Synthesis of a new class of imidazole-based cyclic peptides

Article abstract of DOI:10.1016/S0040-4039(02)01365-5

A new class of cyclic peptides based on dipeptidyl imidazoles is presented. Their structure consists of imidazole units alternating with standard amino acid residues and resembles naturally occurring marine cyclopeptides such as westiellamide and ascidiacyclamide.

Full text of DOI:10.1016/S0040-4039(02)01365-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6335–6338
Synthesis of a new class of imidazole-based cyclic peptides
Gebhard Haberhauer* and Frank Rominger
Organisch-Chemisches Institut, Universita¨t Heidelberg, Im Neuenheimer Feld 270, D-69120 Heidelberg, Germany
Received 19 June 2002; accepted 8 July 2002
Abstract—A new class of cyclic peptides based on dipeptidyl imidazoles is presented. Their structure consists of imidazole units
alternating with standard amino acid residues and resembles naturally occurring marine cyclopeptides such as westiellamide and
ascidiacyclamide. © 2002 Elsevier Science Ltd. All rights reserved.
In recent years a number of cyclopeptides incorporating
five-membered heterocyclic rings have been isolated
from marine sources.1 These compounds were usually
identified as secondary metabolites of algae, fungi and
primitive marine organisms with various biological
activities, including cytotoxicity, antibacterial and
antiviral activities.2 Examples have been found for their
ability to overcome multidrug resistance or to act as
antineoplastic agents.3
tion properties of Lissoclinum cyclopeptide alkaloids is
given by metal ion binding studies to westiellamide,
patellamides and ascidiacyclamide5 and by metal-cata-
lyzed templated assemblies of oxazole and thiazole-
based amino acids.6 The unique macrocyclic
heterocyclic scaffolds present in Lissoclinum cyclopep-
tide offer great opportunities for molecular recognition7
and the preparation of new tubular and cage
structures.8
In Lissoclinum cyclopeptide alkaloids, oxazole, thiazole,
oxazoline and thiazoline moieties alternate with stan-
dard amino acid residues (Fig. 1).1 These five-mem-
bered heterocyclic rings result from condensation of
serine, threonine and cysteine side chains with the
preceding carbonyl groups in a peptide sequence. The
size and conformation of these macrocycles and the
functional groups they possess have led to the specula-
tion that they may function as metal complexation and
transport agents in vivo.4 Evidence for metal complexa-
Cyclopeptides containing imidazole units in the scaffold
have not been isolated from nature yet. This may be
due to the fact that the diaminopropanoic acid (Dap),
which is formally the amino analogue of serine, occurs
rarely in natural sources.9 Moreover, non-natural
cyclopeptides incorporating dipeptidyl imidazoles in the
backbone have not been described in literature, neither.
We consider the unique feature of imidazoles, con-
strained into an asymmetric macrocyclic peptidylic
framework, to be highly promising for the development
of new classes of metal chelators and asymmetric cata-
lysts. For example, imidazoles are well known as lig-
ands in many metalloenzymes (e.g. metalloproteases) as
well as in non-natural metal complexes.10 Furthermore,
the basicity of imidazoles is significantly higher than
that of the corresponding oxazoles and thiazoles.11 For
this reason, imidazoles have been proven to be a key
structural element in basic active sites of asymmetric
catalysts.12
We now wish to report the synthesis of the cyclic
peptides 7a–c and 8a–c (see Scheme 1) based on the
dipeptidyl imidazoles 4a–c. The synthesis starts with the
activation of the Boc-protected valine (1a), the Boc-
protected phenylalanine (1b) or the bis-N-protected
b-aminoalanine derivative 1c as the mixed anhydride
using isobutyl chloroformate and their coupling to the
Figure 1. Natural marine cyclopeptides with heterocyclic scaf-
folds.
* Corresponding author. Tel.: +49 (0)6221 546239; fax: +49 (0)6221
544205; e-mail: gebhard.haberhauer@urz.uni-heidelberg.de
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01365-5

6336
G. Haberhauer, F. Rominger / Tetrahedron Letters 43 (2002) 6335–6338
Scheme 1. Reagents and conditions: (i) isobutyl chloroformate, NMM, THF, −20°C, 85%; (ii) MeNH2, AcOH, xylenes, reflux,
70%; (iii) 2 M NaOH, MeOH/dioxane, rt, 95%; (iv) HCl/AcOEt, rt, quant.; (v) DPPA, iPr2NEt, CH3CN, rt, 25–35% for 7a–c,
5–10% for 8a,b.
keto ester 213 at −20°C. The resulting amidoketones 3a–c
were condensed to the imidazoles 4a–c with methylamine
in the presence of acetic acid in refluxing xylenes with
azeotropic removal of water.14 Saponification of the
methyl esters 4a–c with NaOH provided the correspond-
ing carbocyclic acids 5a–c, which were subsequently
subjected to amine deprotection using HCl in ethyl
acetate, leading to the amino acids 6a–c. Several methods
for a one-pot macrocyclization of the imidazoles 6a–c
were examined. The most advantageous route proved to
be reacting the monomers with diphenyl phosphorazidate
(DPPA) in the presence of an excess of Hu¨nig’s base in
acetonitrile under high dilution conditions (0.05 M) at
room temperature.15 This method provided the trimers
7a–c in rather good yields (25–35%).16 The tetrameric
compounds 8a and 8b were obtained in lower yields
(5–10%)17 whereas the yield for the tetramer 8c was so
poor that it could not be isolated but only observed by
FAB mass spectrometry.
Due to the low yields of the tetramers and to the
difficulties occurring during the separation of the tet-
ramers from the trimers, we also elaborated an alter-
native synthetic route which could provide the
tetramers in significantly increased yields and in
higher purity. An appropriate way for the improved
preparation of the tetramer 8a is presented in Scheme
2. Acid cleavage of the Boc group of 4a with HCl in
ethyl acetate provided the ammonium salt 9 which
was coupled to the free acid building block 5a via
DPPA activation to give the protected linear dimer
10 in a 70% yield. Deprotection of the carboxyl
group by saponification and removal of the Boc
group with HCl in ethyl acetate afforded the com-
pletely deprotected linear dimer 12. The macrodimer-
ization was carried out by pentafluorophenyl
diphenylphosphinate (FDPP) activation and addition
of Hu¨nig’s base in acetonitrile, and yielded the tetra-
mer 8a in 40%.
Scheme 2. Reagents and conditions: (i) HCl/AcOEt, rt, quant.; (ii) 2 M NaOH, MeOH/dioxane, rt, 95%; (iii) DPPA, iPr2NEt,
CH3CN, rt, 70%; (iv) 2 M NaOH, MeOH/dioxane, rt, 95%; (v) HCl/AcOEt, rt, quant.; (vi) FDPP, iPr2NEt, CH3CN, rt, 40%.

G. Haberhauer, F. Rominger / Tetrahedron Letters 43 (2002) 6335–6338
6337
4. Michael, J. P.; Pattenden, G. Angew. Chem., Int. Ed. Engl.
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Figure 2. X-Ray structure of 7a: top view (left) and side view
(right).
X-Ray quality crystals of 7a were obtained by crystal-
lization in acetone-d6.18 The X-ray structure indicates
that 7a is a rigid molecule in which all lone pairs of the
imidazole nitrogens and the hydrogens of the secondary
amides point towards the center of the macrocycle (Fig.
2). The valine side chains all lie on the same face of the
molecule and adopt axial positions. The imidazole moi-
eties do not form a single plane but a cone-like
structure.
6. (a) Bertram, A.; Pattenden, G. Synlett 2001, 1873; (b)
Blake, A. J.; Hannam, J. S.; Jolliffe, K. A.; Pattenden, G.
Synlett 2000, 1515.
7. (a) Somogyi, L.; Haberhauer, G.; Rebek, J., Jr. Tetra-
hedron 2001, 57, 1699; (b) Haberhauer, G.; Somogyi, L.;
Rebek, J., Jr. Tetrahedron Lett. 2000, 41, 5013; (c) Boss,
C.; Rasmussen, P. H.; Wartini, A. R.; Waldvogel, S. R.
Tetrahedron Lett. 2000, 41, 6327; (d) Mink, D.; Mecozzi,
S.; Rebek, J., Jr. Tetrahedron Lett. 1998, 39, 5709.
8. (a) Pattenden, G.; Thompson, T. Tetrahedron Lett. 2002,
43, 2459; (b) Singh, Y.; Sokolenko, N.; Kelso, M. J.;
Gahan, L. R.; Abbenante, G.; Fairlie, D. P. J. Am. Chem.
Soc. 2001, 123, 333; (c) Pattenden, G.; Thompson, T.
Chem. Commun. 2001, 717.
9. (a) Ikegami, F.; Murakoshi, I. Phytochemistry 1994, 35,
1089; (b) Wang, M.; Gould, S. J. J. Org. Chem. 1993, 58,
5176.
10. For examples, see: (a) Navarro, J. A. R.; Lippert, B. Coord.
Chem. Rev. 2001, 222, 219; (b) Se´ne`que, O.; Giorgi, M.;
Reinaud, O. Chem. Commun. 2001, 984; (c) Kondo, S.;
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Chem. Soc., Perkin Trans. 2 2001, 128; (d) Buncel, E.;
Clement, O.; Onyido, I. Acc. Chem. Res. 2000, 33, 672; (e)
Investigations concerning metal complexation proper-
ties of this new class of imidazole-based cyclic peptides
and their application in asymmetric synthesis are ongo-
ing in our lab.
Acknowledgements
Financial support from the Deutsche Forschungsge-
meinschaft is gratefully acknowledged. The authors
would also like to express their special thanks to Pro-
fessor Rolf Gleiter (University of Heidelberg) and Dr.
Rolf Roers (Bayer AG) for advice and encouragement.
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15. General procedure for the oligomerization: To a suspen-
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6338
G. Haberhauer, F. Rominger / Tetrahedron Letters 43 (2002) 6335–6338
brine, then dried over MgSO4 and concentrated in vacuo.
empirical absorption and crystal oversize correction was
applied using SADABS19 based on the Laue symmetry of
the reciprocal space, v=0.081 mm−1, Tmin/Tmax ratio=
0.64, structure solved by direct methods and refined against
F2 with a full-matrix least-squares algorithm using the
SHELXTL-PLUS (5.10) software package,20 methylgroup
C52 is disordered over two positions with similar occu-
pancy, leading to two different orientations of the corre-
sponding isopropylgroup, 1 mol of acetone and 1.5 mol of
water were found, 449 parameters refined, hydrogen atoms
were treated using appropriate riding models, final residual
Purification was accomplished by chromatography on
silica gel.
1
16. Spectroscopic data for 7a: H NMR (300 MHz, acetone-
d6): 8.36 (d, 3H, J=8.9 Hz), 5.14 (dd, 3H, J=9.2, 5.5 Hz),
3.62 (s, 9H), 2.52 (s, 9H), 2.09 (m, 3H), 1.01 (d, 9H, J=6.6
Hz), 0.95 (d, 9H, J=6.6 Hz). 13C NMR (75 MHz,
acetone-d6): 163.42, 147.51, 132.88, 130.14, 49.92, 35.24,
30.45, 19.67, 17.85, 9.43. HRMS (FAB+) [M+H]+ calcu-
lated: 580.3724; observed: 580.3707.
1
17. Spectroscopic data for 8a: H NMR (300 MHz, acetone-
d6): 7.53 (d, 4H, J=9.2 Hz), 4.90 (m, 4H), 3.67 (s, 12H),
2.47 (s, 12H), 2.41 (m, 4H), 1.10 (d, 12H, J=6.6 Hz), 0.87
(d, 12H, J=6.6 Hz). 13C NMR (75 MHz, acetone-d6):
164.83, 149.35, 133.81, 131.06, 51.39, 34.18, 31.43, 20.98,
20.47, 10.69. HRMS (FAB+) [M+H]+ calculated: 773.4939;
observed: 773.4896.
values R(F)=0.060, wR(F2)=0.162 for observed reflec-
−3
,
tions, residual electron density −0.16 to 0.19 e A
.
Crystallographic data (excluding structure factors) for the
structure in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publication numbers CCDC 187958. Copies of the
data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
+44 (0) 1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].
19. Sheldrick, G. M., unpublished work, 1996, based on the
method described in: Blessing, R. H. Acta Crystallogr.,
Sect. A 1995, 51, 33.
18. Crystal data for 7a: C33H54N9O5.50, M=664.85, crystal
dimensions 5.00×0.34×0.22 mm3, crystal system mono-
clinic, space group C2, Z=4, a=22.7890(5), b=
,
13.5759(3),
c=12.2504(3)
A,
i=92.005(1)°,
3
V=3787.72(15) A , z=1.166 g cm−3, 2qmax=48.2°, radia-
,
,
tion Mo Ka, u=0.71073 A, 0.3° ꢀ-scans with CCD area
detector, T=298 K, 14917 reflections measured, 5973
unique (Rint=0.0305), 5109 observed (I>2|(I)), intensities
were corrected for Lorentz and polarization effects, an
20. Sheldrick, G. M. Bruker Analytical X-ray Division,
Madison, WI, 1995.