Control of helicity in C3-symmetric systems by peptide-like β-turns

Article abstract of DOI:10.1016/j.tetlet.2008.02.065

Cyclic imidazole-containing hexapeptides with three arms bound to the peptide scaffold via the secondary nitrogen atoms of the imidazoles are presented; these arms, together with a part of the macrocycle, form peptide-like β-turns making their helicity pr

Full text of DOI:10.1016/j.tetlet.2008.02.065

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2421–2424
Control of helicity in C3-symmetric systems by peptide-like b-turns
Gebhard Haberhauer *
Institut fu¨r Organische Chemie, Fachbereich Chemie, Universita¨t Duisburg-Essen, Universita¨tsstraße 5, D-45117 Essen, Germany
Received 11 December 2007; revised 6 February 2008; accepted 11 February 2008
Available online 14 February 2008
Abstract
Cyclic imidazole-containing hexapeptides with three arms bound to the peptide scaffold via the secondary nitrogen atoms of the
imidazoles are presented; these arms, together with a part of the macrocycle, form peptide-like b-turns making their helicity predeter-
minable and allowing the diastereoselective synthesis of K-metal complexes.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Chirality; Imidazoles; Peptides; Peptidic b-turns
C3-Symmetric systems have been studied extensively for
the last decade1 as they can be used as catalysts2 in organic
syntheses, ligands3 for metal complexes, supramolecular
hosts4 or nanoscale devices.5 For the control of the helicity
of C3-symmetric systems, chiral centers and chiral axes are
predominantly used and the stereochemical information is
passed on by repulsive interactions.6 It would, however, be
of interest to provide systems wherein the helicity is addi-
tionally or alternatively predetermined by conformation-
controlling hydrogen bonds, like peptidic or peptide-like
b-turns. Herein, we present the synthesis of a system in
which the helicity is controlled by three peptide-like b-turns
(1 shown in Fig. 1). The system consists of an imidazole-
containing cyclic hexapeptide as a scaffold to which are
attached three flexible arms via the secondary nitrogen
atoms of the imidazole units. The hydrogen atoms of the
amide bond of the arms should be able to form hydrogen
bonds with the carbonyl groups of the peptidic scaffold.
O
R
N
*
R
N
O
H
N
H
N
O
N
O
N
H
NH
H
N
O
αC(3)
N
H
N
αC(3)
αC(2)
N
αC(2)
NH
H
N
N
O
O
NH
C(1)
N
O
H
N(4)
R
N
O
N(4)
N
H
O
C(1)
N
*
O
R
a)
b)
c)
1
Fig. 1. (a) Cyclic hexapeptide 1 with the control of helicity via three peptide-like b-turns; (b) peptide-like b-turns motif of 1; and (c) peptidic b-turn.
*
Tel.: +49 (0)201 183 3615; fax: +49 (0)201 183 4252.
E-mail address: gebhard.haberhauer@uni-due.de
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.065

2422
G. Haberhauer / Tetrahedron Letters 49 (2008) 2421–2424
COOR
N
HN
O
O
N
N
HN
N
HN
N
O
NH
N
O
NH
N
a, b
H
N
NH
H
N
N
N
N
COOR
H
O
O
ROOC
3a R = tert-butyl
3b R = H
2
CONHR
N
N
O
1a R = butyl
1b R = phenyl
HN
O
NH
c
N
1c R =
1d R =
N
N
N
H
N
N
N
N
CONHR
O
RHNOC
1a-d
Scheme 1. Reagents and conditions: (a) K2CO3, BrCH2COOtert-Bu, CH3CN, D, 90%; (b) TFA, DCM, quant.; (c) DMC, RNH2, Et3N, DCM, 0 °C?rt,
35–90%.
The three formed spatially arranged units resemble in their
form peptide b-turns, the central amide bond of which is
incorporated into an imidazole (Formula 1). The spatial
orientation of the three arms is determined by the chirality
of the macrocycle. Accordingly, the helicity of the total sys-
tem is unambiguously predetermined by the formation of
peptide-like b-turns composed of a part of the cyclic scaf-
fold and the flexible arms.
The synthesis of compounds 1 starts from the backbone-
modified cyclic peptide 27 (Scheme 1). This can be prepared
in only a few steps and in large quantities from L-valine and
a simple amino ketone. Threefold alkylation of the second-
ary nitrogen atoms of the imidazoles with tert-butyl
bromoacetate affords triester 3a, which can subsequently
be converted with trifluoroacetic acid into triacid 3b. The
amide formation is carried out by reaction with the desired
amine in the presence of 2-chloro-1,3-dimethylimidazolidi-
nium chloride (DMC)8 as the coupling agent and triethyl-
amine in dichloromethane. By this pathway, we could
synthesize several helical systems of type 1 (Scheme 1).
To investigate the formation of the peptide-like b-turns
in 1, molecular-modeling calculations were carried out for
1b. The energies of the conformers of 1b were determined
with the DFT method (B3LYP) using the 6-31G* basis
set.9 The results show that the two types of b-turns can
be present in 1b. More precisely, a dihedral angle
all three arms point into the same direction and are heli-
cally arranged (1bA shown in Fig. 2). In total, the system
has M-helicity, which is induced by the turn formation.
If, however, all three loops have a dihedral angle of 85°,
the arms are arranged in one plane (1bB shown in Fig. 2).
The energy difference between these two conformers was
calculated to be 19.8 kJ molÀ1, the helical conformer 1bA
being energetically more favored. If only one of the three
loops takes a dihedral angle of 85°, the remaining two tak-
ing the more advantageous angle of 5°, the energy differ-
ence to 1bA amounts to only 3.5 kJ molÀ1. If two of the
loops take the dihedral angle of 85°, the energy difference
to 1bA amounts to 11.8 kJ molÀ1. Apart from the C3-sym-
metric conformers 1bA and 1bB, an energetic minimum for
a further C3-symmetric conformer (1bC) of 1b was found.
C
(1)–aC(2)–aC(3)–N(4) of either 5° or 85° can be taken
Fig. 2. Molecular structures of 1bA and 1bB calculated with B3LYP/
6-31G*. All hydrogen atoms were omitted for clarity.
(Fig. 1).10 If all three loops have a dihedral angle of 5°,

G. Haberhauer / Tetrahedron Letters 49 (2008) 2421–2424
2423
In this case, the three arms point into the same direction as
the isopropyl groups, and the total system has also M-
helicity. However, this conformation is not stabilized by
hydrogen bonds, and, accordingly, 1bC is destabilized by
43.7 kJ molÀ1 vis-a-vis 1bA. An energy minimum for a con-
`
formation where the three arms are oriented in a P-helix
could not be found with B3LYP/6-31G*. This is in accor-
dance with the hypothesis that the peptide-like b-turns
have a conformation-stabilizing effect, since in P-helices
no advantageous hydrogen bonds can be formed.
For a further confirmation of the hypothesis that in
molecule 1 three peptide-like b-turns are formed, we car-
ried out 1H NMR investigations with 1b. As expected,
1
the H NMR spectrum of 1b in CDCl3 (10 mM) shows a
broad signal for the NH-amide hydrogens of the anilide
units having a mean value of 10.3 ppm, which indicates
strong hydrogen bonds: this can be deduced from the com-
parison with acetanilide, which has an amide signal at
(only) 7.2 ppm in CDCl3 (30 mM). The assumption that
the hydrogen bonds are primarily intramolecular hydrogen
bonds can be confirmed by two further experiments:11
1
firstly, the anilide signal in the H NMR spectrum of 1b
remains at a mean value of 10.2 ppm even at 10 times lower
concentration of 1b (1 mM)—in the case of intermolecular
hydrogen bonds, a significant shift of the signal would
have been expected. Secondly, amide proton–deuterium
exchange rates were assessed to provide a further support-
ing evidence for the role of the anilide in generating stable
intramolecular hydrogen-bonds. Exchange rates with deu-
terated methanol, with a 1:2 CD3OD/CDCl3 solution of
1b, demonstrated the exceptional stability of the anilide
NH hydrogen bond, as its NMR signal was still present
after 2 h, whereas the anilide protons of the reference sys-
tem (acetanilide) under equivalent conditions exchanged
with deuterium instantly. This shows that the anilide
hydrogen atoms of 1b can be reached only difficultly by
the solvent molecules, which indicates the presence of
strong intramolecular hydrogen bonds.
The predetermination of the helicity caused by the loop-
like arrangement of the arms can best be proven by the dia-
stereoselective synthesis of helix-like metal complexes.
Thus, ligands with an M-helix-like arrangement of the
arms should selectively form the corresponding K-metal
complexes. For verifying this assumption, ligand 1d was
reacted with various divalent metal salts and the respective
UV, CD, and high resolution ESI mass spectra were
recorded. The mass spectra of the solution indicate the
formation of 1:1 complexes. For all metal complexes and
independently from the used solvent, a positive Cotton
effect can be observed at 320–330 nm and a negative
Cotton effect at 300 nm (Fig. 3 and Table 1). These two
effects are typical for K-trisbipyridyl metal complexes.12,13
To our knowledge, this is the first description of a dia-
stereoselective preparation of Ca, Cu, and Mn trisbipyridyl
complexes. The extent of the energetic favorization of the
Fig. 3. CD spectra of the receptors (a) 1d (green) and (b) 1c (green) with
Ni(NO3)2 (red), Cu(CF3SO3)2 (yellow) and Zn(CF3SO3)2 (blue) in
CH3CN.
Table 1
CD spectra of the complexes of receptors 1c and 1d with metal ions
([1] = 2.0 Â 10À4 mM and 1:Mn+ = 1:1)
Mn+
De/MÀ1 cmÀ1 (wave length/nm)
1ca
—
23.3 (236), À41.8 (256), 3.6 (279)
1ca Ni2+
16.3 (232), À45.0 (257), 9.9 (274), À1.3 (295)
1ca Cu2+ 29.2 (233), À49.2 (258), 2.2 (280), À4.2 (296)
1ca Zn2+ À47.0 (257), 6.6 (278)
1da
—
19.6 (233), À50.6 (252), 26.0 (303), 25.3 (309)
1da Ca2+ 38.8 (234), À48.0 (255), 2.4 (287), À13.4 (298), 57.8 (320)
1da Mn2+ 10.6 (236), À65.2 (254), 13.7 (280), À37.1 (304), 143.4 (331)
1db Fe2+
24.6 (238), À50.4 (259), À67.2 (302), 114.5 (324), À2.03
(393), 5.33 (481), À9.81 (550)
1da Co2+ 15.5 (235), À53.1 (255), 3.4 (283), À16.6 (303), 93.1 (328)
1da Ni2+
À47.0 (254), 0.6 (282), À24.3 (306), 93.9 (332)
1da Cu2+ 28.3 (236), À53.2 (256), À41.3 (305), 103.0 (333)
1da Zn2+ 34.8 (236), À46.5 (256), À62.7 (305), 166.4 (332)
1db Zn2+ 41.5 (237), À62.2 (257), À39.6 (304), 124.8 (333)
1dc Zn2+ 100.0 (243), À76.3 (263), À56.1 (299), 150.1 (324)
a
In CH3CN.
In MeOH.
In MeOH/H2O (1:9).
b
c
tion of 1dÁZn2+, the energy difference between the K-isomer
with the lowest energy and the D-isomer with the lowest
energy is more than 118.1 kJ molÀ1. Although the transfer
of results calculated in the gas phase to the situation in the
condensed phase has to be made with precaution, such a
large energy difference nevertheless allows the conclusion
that only the K-isomer is present in solution.
`
K-complexes vis-a-vis the D-complexes was determined by
DFT calculations. According to B3LYP/6-31G* calcula-

2424
G. Haberhauer / Tetrahedron Letters 49 (2008) 2421–2424
E.; MacGloinn, C. Chem. Commun. 2003, 1274; (c) Nagasato, S.;
In the case of the tridentate ligand 1c, too, the reaction
Sunatsuki, Y.; Ohsato, S.; Kido, T.; Matsumoto, N.; Kojima, M.
Chem. Commun. 2002, 14; (d) Matsumoto, K.; Ozawa, T.; Jitsukawa,
K.; Einaga, H.; Masuda, H. Chem. Commun. 2001, 978; (e) Uppadine,
L. H.; Drew, M. G. B.; Beer, P. D. Chem. Commun. 2001, 291; (f)
Weizman, H.; Libman, J.; Shanzer, A. J. Am. Chem. Soc. 1998, 120,
2188; (g) Tor, Y.; Libman, J.; Shanzer, A.; Felder, C. E.; Lifson, S. J.
Am. Chem. Soc. 1992, 114, 6661.
with metal salts leads to a diastereoselective complex
formation (Fig. 3 and Table 1). The three pyridine arms
are arranged propeller-like around the metal center. Such
a helically controlled propeller-like arrangement in labile
coordination complexes has been observed in only a few
systems up to date.14 According to B3LYP/6-31G* calcula-
tions, the energy difference between the K-isomer of
4. See, for example: (a) Fabris, F.; Pellizzaro, L.; Zonta, C.; De Lucchi,
O. Eur. J. Org. Chem. 2007, 283; (b) Heinrichs, G.; Kubik, S.; Lacour,
J.; Vial, L. J. Org. Chem. 2005, 70, 4498; (c) Postnikova, B. J.; Anslyn,
E. V. Tetrahedron Lett. 2004, 45, 501; (d) Schopohl, M. C.; Siering,
C.; Kataeva, O.; Waldvogel, S. R. Angew. Chem., Int. Ed. 2003, 42,
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Kim, S.-G.; Kim, K.-H.; Jung, J.; Shin, S. K.; Ahn, K. H. J. Am.
Chem. Soc. 2002, 124, 591; (g) Hennrich, G.; Anslyn, E. V. Chem. Eur.
J. 2002, 8, 2218; (h) Cousins, G. R. L.; Furlan, R. L. E.; Ng, Y.-F.;
Redman, J. E.; Sanders, J. K. M. Angew. Chem., Int. Ed. 2001, 40,
423; (i) McDonald, D. Q.; Still, W. C. J. Am. Chem. Soc. 1996, 118,
2073.
1cÁZn2+ and the D-isomer amounts to 33.3 kJ molÀ1
.
In summary, we could show that three arms can be fixed
on an imidazole-containing hexapeptide, the conformation
of which is controlled via three peptide-like b-turns. The
helicity of the arms thus can be predicted, which allows
the diastereoselective synthesis of various—even kinetically
labile—octahedral metal complexes. This concept of using
peptide-like b-turns for the structure formation in C3-sym-
metric systems should be applicable to other systems, too.
5. See, for example: (a) Hennrich, G.; Omenat, A.; Asselberghs, I.;
Foerier, S.; Clays, K.; Verbiest, T.; Serrano, J. L. Angew. Chem., Int.
Acknowledgments
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¨
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The authors thank the DFG for financial support. We
are grateful to Dr. Andreea Schuster for many helpful
discussions.
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Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2008.02.065.
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References and notes
9. All computations were performed with the GAUSSIAN 03 program-
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29, 21; (b) Dro, C.; Bellemin-Laponnaz, S.; Welter, R.; Gade, L. H.
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´
12. Mason, S. F.; Peart, B. J. J. Chem Soc., Dalton Trans. 1973, 949.
13. The changes in the CD spectra exclusively come from the formation
of the K-trisbipyridyl metal complexes; the addition of metal ions to
1b does not lead to any change in the CD spectra.
14. Carnary, J. W.; Allen, C. S.; Castagnetto, J. M.; Wang, Y. J. Am.
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Perez-Prieto, J. Angew. Chem., Int. Ed. 2006, 45, 6741; (e) Bellemin-
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