H)1 (N O)1 (CdO H)1 (CdO N)1 (NH O)1 (O H)2 (N O)2 (CdO H)2 (CdO N)2 (NH O)2
3 3 3
3 3 3
3 3 3
3 3 3
3 3 3
3 3 3
3 3 3
3 3 3
3 3 3
3 3 3
1b
3a
2a
4a
carboxamide
carboxamide
sulfonamide
sulfonamide
1.89
1.95
2.04
2.18
2.63
2.61
2.90
2.95
99
100
119
116
87
89
119
115
140
133
179
148
1.95
2.65
98
86
137
146
2.072
2.826
114
118
values of all crystal structures unambiguously confirms the
disparity of the geometrical preferences of carboxamides
(ω ∼ 180°) and sulfonamides (ω ∼ 90°).5
phenomenon associated with Pro having the N-terminus
Boc carbamate group causing cisÀtrans isomerization at
the N-terminal carbamate carbonyl.6 This problem could
be efficiently circumvented by attaching a pivaloyl group
at the N-terminus, resulting in a sharp single set of signals
(Supporting Information, S26ÀS29). Interestingly, the
sulfonamide counterparts did not experience the rotamer
problem arising from the slow rotation of the N-terminus
Boc-carbamate group, primarily due to the fact that the
Boc-carbamate carbonyl is locked in intramolecular C11
H-bonding. Two-dimensional NOESY study of the hexa-
peptide 3b exhibited inter-residual nOes between Piv-CH3
(C36H) versus Aib1-CH3 (C15H), supporting the folded
conformation, similar to the one found in the crystal
structure. Similarly, the 2D NOESY data of hexapeptide
4a revealed several inter-residual nOes, for instance, Boc-
CH3 (C34H) vs NH2, Boc-CH3 (C34H) vs Pro1-C20H,
Aib1-CH3 (C14H) vs NH4, and Pro2-C17H vs Aro C9H
(Figure 3 and Supporting Information, S54ÀS73), sup-
porting a folded conformation, as seen in the solid state.
The existence of intramolecular hydrogen bonding in the
oligomers was confirmed by DMSO-d6 titration and
The hydrogen-bonding distances [d(NÀH OdC)] of
3 3 3
˚
1b and 3a have been found to range from 1.89 to 1.95 A,
respectively, suggesting a strong C6 H-bonded network
(Table 2). The C11 H-bonded network in the sulfonamide
counterparts 2a and 4a were also found to range from
˚
2.04 to 2.18 A, respectively. The H-bonding angles
[Δ(CdO N)] of Pro-Ant-Aib and Pro-SAnt-Aib oligo-
3 3 3
mers are ∼87 and 117°, respectively.
The conformational characteristics of the oligomers in
the solution state were investigated by extensive NMR
studies. All oligomers were readily soluble in nonpolar
organic solvents (.100 mM in CDCl3, CD3CN) at ambi-
ent conditions. The results obtained from NMR dilution
studies of 3b and 4a (Δδ(NH) < 0.33, Supporting Infor-
mation, S43ÀS44) suggest absence of aggregation caused
by intermolecular hydrogen bonding. The signal assign-
ments of all oligomers have been done using a combination
of 2D COSY, NOESY, HMBC, HSQC, and TOCSY
(concentration = 80À100 mmol). Some of the character-
istic NOE patterns observed for 3b and 4a are given in
Figure 3, which is consistent with the helical conformation
observed in the crystal structure (detailed signal assign-
ments in Supporting Information S54ÀS73). It is note-
worthy that multiple NMR signals, due to rotamer
formation, are observed for the carboxamide oligomers
having the N-terminal Boc-Pro residue. This is a well-known
(6) (a) Chatterjee, B.; Saha, I.; Raghothama, S.; Aravinda, S.; Rai,
R.; Shamala, N.; Balaram, P. Chem.;Eur. J. 2008, 14, 6192. (b)
Prabhakaran, P.; Kale, S. S.; Puranik, V. G.; Rajamohanan, P. R.;
Chetina, O.; Howard, J. A. K.; Hofmann, H. J.; Sanjayan, G. J. J. Am.
Chem. Soc. 2008, 130, 17743.
(7) Crystallographic data for 1b and 2aÀ4a have been deposited with
the Cambridge Crystallographic Data Centre as supplementary pub-
lication no. CCDC-914493À914496, respectively.
Org. Lett., Vol. XX, No. XX, XXXX
C

in 11-membered H-bonding also show negligible shift in
DMSO titration experiments (Supporting Information,
S47ÀS48). Variable-temperature studies of 1b, 3b, 2a,
and 4a further support intramolecular hydrogen bonding
wherein the NHs involved in the intramolecular H-bond-
ing show a temperature coefficient (Δδ/ΔT) >À5 ppb/K [for
1b (Δδ/ΔT)NH1 = À3.6 ppb, for 3b (Δδ/ΔT)NH1 = À2.7
ppb, (Δδ/ΔT)NH3 = À0.6 ppb, for 2a (Δδ/ΔT)NH2 =
À3.8 ppb, for 4a (Δδ/ΔT)NH2=À4.7 ppb, (Δδ/ΔT)NH4=
À2.2 ppb; Supporting Information, S49ÀS53].
In conclusion, this communication describes a striking
case of conformational comparison between two closely
resembling synthetic oligomers featuring strategically po-
sitioned carboxamide and sulfonamide bonds on the back-
bone. Whereas the carboxamide oligomers (Pro-Ant-Aib)n
display a periodically repeating six-membered intramole-
cular hydrogen-bonded left-handed helical structure, the
(Pro-SAnt-Aib)n oligomers display an 11-membered intra-
molecular hydrogen-bonded right-handed helical architec-
ture. The substantial difference in the torsional angles ψ
and ω of the aromatic amino acids would explain their
conformational differences. The structural differences,
which could be learned from this study, would have a
bearing in practical importance, particularly in the de novo
design of novel sulfonamide-based synthetic peptides.
Figure 3. Selected NOE extracts from the 2D NOESY data of 3b
(CDCl3) and 4a [(CD3)2CO] (500 MHz). Detailed analysis given
in Supporting Information.
Acknowledgment. Dedicated to Prof. K. N. Ganesh on
the occasion of his 60th birthday. V.V.R., S.S.K., and A.S.K.
thank CSIR, New Delhi, for research fellowships. This
work was funded by NCL-IGIB-JRI.
variable-temperature studies. The amide NHs of carbox-
amide oligomers 1b [Δδ(NH) < 0.11 ppm] and 3b
[Δδ(NH1) < 0.23 ppm and Δδ(NH3) < 0.34 ppm] involved
in the six-membered intramolecular H-bonding show neg-
ligible shift in DMSO titration experiments (Supporting
Information, S45ÀS46). The amide NHs of the sulfona-
mide counterparts 2a [Δδ(NH) < 0.09 ppm] and 4a
[Δδ(NH2) < 0.22 ppm and Δδ(NH4) < 0.18 ppm] involved
Supporting Information Available. Experimental pro-
cedures, NMR data for all compounds, and cif file for 1b,
2a, 3a. and 4a. This material is available free of charge via
the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX