New family of peptidomimetics based on the imidazole motif

Article abstract of DOI:10.1021/ol102118u

Starting from amino acid esters, new peptidomimetics based on the imidazole scaffold were prepared. An efficient and rapid sequence consisting of two subsequent one-pot procedures was developed and applied to various aminoacids. As they provide more substitution patterns, these heterocyclic mimics are promising tools for structural and biological studies.

Full text of DOI:10.1021/ol102118u

ORGANIC
LETTERS
2010
Vol. 12, No. 21
4928-4931
New Family of Peptidomimetics Based
on the Imidazole Motif
Sylvain Petit, Corinne Fruit, and Laurent Bischoff*
IRCOF-INSA Rouen - CNRS UMR 6014 COBRA, UniVersite´ de Rouen, place Emile
Blondel 76130 Mont-Saint-Aignan, France
laurent.bischoff@insa-rouen.fr
Received September 6, 2010
ABSTRACT
Starting from amino acid esters, new peptidomimetics based on the imidazole scaffold were prepared. An efficient and rapid sequence consisting
of two subsequent one-pot procedures was developed and applied to various aminoacids. As they provide more substitution patterns, these
heterocyclic mimics are promising tools for structural and biological studies.
Peptide-protein or protein-protein interactions play a vital
role in biochemistry, and their understanding is often the
key to the design of new bioactive compounds. Owing to
great advances in molecular modeling, X-ray structural
analysis, and NMR techniques, the secondary and/or tertiary
structures of peptidic scaffolds increasingly have been
elucidated. However, due to the ubiquitous presence of
peptidases, most bioactive peptides cannot be administered
as drugs, since their rapid degradation or low biodisponibility
prevent them from reaching their targets. Over the years,
many groups have focused on the synthesis of constrained
peptidomimetics for the better understanding of bioactive
conformations or enhanced metabolic stabilities. More
recently, the efforts have focused on the cis and trans
conformations in natural peptides, especially those bearing
proline, pipecolic acid, or N-methylated amino acids. It is
now well established that a wide panel of heterocyclic
synthons, such as bicyclic analogues,1 or the simple replace-
ment of the scissile peptide bond by a five-membered ring
heterocycle could lead to interesting mimics.
In particular, aza heterocycles such as tetrazoles,2 1,2,4-
triazole,s3 and more often 1,2,3-triazoles were synthesized.
Early work in this area had focused on the use of 1,4-
substituted triazoles,4 which were obtained by CuI-mediated
Huisgen reaction,5 but recent developments of this reaction
allowed a reversed regioselectivity owing to the use of
ruthenium catalysts.6 Recently, elegant ligation strategies,
in which a cis-peptide bond analogue is replaced by a 1,5-
disubstituted triazole, were described.7
(2) Yu, K. L.; Johnson, R. L. J. Org. Chem. 1987, 52, 2051.
(3) (a) Hitotsuyanagi, Y.; Motegi, S.; Fukaya, H.; Takeya, K. J. Org.
Chem. 2002, 67, 3266. (b) Boeglin, D.; Cantel, S.; Heitz, A.; Martinez, J.;
Fehrentz, J.-A. Org. Lett. 2003, 5, 4465. (c) Hitotsuyanagi, Y.; Motegi, S.;
Hasuda, T.; Takeya, K. Org. Lett. 2004, 6, 1111.
(4) Angell, Y. L.; Burgess, K. Chem. Soc. ReV. 2007, 36, 1674.
(5) (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2001, 40, 2004.
(6) Majireck, M. M.; Weinreb, S. M. J. Org. Chem. 2006, 71, 8680.
(7) (a) Tam, A.; Arnold, U.; Soellner, M. B.; Raines, R. T. J. Am. Chem.
Soc. 2007, 129, 12670. (b) Ahsanullah; Schmieder, P.; Ku¨hne, R.;
Rademann, J. Angew. Chem., Int. Ed. 2009, 48, 5042. (c) Ahsanullah;
Rademann, J. Angew. Chem., Int. Ed. 2010, 49, 5378.
(1) Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.; Lubell,
W. D. Tetrahedron 1997, 53, 12789.
10.1021/ol102118u  2010 American Chemical Society
Published on Web 10/12/2010

As shown in Scheme 1, we could overcome this difficulty
by using a carboxamide instead of a nitrile as the thioamide
Scheme 1. Aminoacetonitrile/Aminoacetamide Pathways
Figure 1. Examples of aza-heterocyclic mimics of the amide bond.
The global aim of this work was the synthesis of
1,5-disubstituted imidazole-based peptidomimetics. The choice
of this heterocycle was suggested by a close resemblance
with the amide bond, of greater diversity than afforded with
triazoles. In addition, as our synthetic route uses mercap-
toimidazole intermediates, the presence of the sulfur atom
can lead to functionalized side-chains or modulate the
basicity of the imidazole by oxidizing a thioether to a sulfone.
Furthermore, imidazole being a naturally occurring 5-mem-
bers heterocycle, its pharmacological implications may be
better understood than those of other heterocycles.
precursor. The best results for the coupling step were
obtained with propanephosphonic anhydride T3P. Starting
from H-Ala-OMe hydrochloride, the amino group was
alkylated with iodoacetamide in 53% yield, followed by
coupling with Cbz-Ala in 59% yield. Hydrophobic aminoac-
ids such as phenylalanine gave better results, due to their
easier extraction. Subsequent treatment of these compounds
with Lawesson’s reagent cleanly led to selective thionation
of the primary amide10 versus the peptidic bond, for instance
a 92% yield was obtained on the Ala-Ala model substrate.
To make this synthetic route shorter, we tested a one-pot
procedure, in which iodoacetamide and DIEA were added
to the aminoester, followed by N-protected aminoacid and
T3P, and finally Lawesson’s reagent. Better yields were
obtained using this procedure, and only the final thioamides
3a-h listed in Table 1 required purification to discard the
Lawesson’s reagent byproduct.
In a previous work,8 we had studied the replacement of
the carboxyl group of amino acids by an imidazole, as well
as the incorporation of the nitrogen atom of the amino
group itself in the heterocycle. The C-terminus replace-
ment by imidazoles9 or imidazolines10 has also been
studied by other groups who proposed various efficient
synthetic pathways, such as palladium cyclization of
amidoximes,9b thio-Ugi reaction,9c or using azavinyl
azomethine ylides as precursors.9d
Our retrosynthetic approach is summarized in Figure 2,
the key intermediate being the dipeptide bearing a thiocar-
We also observed that the carboxamide 2b could also be
readily dehydrated via treatment with trifluoroacetic anhy-
dride,11 affording the nitrile 1b in 86% yield. Thioamides
in this series can also lead to the corresponding nitriles upon
treatment with DCC.
The formation of the imidazole ring being a crucial step
of the synthesis, we thoroughly optimized it for these
substrates. This reaction was first described by Hopkins12
for the synthesis of mercaptoimidazoles bearing alkyl sub-
stituents. Our preliminary findings had shown that trapping
the transient thiol with CH3I or Boc2O was required to both
increase the yields and facilitate the isolation of the products.
Figure 2. Retrosynthetic pathway.
boxamide, which will be condensed with the peptidic bond
itself. Contrary to our preliminary observations for synthons
incorporating a single amino acid, the very strong deactivat-
ing effect of the N-cyanomethyl group made the initial
coupling step almost impossible for dipeptidic synthons, with
classical coupling reagents such as EDCI, HATU, HBTU,
BOP.
(9) (a) Haberhauer, G.; Rominger, F. Eur. J. Org. Chem. 2003, 3209.
(b) Zaman, S.; Mitsuru, K.; Abell, A. D. Org. Lett. 2005, 7, 609. (c)
Gulevich, A. V.; Balenkova, E. S.; Nenaijdenko, V. G. J. Org. Chem. 2007,
72, 7878. (d) Attanasi, O. A.; Davoli, P.; Favi, G.; Filippone, P.; Forni, A.;
Moscatelli, G.; Prati, F. Org. Lett. 2007, 9, 3461. (e) Attanasi, O. A.; Caselli,
E.; Davoli, P.; Favi, G.; Mantellini, F.; Ori, C.; Prati, F. Org. Lett. 2009,
11, 2840.
(10) (a) You, S.-L.; Kelly, J. W. Org. Lett. 2004, 6, 1681. (b) Loos, P.;
Riedrich, M.; Arndt, H.-D. Chem. Commun. 2009, 1900.
(11) Campagna, F.; Carotti, A.; Casini, G. Tetrahedron: Lett. 1977, 18,
1813.
(8) Cre´pin, A.; Wattier, N.; Petit, S.; Bischoff, L.; Fruit, C.; Marsais, F.
Org. Biomol. Chem. 2009, 7, 128.
(12) Spaltenstein, A.; Holler, T. P.; Hopkins, P. B. J. Org. Chem. 1987,
52, 2977.
Org. Lett., Vol. 12, No. 21, 2010
4929

a nearly quantitative conversion. However, the subsequent
elimination of TMSOH appears to be a very slow step,
especially with aminoacids bearing bulky side-chains. This
process does not necessarily require a base, since it can be
accomplished either by heating in toluene for 1 h, or by
simply keeping the neat compound at room temperature over
a 24 h period of time. In both cases, the disulfide was
recovered. This implies a final air-induced oxidation step
which necessitates a stoichiometric amount of oxygen.
All of these observations led us to propose an experimental
one-pot procedure that consisted of a rapid silylation by
TMSOTf, followed by methanolysis of excess reagent, then
heating in toluene under an air atmosphere, reduction of the
disulfide 6 with DTT, and alkylation with CH3I. Under those
conditions, good yields were obtained, even for more
hindered aminoacids. The results are listed in Table 2.
Table 1. One-Pot Procedure for the Preparation of
Thioamide-Bearing Dipeptides
entry
dipeptide
compd nr
yield %
1
2
3
4
5
6
7
8
Z-Ala-Ala-OMe
3a
3b
3c
3d
3e
3f
46
77
42
36
47
63
41
33
Z-Tyr(OBzl)-Ala-OMe
Z-Asp(OBzl)-Phe-OEt
Z-Ala-Lys(Z)-OBn
Z-Pro-Phe-OMe
Z-Phg-Phe-OMe
Z-Pro-Leu-OMe
3g
3h
Fmoc-Ile-Ala-OMe
Table 2. Formation of the Imidazole Peptidomimetics
However, the presence of the second aminoacid significantly
reduced the reactivity and therefore we had to modify the
procedure. We used compound 3a (Ala-Ala derivative) as a
model for this study. First attempts with N-Boc and t-butyl
ester protecting groups leading to TMSOTf-promoted depro-
tection, N-Cbz and N-Fmoc amino acid methyl esters, were
employed. Mechanistic considerations initially suggested that
a S-TMS intermediate could be first obtained once the
cyclization achieved, requiring a S-desilylation step before
trapping with the electrophile. Thus, following the reaction
with TMSOTf, desilylation could be achieved by treatment
with methanol; however, TBAF gave lower yields.
This reaction was even less efficient with more hindered
dipeptides, leading to a product of very low polarity.
Identification of this compound by means of various NMR
experiments revealed a structure corresponding to the bis-
TMS intermediate 5, (Scheme 2) obtained in 47% yield after
entry
compd nr
dipeptide analogue
yield %
1
2
3
4
5
6
7
8
9
10
4a
4b
4c
4d
4e
4f
4g
4h
4i
Z-Ala-Ala-OMe
62
75
68
61
65
72
47
61
41
28
Z-Ala-Ala-OMea
Z-Ala-Ala-OMeb
Z-Tyr(OBzl)-Ala-OMe
Z-Asp(OBzl)-Phe-OMe
Z-Ala-Lys(Z)-OMe
Z-Pro-Phe-OMe
Z-Phg-Phe-OMe
Z-Pro-Leu-OMe
Fmoc-Ile-Ala-OMe
4j
a Trapping the thiol with Boc2O. b Trapping the thiol with t-butyl
acrylate.
Scheme 2. One-Pot Procedure via a Silylated Intermediate
Several dipeptides were tested for this reaction. Amino acids
bearing unfunctionalized side-chains such as Ala, Phe, and
Ile gave good yields of imidazoles. Other amino acids having
functional groups on the side-chain, such as Asp or Lys, also
gave good yields.
Interestingly, the aspartic derivative, rather prone to
racemization, showed a good retention of the chiral center.
However, the much more sensitive amino acid phenylglycine
led to complete epimerization, and the same mixture of
diastereomers was obtained, whatever the configuration of
the starting phenylglycine. Therefore, our method appears
suitable for classical amino acids but, not surprisingly,
phenylglycine derivatives epimerized under heating in tolu-
ene.
chromatography through silica gel. The latter could be
expected according to the mechanism, that is, selective
O-silylation with TMSOTf then addition of the nitrogen atom
of the thioamide. Monitoring the reaction led us to observe
that this first step occurs in a few minutes at -78 °C, with
As shown in entries 2 and 3, trapping the thiol with
different electrophiles such as t-butyl acrylate or Boc2O gave
the resulting S-Boc and S(CH2)2COOtBu imidazoles in good
yields. This can be of particular interest, since compound
4c could be further deprotected to afford the S-carboxyethyl
4930
Org. Lett., Vol. 12, No. 21, 2010

group that can be used either as an anchoring moiety, or as
a water-soluble substituent.
the desulfurization. We also oxidized the S-Me group to the
corresponding sulfone. Upon N-deprotection and treatment
with hydrogenocarbonate-loaded Amberlite resin, the cy-
clization was almost instantaneous and afforded clean
diketopiperazines.
Another significant feature concerning those peptidomi-
metics relies on their low basicity, compared to N-alkyl
imidazoles. In fact, these new mimics of the amide bond
should not be protonated at neutral pH. To confirm this
hypothesis, we prepared water-soluble diketopiperazines13
derived from Ala-Ala analogue, following the synthesis
described in Scheme 3.
The pKas of the three diketopiperazines bearing the
imidazole ring were measured by titration with NaOH from
their hydrochloride salts. N-methyl imidazole was used as a
reference, a pKa of 6.90 was found (lit. 6.95).14 As expected,
the unsubstituted imidazole 9 was the most basic, exhibiting
a 4.8 value. Interestingly, the electron-withdrawing effect
of the amide group accounts for a loss of basicity by 2 orders
of magnitude. The presence of the S-methyl group in 12
further lowered the pKa to 3.3 and, as expected, the sulfone
11 gave the lowest basicity with a pKa value of 2.5.
In conclusion, we developed an efficient protocol for the
preparation of peptidomimetics mimicking the cis-locked
rotamers of peptides in good and reproducible yields, in very
few steps. Those analogues show promising further develop-
ments due to their possibility of bearing various substituents,
especially the methylsulfonyl group which accounts for a
dramatic decrease of the basicity. Further biological evalu-
ations of these compounds are currently in progress.
Scheme 3
.
Protective Group Modifications and Diketopiperazine
Formation
Acknowledgment. S.P. is grateful to the Re´gion Haute
Normandie, poˆle Chimie-Biologie-Sante´, CRUNCH network,
Interreg ISCE-CHEM funding for generous financial support.
Dr Catherine Taillier (Universite´ du Havre) and Dr. Bernhard
Witulski (LCMT, Caen) are gratefully acknowledged for
useful discussions concerning T3P.
Supporting Information Available: Analytical data,
copies of NMR spectra, and experimental preparations of
all compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
As the N-Cbz group was likely to react with Raney nickel,
we first replaced this protecting group before carrying out
(13) (a) Bajusz, S.; Szell, E.; Bagdy, D.; Barabas, E.; Horvath, G.;
Dioszegi, M.; Fittler, Z.; Szabo, G.; Juhasz, A.; Tomori, E.; Szilagyi, G.
J. Med. Chem. 1990, 33, 1729. (b) Yael Kogon, Y.; Goren, L.; Pappo, D.;
Rudi, A.; Kashman, Y. Eur. J. Org. Chem. 2009, 1852.
OL102118U
(14) Wood, J. L. Biochem. J. 1974, 143, 775.
Org. Lett., Vol. 12, No. 21, 2010
4931