New macrocyclic peptidomimetics containing 5-aminothiophene subunits

Article abstract of DOI:10.1002/ejoc.201001066

The synthesis of a new class of cyclic peptidomimetics containing 5-aminothiophene subunits in their backbone is presented. A modified Gewald reaction was applied as a key step in the synthesis of the thiophene amino acid that was used as a building block

Full text of DOI:10.1002/ejoc.201001066

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201001066
New Macrocyclic Peptidomimetics Containing 5-Aminothiophene Subunits
Hülya Özbek,[a] Dieter Lentz,[a][‡] and Hans-Ulrich Reissig*[a]
Keywords: Amino acids / Peptidomimetics / Sulfur heterocycles / Macrocycles / Hydrogen bonds
The synthesis of a new class of cyclic peptidomimetics con-
taining 5-aminothiophene subunits in their backbone is pre-
sented. A modified Gewald reaction was applied as a key
step in the synthesis of the thiophene amino acid that was
used as a building block in the synthesis of linear oligomers
by using standard peptide coupling protocols. Macrocycliza-
tion was achieved under high dilution by using EDCI as a
coupling reagent. The conformations of an acyclic dimer and
a cyclic tetramer were determined by X-ray crystallographic
analyses.
Introduction
Many cyclopeptides incorporating five-membered hetero-
cycles have been isolated from marine and other sources.[1]
As a prominent example, the Lissoclinum class of cyclic
peptides is characterized by the presence of unusual oxazole
and thiazole amino acids or their reduced analogues in the
macrocyclic skeleton. The structural variety of these back-
bone-modified cyclopeptides and their biological activities
resulted in a considerable number of structural and syn-
thetic studies.[2] These examples can be regarded as natural
peptidomimetics[3] where unusual amino acids or their ana-
logues together with the induced conformational restric-
tions confer new properties. This concept has also been ap-
plied to unnatural cyclic mimetics in the hope to generate
molecules with new and superior (biological) activity.[4]
Our group reported simple access to new 5-aminothio-
phene carboxylic acids 3, which are regarded as dipeptide
isosteres (Scheme 1).[5] A three-component Gewald reaction
by employing methyl 2-siloxycyclopropanecarboxylates 1[6]
smoothly afforded unusual δ-amino acids[7] 3. Cyclopro-
panes 1 serve here as equivalents of carbonyl compounds 4.
Smooth in situ ring opening of 1 in methanol or in the
presence of fluoride reagents generates carbonyl com-
pounds 4 that undergo multistep condensation with 2 and
sulfur.
Scheme 1. Synthesis of 5-aminothiophene carboxylic acids 3 by a
modified Gewald reaction by employing siloxycyclopropane 1.
using aminothiophene carboxylic acids as only components.
The functionalized thiophene moiety should allow a variety
of modifications that are of interest for the function of the
resulting macrocyclic peptidomimetics. Herein, we report
the synthesis of 36-membered and 24-membered cyclic pep-
tidomimetics 13 and 14 by using 5-aminothiophene carbox-
ylic acid 3a as a key building block. To the best of our
knowledge, no cyclopeptides containing dipeptidyl thio-
phenes in the backbone have been synthesized so far.
At the beginning of this study we assumed that new
macrocycles incorporating aminothiophene carboxylic ac-
ids such as 3 should have interesting chemical, structural,
and biological properties. These cyclic peptidomimetics can
be constructed from 3 together with proteinogenic amino
acids, but alternative compounds should be available by
Results and Discussion
The synthesis of aminothiophene 3a was achieved ac-
cording to a literature procedure in 66% yield.[5] Com-
pound 3a was used both directly as the amino component
and, following protective group modification to give 5, as
the carboxylic acid in the peptide coupling to furnish dimer
6 (Scheme 2). Protection of 3a with Cbz and saponification
of the resulting carbamate with lithium hydroxide gave car-
boxylic acid 5 in very good yield. We examined different
protecting groups at the N-terminus of 3a, but only Cbz[8]
proved to be compatible with the conditions of the follow-
View this journal online at
[a] Institut für Chemie und Biochemie, Freie Universität Berlin,
Takustr. 3, 14195 Berlin, Germany
Fax: +49-30-838-55367
E-mail: hans.Reissig@chemie.fu-berlin.de
[‡] Responsible for X-ray crystal structure determination.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001066.
wileyonlinelibrary.com
Eur. J. Org. Chem. 2010, 6319–6322
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6319

H. Özbek, D. Lentz, H.-U. Reissig
SHORT COMMUNICATION
ing steps.[9] The conditions for the amide formation were
carefully optimized. We found that activation of carboxylic
acid 5 with 1-ethyl-3-[3-(dimethylamino)propyl]carbodi-
imide (EDCI)[10] in CH2Cl2 was superior, affording desired
dimer 6 in 81% yield.
Scheme 3. Synthesis of C-protected dimer 7 and N-Cbz-protected
dimer 8.
Carboxylic acid 8 was successfully coupled to monomer
amine 3a by using carbodiimide methodology to furnish
trimer 9 in 69% yield (Scheme 4). Removal of the N-Cbz
group of 9 was followed by treatment with LiOH in a mix-
ture of tetrahydrofuran/water to give the fully deprotected
trimer 10, which was used without further purification in
the subsequent attempted macrocyclization.
Scheme 2. Synthesis of Cbz-protected thiophene carboxylic acid 5
and peptide coupling with 5-aminothiophene 3a.
The solid-state structure of 6 was investigated by X-ray
crystallography (Figure 1), which revealed that the confor-
mation is dominated by two intramolecular hydrogen bonds
of the amide protons to the oxygen atoms of the tert-but-
oxycarbonyl group.[11] The two thiophene rings together
with the amide bonds are planar and oriented perpendicu-
larly to the plane defined by carbon atoms C6–C5–C4 with
the two thiophene sulfur atoms pointing in the same direc-
tion.
Scheme 4. Synthesis of C- and N-deprotected trimer 10.
The EDCI-mediated coupling of carboxylic acid 8 with
amine 7 furnished tetramer 11 in good yield (Scheme 5).
Cleavage of the terminal N-Cbz group and subsequent sa-
ponification utilizing the conditions described for the con-
version of 9 into 10 also provided cyclization precursor 12
in good overall yield.
We examined several condensation reagents for the
macrocyclization of acyclic precursor compounds 10 and
12. EDCI proved to be the most advantageous peptide cou-
pling reagent in these examples. These macrocyclization ex-
Figure 1. Molecular structure (ORTEP[12]) of dimer 6.
After cleavage of the terminal N-Cbz group of dimer 6 periments were performed under high-dilution conditions
under catalytic transfer hydrogenolysis[13] with palladium (0.004 ) at room temperature for 3 d (Scheme 6). Acyclic
black (Pd/b),[14] amine 7 was isolated in excellent yield, and tetramer precursor 12 was successfully converted into the
the hydrolysis of methyl ester 6 with lithium hydroxide pro- desired 24-membered cyclic peptide 14 in 18% yield. In
vided carboxylic acid 8 in 91% yield (Scheme 3).
contrast, no cyclization of trimer 10 to the corresponding
6320
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6319–6322

New Macrocyclic Peptidomimetics Containing 5-Aminothiophene Subunits
macrocycles 13 and 14 was confirmed by mass spectrome-
try.
X-ray quality crystals of 14 were obtained by slow dif-
fusion of hexane into a dichloromethane solution of the
cyclic peptide, which allowed detailed analysis of the solid-
state structure (Figure 2). Remarkably, the macrocycle in-
cludes one molecule of hexane. Apparently, the cavity of
the cyclotetramer has a diameter of ca. 8 Å and hence is
sufficiently wide to extract a hexane molecule from the sol-
vent mixture. Half of molecule 14 (strongly resembling di-
mer 6, see Figure 1) and half of a hexane molecule form the
asymmetric unit. The molecule is completed by a crystallo-
graphic inversion center resulting in an up/up/down/down
arrangement of the four sulfur atoms. The structure shows
that 14 is a fairly rigid molecule with a diamond core close
to a square (angles of 84.9 and 95.1°), in which the sp3-
hybridized carbon atoms C5–C11–C5i–C11i form the cor-
ners. The thiophene rings are oriented almost perpendicular
to the plane defined by these four carbon atoms. Intramo-
lecular hydrogen bonds exist again between the amide pro-
tons and the oxygen atoms of the tert-butoxycarbonyl
groups. This is consistent with the values determined by 1H
NMR spectroscopy, where the signals of the amide protons
are shifted downfield.
Scheme 5. Synthesis of acyclic tetrameric precursor 12.
18-membered cyclic peptide was observed. Surprisingly, 1%
of the unexpected 36-membered cyclohexapeptide 13 was
isolated. Despite the high-dilution conditions, dimerization
followed by cyclization was the pathway leading to the only
low molecular mass product. The missing material appar-
ently was consumed by the formation of higher (acyclic)
oligomers.[15]
Figure 2. Molecular structure (ORTEP[12]) of macrocyclic peptido-
mimetic 14 including one molecule of hexane.
Conclusions
In conclusion, we have demonstrated the synthesis of
new 36-membered and 24-membered macrocyclic peptido-
mimetics 13 and 14 based on new thiophene amino acid 5.
Scheme 6. Synthesis of 36-membered and 24-membered cyclic pep-
tidomimetics 13 and 14.
1H and 13C NMR spectra of cyclic peptides 13 and 14 in These compounds are the first macrocycles incorporating
CDCl3 are very similar at room temperature. The spectra aminothiophene subunits. Studies of the properties of these
indicate the presence of symmetric compounds, showing peptidomimetics and preparation of chiral macrocycles also
just four signals for the four different types of protons at- incorporating proteinogenic amino acids are currently been
tached to each subunit. The definite number of subunits in performed.
Eur. J. Org. Chem. 2010, 6319–6322
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6321

H. Özbek, D. Lentz, H.-U. Reissig
SHORT COMMUNICATION
(Eds.), Synthesis of Peptides and Peptidomimetics, Thieme,
Stuttgart, 2004; d) A. Grauer, B. König, Eur. J. Org. Chem.
2009, 5099–5111.
CCDC-780179 (for 6) and -780180 (for 14) contain the supplemen-
tary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[4] a) A. Bertram, J. S. Hannam, K. A. Jolliffe, F. G.-L. de Turiso,
G. Pattenden, Synlett 1999, 1723–1726; b) P. Wipf, C. P. Miller,
C. M. Grant, Tetrahedron 2000, 56, 9143–9150; c) A. J. Blake,
J. S. Hannam, K. A. Jolliffe, G. Pattenden, Synlett 2000, 1515–
1518; d) L. Somogyi, G. Haberhauer, J. Rebek Jr., Tetrahedron
2001, 57, 1699–1708; e) G. Haberhauer, F. Rominger, Eur. J.
Org. Chem. 2003, 3209–3218; f) E. Ziegler, G. Haberhauer, Eur.
J. Org. Chem. 2009, 3432–3438; g) Á. E. Pintér, G. Haberhauer,
Synlett 2009, 3082–3098.
Supporting Information (see footnote on the first page of this arti-
cle): Detailed description of all experimental procedures and ana-
lytical data for all compounds.
Acknowledgments
[5] H. Özbek, I. S. Veljkovic, H.-U. Reissig, Synlett 2008, 3145–
Generous support by the Graduiertenkolleg 788 (PhD fellowship
to H.Ö.), the Fonds der Chemischen Industrie, and the Bayer
Schering Pharma AG is most gratefully acknowledged. We also
thank Dr. I. S. Veljkovic and M.Sc. H. Al-Ajmi for preliminary
studies in this field and Dr. R. Zimmer for help during preparation
of this manuscript.
3148.
[6] a) E. Kunkel, I. Reichelt, H.-U. Reissig, Liebigs Ann. Chem.
1984, 512–530; for recent reviews of donor–acceptor-substi-
tuted cyclopropanes, see: b) H.-U. Reissig, Top. Curr. Chem.
1988, 144, 73–135; c) H.-U. Reissig, R. Zimmer, Chem. Rev.
2003, 103, 1151–1196; d) M. Yu, B. L. Pagenkopf, Tetrahedron
2005, 61, 321–347; F. De Simone, J. Waser, Synthesis 2009,
3353–3374.
[1] a) Y. Hamamoto, M. Endo, M. Nakagawa, T. Nakanishi, K.
Mizukawa, J. Chem. Soc., Chem. Commun. 1983, 323–324; b)
Y. Hamada, S. Kato, T. Shioiri, Tetrahedron Lett. 1985, 26,
3223–3226; c) B. M. Degnan, C. J. Hawkins, M. F. Lavin, E. J.
McCaffrey, D. L. Parry, A. L. van den Brenk, D. J. Watters, J.
Med. Chem. 1989, 32, 1349–1354; d) M. P. Foster, G. P. Con-
cepción, G. B. Caraan, C. M. Ireland, J. Org. Chem. 1992, 57,
6671–6675; e) T. W. Hambley, C. J. Hawkins, M. F. Lavin, A.
van den Brenk, D. J. Watters, Tetrahedron 1992, 48, 341–348; f)
A. K. Todorova, F. Jüttner, J. Org. Chem. 1995, 60, 7891–7895;
g) J. Ogino, R. E. Moore, G. M. L. Patterson, C. D. Smith, J.
Nat. Prod. 1996, 59, 581–586; h) H. Sone, H. Kigoshi, K. Yam-
ada, Tetrahedron 1997, 53, 8149–8154; i) T. Shioiri, Tetrahedron
2007, 63, 8571–8575.
[2] For a recent review on ascidians, for example, Lissoclinum pa-
tella, as producer of amino acid derived metabolites, see: B. S.
Davidson, Chem. Rev. 1993, 93, 1771–1791. For a recent review
on synthetic studies of biologically active marine cyclopeptides,
such as Lissoclinum peptides, see: P. Wipf, Chem. Rev. 1995, 95,
2115–2134. For selected recent examples, see: a) S. V. Downing,
E. Aguilar, A. I. Meyers, J. Org. Chem. 1999, 64, 826–831; b)
S.-L. You, J. W. Kelly, J. Org. Chem. 2003, 68, 9506–9509; c) T.
Matsumoto, E. Morishita, T. Shioiri, Tetrahedron 2007, 63,
8571–8575.
[7] a) C. Bonauer, M. Zabel, B. König, Org. Lett. 2004, 6, 1349–
1352; b) J. Gervay, P. S. Ramamoorthy, N. N. Mamuya, Tetra-
hedron 1997, 53, 11039–11048; c) J. Gervay, T. M. Flaherty, C.
Nguyen, Tetrahedron Lett. 1997, 38, 1493–1496; d) C. Baldauf,
R. Günther, H.-J. Hofmann, J. Org. Chem. 2004, 69, 6214–
6220; e) H. W. Sünnemann, A. Hofmeister, J. Magull, A.
de Meijere, Chem. Eur. J. 2006, 12, 8336–8344.
[8] C. H. Kruse, K. G. Holden, J. Org. Chem. 1985, 50, 2792–2794.
[9]
a) Fmoc: not compatible to basic hydrolysis of the methyl ester;
b) Boc: problems in the deprotection of a tetramer analogue of
11; c) Troc: failed in deprotection of the trimer analogue of 9.
a) J. C. Sheehan, P. A. Cruickshank, G. L. Boshart, J. Org.
Chem. 1961, 26, 2525–2528; b) J. C. Sheehan, J. Preston, P. A.
Cruickshank, J. Am. Chem. Soc. 1965, 87, 2492–2493.
This fact is confirmed by the values determined by H NMR
spectroscopy, where the signals of the amide protons are
strongly shifted to lower field.
[10]
[11]
[12]
1
ORTEP-3v2 for windows: L. J. Farrugia, J. Appl. Crystallogr.
1997, 30, 565.
[13]
[14]
A. E. Jackson, R. A. W. Johnstone, Synthesis 1976, 685–687.
G. M. Anantharamaiah, K. M. Sivanandaiah, J. Chem. Soc.
Perkin Trans. 1 1977, 490–491.
[15]
A similar cyclodimerization was observed for 12 under modi-
fied reaction conditions (TFFH, 2,4,6-collidine). Together with
3% of 14, 3% of the cyclic compound with eight thiophene
subunits was obtained.
[3] For reviews on peptidomimetics, see: a) R. Hirschmann, An-
gew. Chem. 1991, 103, 1305–1330; Angew. Chem. Int. Ed. Engl.
1991, 30, 1278–1301; b) A. Giannis, T. Kolter, Angew. Chem.
1993, 105, 1303–1326; Angew. Chem. Int. Ed. Engl. 1993, 32,
1244–1267; c) M. Goodman, A. Felix, L. Moroder, C. Toniolo
Received: July 27, 2010
Published Online: October 12, 2010
6322
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6319–6322