Synthesis of an oxazole-pyrrole-piperazine scaffold as an α-helix mimetic

Article abstract of DOI:10.1002/ejoc.200701164

The synthesis of nonpeptidic α-helix mimetics based on a tricyclic oxazole-pyrrole-piperazine scaffold is described. The scaffold presents both a hydrophobic surface for recognition and a hydrophilic edge that enhances solubility. The synthesis is highly modular and allows the targeting of a range of protein-protein interactions involving α-helices. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200701164

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200701164
Synthesis of an Oxazole–Pyrrole–Piperazine Scaffold as an α-Helix Mimetic
Lionel Moisan,[a] Severin Odermatt,[a] Naran Gombosuren,[a] Alexandre Carella,[a] and
Julius Rebek Jr.*[a]
Keywords: Helical structures / Mimetics / Inverse electron demand Diels–Alder reactions / Nitrogen heterocycles
The synthesis of nonpeptidic α-helix mimetics based on a tri-
cyclic oxazole–pyrrole–piperazine scaffold is described. The
scaffold presents both a hydrophobic surface for recognition
and a hydrophilic edge that enhances solubility. The synthe-
sis is highly modular and allows the targeting of a range of
protein–protein interactions involving α-helices.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
workers that led to nonpeptidic α-helix mimetics able to
Introduction
efficiently disrupt protein–protein interactions,[3] such as,
[4]
α-Helices are key secondary structures involved in protein– Bak/Bcl-XL or p53/HDM2.[5] These molecules are based
protein recognition, and they contain side chains in posi- on terphenyl and related scaffolds that can mimic the spatial
tions i, i+3/i+4, and i+7 at the interaction interface.[1a] position and angular orientation of amino acid side chains
Since the early 90s, attempts to mimic the spatial disposi- on one “face” of an α-helix. As part of our own efforts in
tion of the side chains of an α-helix have been reported,[2] the synthesis of protein–protein interaction inhibitors,[6] we
but only during the past few years has much effort been developed methodology for the synthesis of amphiphilic α-
devoted to the design and synthesis of such mimetics.[1] The helix mimetics featuring more hydrophilic components.[7]
A
best of them are the developments by Hamilton and co- general depiction of the target molecules described in this
Figure 1. (a) Overlay of 1 with a generic α-helix;[8] (b) general retrosynthetic approach to scaffold 1.
article is shown in Figure 1b along with an overlay of an α-
[a] The Skaggs Institute for Chemical Biology, The Scripps Re-
helix (Figure 1a). These molecules feature a linear arrange-
ment of oxazole, pyrrole, and piperazine units and may be
thought of as synthetic counterparts to amphiphilic α-heli-
ces. The scaffold is intended to present both a hydrophobic
surface for recognition and a hydrophilic edge that is rich
in hydrogen-bond donors and acceptors.
search Institute,
Mail MB-26, 10550 North Torrey Pines Road, La Jolla, CA
92037, USA
Fax: +1-858-784-2876
E-mail: jrebek@scripps.edu
Supporting information for this article is available on the
WWW under http://www.eurjoc.org/ or from the author.
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L. Moisan, S. Odermatt, N. Gombosuren, A. Carella, J. Rebek Jr.
SHORT COMMUNICATION
Table 1. Inverse-electron-demand Diels–Alder reactions of tetraz-
ine 5 with various dienophiles.
Results and Discussion
The general retrosynthetic approach is laid out in Fig-
ure 1b. The major disconnections from final OPP com-
pound 1 are made at the amide bonds to give pyridazine
diester 3, which is the precursor to the pyrrole, amino
alcohol 2, and piperazine unit 4. This synthesis is modular
and involves mostly amide bond-forming reactions after the
initial cycloaddition. Many amino alcohols, as well as a
variety of Boc-protected 2-substituted piperazines bearing
standard hydrophobic side chains, are commercially avail-
able. The central pyridazine ring is readily available from
the inverse-electron-demand Diels–Alder reaction of known
dimethyl-1,2,4,5-tetrazinedicarboxylate (5) and a suitable
dienophile.[9] The oxazole–pyrrole substructure can also be
found in some marine alkaloids such as the Phorbazole
family.[10]
Tetrazine 5 was prepared according to the procedure de-
scribed by Boger et al.[11] Alkynes, enamines, and enol
ethers are well-known dienophiles for the reaction with
tetrazine derivatives.[12] Benzyl or isobutyl groups were in-
troduced by using the corresponding commercially available
alkynes 6a and 6b, which gave pyridazines 3a[7c] and 3b in
good yields (Table 1). A large aromatic side chain such as
naphthalene, often used to mimic the indole-containing side
chain of a tryptophan residue (compound 3c[7d]), was also acid. The hydrolysis of the methyl ester moieties in 9 with
prepared. In this case, we used enol ether 7, which was ob- LiOH (Scheme 1) at room temperature was quite slow, but
tained by methylenation of methyl 1-naphthaleneacetate after several days, pyrrole 10 was isolated in 54% yield. Pyr-
with the Tebbe reagent.[13] Short side chains were also desir- role 10 was then coupled with piperazine 4a (R3 = H) by
able but most of the corresponding alkynes are gases and using PyBroP to give compound 11 in good yield.
are not conveniently handled. For these, we introduced the
Subsequent modifications to the remaining methyl ester
to introduce the oxazole moiety were problematic: saponifi-
isopropyl group to mimic a valine residue (compound 3d[7c]
)
by using the addition of enamine 8 obtained by the conden- cation with LiOH in MeOH was not chemoselective, and
sation of isovaleraldehyde and pyrrolidine.[14]
other conditions such as demethylation with LiI in hot pyr-
With this series of substituted pyridazines in hand, we idine gave low yields and failed to afford compound 12
next examined their reduction to the pyrrole. This synthetic cleanly.
transformation usually gives the expected pyrrole in yields
A strategy that postponed the reduction step to the pyr-
ranging from 27 to 70%.[15,16] Starting from pyridazine 3a, role to a more advanced stage fared little better. The selec-
pyrrole 9 could be obtained in 50% yield by using an excess tive saponification/peptide coupling sequence was used on
amount of zinc in acetic acid. We intended to introduce the pyridazine 3 as described earlier.[7c] The methyl ester in the
piperazine moiety by a standard peptide coupling from the 3-position of pyridazine 3b is more sterically hindered and
Scheme 1. First strategy towards the synthesis of the OPP scaffold.
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Eur. J. Org. Chem. 2008, 1673–1676

An Oxazole–Pyrrole–Piperazine Scaffold as an α-Helix Mimetic
Scheme 2. Synthetic route for the synthesis of the OPP scaffold.
selective saponification of the methyl ester in the 6-position aldehydes, which were then directly exposed to the oxazole-
was possible with one equivalent of LiOH in a THF/water formation conditions [PPh3, 2,6-di-tert-butylpyridine
mixture at 0 °C. This gave clean hydrolysis of the ester to (DTBP), dibromotetrachloroethane, and then DBU][19] to
the corresponding carboxylic acid. The piperazine was then give desired oxazoles 16a–d in good yields over the two
coupled under standard peptide-coupling conditions with steps. The stage was thus set to reduce the pyridazine ring
PyBroP in 52% yield over the two steps to give pyridazine– to the corresponding pyrrole. By using the usual conditions
piperazine 13a (Scheme 2, Method A). In the case of pyrid- with an excess amount of zinc in acetic acid, we obtained
azine 3c, the regioselectivity of the hydrolysis was only 4:1 desired compounds 17a–d in only 12–29% yields; these are
in favor of the desired carboxylic acid; therefore, the coup- lower than what was observed previously.[15,16] Final re-
ling was performed by direct activation of the methyl ester moval of the Boc protecting group of compounds 17a–d
by using MgCl2 in CH3CN[17] (Scheme 2, Method B) to af- was performed with TFA in CH2Cl2 to afford cleanly the
ford adduct 13b in 45% yield as the only regioisomer. The desired α-helix mimetics 1a–d in high yields.
scope of the reaction was then extended to substituted pi-
perazines, as pyridazine 3d was coupled with 4b (R3 = iPr)
following Method A to give the pyridazine–piperazine ad-
duct 13c in 52% yield over the two steps.
Conclusions
Introduction of the oxazole moiety was then performed
by coupling an amino alcohol onto the remaining ester. Hy-
The modular synthesis of α-helix mimetics based on an
drolysis of ester 13a in the presence of LiOH followed by a oxazole–pyrrole–piperazine scaffold was performed. This
peptide coupling with -valinol mediated by PyBroP gave scaffold is intended to present both a hydrophobic surface
amido alcohol 15a in 42% yield. Improved yields for this for recognition and a hydrophilic edge that is rich in hydro-
coupling step were obtained by using the Curtius method gen-bond donors and acceptors. Whereas specific deriva-
(Scheme 2, Method C).[18] Methyl esters 13b,c were first tives are prepared and disclosed here, the methodology re-
converted into hydrazides 14b,c with hydrazine, diazotized ported is applicable for a broader, more general decoration
to give the corresponding acyl azides, and then treated with of the scaffold to provide a diversity of compounds. A small
amino alcohols 2a–c (R1 = iPr, R1 = iBu, or R1 = Ph) to library of compounds that bear common hydrophobic
give desired amido alcohols 15b–d in good yields.
amino acid side chains was synthesized with this strategy,
Oxidation of alcohols 15a–d with Dess–Martin and it is currently being evaluated for their effects on vari-
periodinane proceeded smoothly to give the corresponding ous protein–protein interactions.
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L. Moisan, S. Odermatt, N. Gombosuren, A. Carella, J. Rebek Jr.
SHORT COMMUNICATION
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Supporting Information (see footnote on the first page of this arti-
cle): Characterization of compounds 3b, 13a–c, 14b,c, 15a–d, 16a–
d, 17a–d, and 1a–d.
[7]
Acknowledgments
We are grateful to the Skaggs Institute and Novartis for support.
We acknowledge Dr. Dee Hua Huang and Dr. Laura Pasternack
for NMR spectroscopic assistance. We thank Dr. D. Ajami for ad-
vice about modeling. We thank Prof. D. L. Boger for advice and
helpful discussions.
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Received: December 7, 2007
Published Online: February 18, 2008
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