Conformationally constrained aliphatic-aromatic amino-acid-conjugated hybrid foldamers with periodic β-turn motifs

Article abstract of DOI:10.1021/jo0709044

(Chemical Equation Presented) In this note, we describe the design, synthesis, and structural studies of novel hybrid foldamers derived from Aib-Pro-Adb building blocks that display repeat β-turn structure motif. The foldamer having a conformationally con

Full text of DOI:10.1021/jo0709044

In an effort to expand the conformational space available for
foldamer design, synthetic oligomers made of building blocks
of independent conformational preferences were recently de-
veloped. A noteworthy example is the possibility of formation
of special helix types in hybrid peptides derived from alternately
changing aliphatic amino acid residues.5,6 We have recently
demonstrated that synthetic oligomers containing unconventional
foldamer building blocks could mimic protein secondary
structures.7 Herein, isotactic acrylamide tetramers have been
shown to adopt protein â-sheet-like structures, formed by
extensive intermolecular hydrogen bonding interactions of the
individual strands. With an objective of expanding the confor-
mational space available for foldamer design, we recently set
Conformationally Constrained
Aliphatic-Aromatic Amino-Acid-Conjugated
Hybrid Foldamers with Periodic â-Turn Motifs
Deekonda Srinivas,† Rajesh Gonnade,‡
Sapna Ravindranathan,§ and Gangadhar J. Sanjayan*,†
DiVision of Organic Synthesis, Center for Materials
Characterization, and Central NMR Facility, National Chemical
Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
gj.sanjayan@ncl.res.in
ReceiVed May 7, 2007
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In this note, we describe the design, synthesis, and structural
studies of novel hybrid foldamers derived from Aib-Pro-
Adb building blocks that display repeat â-turn structure
motif. The foldamer having a conformationally constrained
aliphatic-aromatic amino acid conjugate adopts a well-
defined, compact, three-dimensional structure, governed by
a combined conformational restriction imposed by the
individual amino acids with which it is made of. Confor-
mational investigations by single-crystal X-ray and solution-
state NMR studies were undertaken to investigate the
conformational preference of these foldamers with a hetero-
backbone. Our findings suggest that constrained aliphatic-
aromatic amino acid conjugates would offer new avenues
for the de novo design of hybrid foldamers with distinctive
structural architectures.
(3) (a) Estroff, L. A.; Incarvito, C. D.; Hamilton, A. D. J. Am. Chem.
Soc. 2004, 126, 2-3. (b) Choi, S.; Clements, D. J.; Pophristic, V.; Ivanov,
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Koeckelberghs, G.; Vekemans, J. A. J. M.; Meijer, E. W. Org. Lett. 2006,
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14244. (e) Zhang, A.; Ferguson, J. S.; Yamato, K.; Zheng, C.; Gong, B.
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C.; Luppi, G.; Monari, M. J. Am. Chem. Soc. 2006, 128, 2410-2420. (l)
Srinivasulu, G.; Kiran Kumar, S.; Sharma, G. V. M.; Kunwar, A. C. J.
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Conformationally ordered synthetic oligomers, also called
foldamers,1,2 show considerable promise for the creation of
unnatural oligomers that mimic the structural features of
biopolymers. The conformational rigidity coupled with their
modifiable shape and size shows potential of developing novel
protein mimics that might be difficult to design based on small-
molecule scaffolds.3 Investigations by various groups have led
to the generation of a multitude of such synthetic oligomers
with diverse backbone structural architectures and functions.4
† Division of Organic Synthesis.
‡ Center for Materials Characterization.
§ Central NMR Facility.
(1) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173-180.
10.1021/jo0709044 CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/10/2007
7022
J. Org. Chem. 2007, 72, 7022-7025

FIGURE 2. Single-crystal X-ray structure (ball and stick representa-
tion) of the Boc-Aib-Pro-Adb-OMe foldamer 3a. H-bonding interactions
are highlighted in salmon colored dashes. In addition to the N-H‚‚‚
OdC â-turn interaction, S(5) type interaction15 is also visible. Hydro-
gens, other than at the hydrogen bonding sites, have been deleted for
clarity.
FIGURE 1. Schematic representation of the intramolecular hydrogen
bonding interaction that stabilizes â-turns (i r i + 3). The ideal values
for the torsion angles φ and ψ (highlighted in bold gray arrows) for
the most common types of â-turns (âI and âII) are indicated.
conformations.12 â-Turns comprise a rather diverse group of
structures with the distance from the CR of the first residue to
the CR of the fourth residue in the range of 4-7 Å. The O1‚‚
‚H4-N hydrogen bonding interaction is not an essential
structural feature but is often an indication of a â-turn structure,
as shown by X-ray crystallography and NMR spectroscopy.10
Design Principles. We designed the Aib-Pro-Adb motif-
based foldamer building block 3 (Scheme 1) anticipating that
the corresponding oligomers would adopt a well-defined,
compact, three-dimensional structure, governed by a combined
conformational restriction imposed by the conformationally
constrained individual amino acid residues: Aib, Pro, and Adb
(the conformationally restricted sp3 backbone bonds in 4 are
highlighted in blue bold bonds). Central to the design strategy
is stabilizing and restoring the 10-membered cyclic hydrogen
bond between residue i and i + 3 defining a â-bend ribbon
spiral motif, a characteristic feature found in peptides with
-(Aib-Pro)- sequence.13
In a sequential peptide, the alternation of a Pro (proline)
residue that disrupts the conventional H-bonding schemes found
in helices and a helix-forming residues such as Aib (R-amino
isobutyric acid) may give rise to a novel helical structure, called
the â-bend ribbon spiral.13 This structure may be viewed as a
subtype of the 310-helix, having somewhat the same helical fold
of the peptide chain with intramolecular N-H‚‚‚OdC H-bonds
of the â-bend type,14 and is characterized by two sets of (φ,ψ)
angles: φi ) -54°, ψi ) -40°; φi+1 ) -78°, ψi+1 ) -10°
associated with the Aib-Pro motif. The complete structural
out to generate novel hybrid foldamers composed of confor-
mationally restricted R-amino acid/aromatic amino acid conju-
gates as building blocks.8,9 By suitable choice of the amino acid
constituents, it was possible to obtain a foldamer exhibiting
doubly bent conformation that stabilizes a polymeric array of
water clusters.8 Using the same strategy, but with different amino
acid constituents, we could also obtain a foldamer displaying
periodic γ-turn motifs, stabilized by extensive intramolecular
hydrogen bonding interactions.9
Within the context of seeking foldamers that form ordered
structures, both in solution and in the solid state, this note
describes the design, synthesis, and conformational studies of
a novel hybrid foldamer 4b, derived from regularly repeating
R-aminoisobutyric acid (Aib), proline (Pro), and 3-amino-4,6-
dimethoxy benzoic acid (Adb)2i residues as subunits (Aib-Pro-
Adb motif), which forms periodic â-turn motifs as evidenced
from various structural studies (vide infra). It is noteworthy that,
among the various secondary structures found in peptides and
proteins, reverse turns (γ- and â-turns) have achieved a
privileged status for considerable mimicking studies. A turn is
defined as a site where the peptide chain reverses its overall
direction.10,11 The terms γ- and â-turn describe turns of three
or four consecutive residues, respectively. These turns may or
may not be stabilized by intramolecular hydrogen bonding
interactions. In â-turns, the CdO of the first residue (i) may be
hydrogen bonded to the NH (amide) of the fourth residue (i +
3), forming a 10-membered ring hydrogen bonded structure
(Figure 1). The term “open” â-turn is used for situations where
no “intraturn” hydrogen bond network is present. Further
classification into specific γ-turn or â-turn classes is based upon
the geometry of the peptide backbone, as described by the φ
and ψ Ramachandran angles in residues i + 1 and i + 2 (â-
turn).10 Among various turn conformations, â-turns have
achieved considerable attention particularly due to the fact that
a multitude of biological receptors recognize peptides in such
(12) For some selected articles on â-turns, see: (a) Fabienne, J.; Eric,
B.; Oleg, M.; Andre, T. J. Am. Chem. Soc. 1998, 120, 6076-6083. (b)
Ramesh, K.; Balaram, P. Biorg. Med. Chem. Lett. 1999, 7, 105-117. (c)
Georges, M.; Esther, K.; Jean-Francois, L. J. Mol. Biol. 1998, 281, 235-
240. (d) Jimenez, A. I.; Cativiela, C.; Aubry, A.; Marraud, M. J. Am. Chem.
Soc. 1998, 120, 9452-9459. (e) Hanissian, S.; Mcnaughton-Smith, G.;
Lombart, H. G.; Lubell, W. D. Tetrahedron 1997, 53, 12789-12854. (f)
Jain, R. M.; Rajashankar, K. R.; Ramakumar, S.; Chauhan, V. S. J. Am.
Chem. Soc. 1997, 119, 3205-3211. (g) Madalengoitia, J. S. J. Am. Chem.
Soc. 2000, 122, 4986-4987. (h) MacDonald, M.; Velde, D. V.; Aube, J.
Org. Lett. 2000, 2, 1653-1655. (i) Belvisi, J.; Bernardi, A.; Mazoni, L.;
Potenza, D.; Scolastico, C. Eur. J. Org. Chem. 2000, 2563-2569. (j) Blank,
J. T.; Guerin, D. J.; Miller, S. J. Org. Lett. 2000, 2, 1247-1249. (k)
Gunasekaran, K.; Gomathi, L.; Ramakrishnan, C.; Chandrasekhar, J.;
Balaram, P. J. Mol. Biol. 1998, 284, 1505-1516.
(13) Karle, I. L.; Flippen-Anderson, J. L.; Sukumar, M.; Balaram, P.
Proc. Natl. Acad. Sci. U.S.A. 1987, 84, 5087-5091.
(14) (a) Venkataram Prasad, B. V.; Balaram, P. Int. J. Biol. Macromol.
1982, 4, 99. (b) Di Blasio, B.; Pavone, V.; Saviano, M.; Lombardi, A.;
Nastri, F.; Pedone, C.; Benedetti, E.; Crisma, M.; Anzolin, M.; Toniolo, C.
J. Am. Chem. Soc. 1992, 114, 6273-6278.
(8) Srinivas, D.; Gonnade, R.; Ravindranathan, S.; Sanjayan, G. J.
Tetrahedron 2006, 62, 10141-10146.
(9) Baruah, P. K.; Sreedevi, N. K.; Gonnade, R.; Ravindranathan, S.;
Damodaran, K.; Hofmann, H.-J.; Sanjayan, G. J. J. Org. Chem. 2007, 72,
636-639.
(10) Sibanda, B. L.; Thornton, J. M. J. Mol. Biol. 1988, 203, 221-231.
(11) Rose, G. D.; Gierasch, L. M.; Smith, J. A. AdV. Protein Chem. 1985,
37, 1-109.
J. Org. Chem, Vol. 72, No. 18, 2007 7023

a
SCHEME 1
a Reagents and conditions: (i) Boc-Pro-OH, IBCF (isobutyl chloroformate), Et3N, dry DCM, rt, 6 h; (ii) dry HCl (gas), dioxane, rt, 5 min; (iii) 2b,
Boc-Aib-OH, DIPEA, TBTU, dry MeCN, rt, 8 h; (iv) dry HCl (gas), dioxane, rt, 5 min; (v) 2 N LiOH, MeOH, rt, 12 h; (vi) DIPEA, TBTU, dry MeCN,
rt, 12 h; (vii) methanolic MeNH2, 50 °C, 70 h, rt. Note: To facilitate identification, the conformationally restricted sp3 backbone bonds in 4 are highlighted
in blue bold bonds.
characterization of this peptide conformation, which may be of
relevance in the development of model systems for peptaibol
antibiotics (e.g., zervamicin)13 and for the numerous (Pro-X)n
(with X * Pro) segments found in globular and fibrous proteins,
was achieved by X-ray diffraction studies of terminally blocked
(L-Pro-Aib)n sequential peptides.14
The Aib-Pro-Adb motif-based foldamer 4b was assembled
from Boc-Aib-Pro-Adb-OMe building block 3a (Scheme 1). The
easily crystallizing building block 3a, readily available by the
TBTU-mediated coupling of the dipeptide H-Pro-Adb-OMe 2b
with BOC-Aib-OH, was subjected to segment doubling strategy
to afford 4a, which could be easily amidated to afford the amide
analogue 4b.
The shorter foldamer 3a could be crystallized readily from
an ethyl acetate/petroleum ether (1:1) solvent mixture. Inves-
tigation of its crystal structure revealed the existence of the
anticipated folded conformation having Aib and Pro residues
taking the i + 1 and i + 2 positions, respectively, of a â-bend
ribbon spiral motif (Figure 2), characteristic of (L-Pro-Aib)n
sequential peptides.13,14 The intramolecular N-H‚‚‚OdC hy-
drogen bonding interaction forming a 10-membered ring
hydrogen-bonded network was relatively weaker with D-H‚‚
‚A distance [d(N-H‚‚‚O)] 3.04 Å and the D-H‚‚‚A angle [ -
(N-H‚‚‚O)] 173.57°. The phi (φ°) and psi (ψ°) dihedral angles
from the crystal structure of 3a were φ1 ) -55, ψ1 ) -36;
φ2) -75, ψ2 ) -11, which are in excellent agreement with
the observed phi and psi dihedral angles observed in (L-Pro-
Aib)n sequential peptides (φ1 ) -54, ψ1 ) -40°; φ2 ) -78°,
ψ2 ) -10°) characterized by the â-bend ribbon spiral motif.13,14
This also means that incorporation of Adb residue (itself a
constrained amino acid) close to the L-Pro-Aib site does not
disrupt the â-bend ribbon spiral motif. It is noteworthy that
incorporation of constrained amino acids into peptide sequences
often causes dramatic conformational flipping.15
hydrogen bonding interaction participates in intermolecular
interaction with the proline CdO of another molecule forming
a self-assembled extended chain structure (Supporting Informa-
tion).
All efforts to crystallize the Aib-Pro-Adb motif-based hexapep-
tide foldamer 4b did not succeed. However, it was possible to
investigate the essential structural features by solution-state
NMR studies (Figure 3). Due to solubility reasons, the solution-
state conformational studies were carried out in CDCl3, in which
the foldamer was readily soluble. It is noteworthy that the
occurrence of periodic â-turn motifs in 4b is strongly supported
by 2D NOESY NMR studies in solution (500 MHz, CDCl3).
One of the most characteristic NOE interactions that can be
anticipated for a repeat turn conformation, as observed in the
solid-state structure of the shorter analogue 3a, would be the
requirement of repeat dipolar couplings between the aryl-NH
and δ-CH of adjacent proline in 4b since they are in spatial
proximity. Analysis of the 2D NOESY data indeed revealed
the existence of sequential dipolar couplings between proline
δ-CH and aryl-NH of the adjacent residues in 4b (NH2/δ1 and
NH4/δ2).
Furthermore, the turn conformation also would require the
spatial proximity of aryl-NH and R-CH of adjacent proline,
which is also readily borne out in the 2D NOESY data (NH2/
R1 and NH4/ R2). The characteristic NOE interactions between
aryl-NH and the adjacent O-aryloxymethyls in 4b (OMe1/NH2;
OMe2/NH3; and OMe3/NH4) strongly suggest their syn ori-
entation, thereby making space for the S(5) type hydrogen
bonded arrangement,16 a prerequisite for the bifurcated hydrogen
bonding in such systems.2g,i Nevertheless, the present study does
not rule out the possibility of rotamer formation/local dynamics
(15) Toniolo, C.; Crisma, M.; Formaggio, F.; Peggion, C. Biopolymers
2001, 60, 396-419.
(16) For a description on various hydrogen bonding interactions, see:
Etter, M. C. Acc. Chem. Res. 1990, 23, 120-126.
Investigation of the crystal structure further revealed that the
amide NH of Aib that does not participate in intramolecular
7024 J. Org. Chem., Vol. 72, No. 18, 2007

FIGURE 3. (a) Molecular structure of 4b with selectively numbered protons: (b, c) partial 2D NOESY spectra of 4b (500 MHz, CDCl3) showing
characteristic nOes.
nuclei on the overall structural architecture of the corresponding
hybrid foldamers containing -(Aib-Pro)- sequences.
Experimental Section
Representative Procedure: {2-[2-{5-{2-[2-{2,4-Dimethoxy-
5-methylcarbamoylphenylcarbamoyl}-pyrrolidin-1-yl]-1,1dim-
ethyl-2-oxoethylcarbamoyl}-2,4-dimethoxyphenylcarbamoyl}-
pyrrolidine-1-yl]-1,1-dimethyl-2-oxoethyl}carbamic acid tert-
butyl ester 4b: To an ice-cold stirred solution of the acid 3c (0.4
g, 0.83 mmol, 1 equiv) and amine 3b (0.35 g, 0.83 mmol, 1 equiv)
in dry acetonitrile (10 mL) was added DIPEA (0.37 mL, 2.08 mmol,
2.5 equiv) followed by TBTU (0.37 g, 1.16 mmol, 1.4 equiv). The
resulting reaction mixture was stirred overnight at room temperature.
The solvent was stripped off under reduced pressure; the residue
was dissolved in dichloromethane (100 mL) and washed sequen-
tially with potassium hydrogen sulfate solution, saturated sodium
bicarbonate and water. Drying and concentration in vacuum yielded
the crude product which on column chromatography (5% methanol/
ethyl acetate, Rf 0.2) afforded 4a (0.45 g, 63%), which was directly
used for the next amidation reaction, without further purification.
FIGURE 4. [D6]DMSO titration graph of the hexapeptide foldamer
4b. The initial concentration of the sample in CDCl3 was 19.5 mM,
and the total amount of [D6]DMSO used was 7.7% of the total volume.
The ester 4a (0.45 g, 0.52 mmol) was taken in saturated methanolic
methylamine solution (15 mL) and stirred at room temperature for
2 days. The solvent was removed under reduced pressure, and the
under the conditions of this NMR study since some of the signals
are broadened.
To confirm that intramolecular hydrogen bonds are clearly
crude product was purified by column chromatography (8%
methanol/ethyl acetate, Rf 0.4) to yield pure 4b (0.4 g, 80%): [R]26
prevalent in solution, we also performed [D6]DMSO titration
studies of 4b. The chemical shift changes of all the amide
protons are presented in Figure 4. Except for the N-terminal
Aib-NH, all other NHs appear in the downfield region and show
little shift when solutions of 4b are titrated gradually with [D6]-
DMSO (∆δ < 0.15 ppm), suggesting their strong involvement
in intramolecular hydrogen bonding interactions. In contrast,
the chemical shift of the N-terminal Aib amide NH proton
undergoes significant chemical shift changes (∆δ ) 1.26 ppm),
on incremental addition of [D6]DMSO, suggesting its involve-
ment in intermolecular hydrogen bonding.
D
-25.6 (CHCl3); mp >248 °C; IR (Nujol) ν (cm-1) 3018, 1645,
1614, 1400, 1215, 758; 1H NMR (400 MHz, CDCl3) δ 8.76 (br s,
1H), 8.62 (br s, 1H), 8.49 (s, 1H), 8.32 (s, 1H), 8.02 (s, 1H), 7.60
(s, 1H), 6.50 (br s, 1H), 6.45 (br s, 1H), 5.28 (br s, 1H), 4.90-4.60
(m, 2H), 3.97 (s, 3H), 3.91 (s, 3H), 3.82 (s, 6H), 3.75-3.45 (m,
4H), 2.92 (d, 3H), 2.25-1.70 (m, 8H), 1.57 (s, 6H), 1.45 (s, 6H),
1.34 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 173.1, 170.8, 169.6,
166.2, 164.1, 156.1, 154.9, 128.6, 127.4, 120.8, 113.9, 113.1, 95.8,
80.1, 62.9, 57.0, 48.3, 28.2, 26.7, 26.1, 25.4; MALDI-TOF m/z
876.36 (M + Na). Anal. Calcd for C42H59N7O12: C, 59.08; H, 6.91;
N, 11.48. Found: C, 58.95; H, 6.87; N, 11.39.
In summary, we have developed novel hybrid foldamers
containing constrained amino acids of independent conforma-
tional preferences as subunits. Conformational investigations
suggest the prevalence of repeat â-turn conformation for these
oligomers, in both solid and solution-state, as evidenced from
single-crystal X-ray and NMR studies, respectively. The findings
suggest that constrained aliphatic-aromatic amino acid conju-
gates would offer new avenues for the de novo design of
foldamers with distinctive structural architectures, entirely
different from their homo-analogues. We are currently inves-
tigating the influence of substitution pattern in the aromatic
Acknowledgment. This work was supported, in part, by
International Foundation for Science (IFS), Sweden (IFS Grant
No. F/4193-1), and NCL In-house project. D.S. is thankful to
CSIR, New Delhi, for a Senior Research Fellowship.
Supporting Information Available: Full experimental proce-
dures, 1H, 13C, and ESI mass spectra of all new compounds (PDF),
and crystal data of 3a (CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
JO0709044
J. Org. Chem, Vol. 72, No. 18, 2007 7025