Synthesis of α-helix mimetics with four side-chains

Article abstract of DOI:10.1016/j.bmcl.2008.06.074

The synthesis of a heterocyclic piperazine-based scaffold that mimics the i, i + 4, i + 8, i + 11 side-chain projections of an α-helix is described. The synthesis is designed to be modular to allow the targeting of a range of protein-protein interactions involving α-helices.

Full text of DOI:10.1016/j.bmcl.2008.06.074

Bioorganic & Medicinal Chemistry Letters 18 (2008) 5909–5911
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Bioorganic & Medicinal Chemistry Letters
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Synthesis of
a-helix mimetics with four side-chains
*
Per Restorp, Julius Rebek Jr.
The Skaggs Institute for Chemical Biology and Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Rd, MB-26, La Jolla, CA 92037, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of a heterocyclic piperazine-based scaffold that mimics the i, i + 4, i + 8, i + 11 side-chain
Received 13 June 2008
Accepted 23 June 2008
Available online 28 June 2008
projections of an
of a range of protein–protein interactions involving
a
-helix is described. The synthesis is designed to be modular to allow the targeting
-helices.
a
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Alfa-helix mimetics
Protein–protein interaction
Heterocycles
Piperazines
N-Arylation
The
a
-helix motif is one of the most abundant secondary pro-
These scaffolds all present three hydrophobic side-chains effec-
tively mimicking the side-chain projections of two turns of an
helix (Fig. 2). Recently, Hamilton and coworkers have described
synthetic foldamers that mimic longer sections of the
-helix.8
Here, we describe the synthesis of an extended class of -helix
mimetics 7. They present four hydrophobic residues and reproduce
the i, i + 4, i + 8, i + 11 side-chains, that is, three turns of an -helix.
The general synthetic approach is outlined in Scheme 1. The
synthesis is modular and allows the incorporation of structurally
different hydrophobic side-chains in the scaffold. The synthesis
of 7 commenced with Cu(I)-catalyzed N-arylation of 1 with
tein structures and is often involved in protein–protein recogni-
tion. The projecting amino-acid residues in i, i + 4, i + 7/i + 8,
i + 11 positions appear at the same side of the
a surface interface for intermolecular interactions with other pro-
teins.1 (Fig. 1) Since protein–protein interactions are involved in
several cell-regulatory processes, significant efforts have been di-
rected towards the synthesis of smaller molecules that can effi-
ciently disrupt these interactions.1,2
a-
a
-helix and define
a
a
a
Hamilton and coworkers pioneered the area of non-peptide-
based
a-helix mimetics and developed small-molecule libraries
based on terphenyl A, terephtalimide, and oligopyridine scaffolds
L
-valine or
L-phenylalanine which proceeded in high yields to give
that display side-chain functionalities with similar spatial and
2.9 Treatment of 2 with 4-(benzyloxy)-2-methylaniline under
angular orientation to those found in an
a
-helix (Fig. 2).3 These
scaffolds were shown to efficiently disrupt protein–protein inter-
4
actions in biologically relevant systems such as Bak/Bcl-XL and
p53-HDM2.5 Recently, König and coworkers described the synthe-
sis of functionalized 1,4-dipiperazino benzenes B and demon-
strated that these compounds adopt a staggered conformation
with the projecting side-chains closely resembling an
a
-helix.6
Our efforts toward the synthesis of structurally similar inhibitors
for protein–protein interactions have revolved around heterocyclic
compounds C containing a central pyridazine ring functionalized
with hydrophobic amino-acid side-chains which were intended
to reproduce the projecting i, i + 4, i + 7 residues of an
These compounds were intended to mimic the amphiphilic nature
of -helices by displaying a hydrophilic surface rich in hydrogen-
a
-helix.7
a
bonding towards the solution and a hydrophobic surface interact-
ing with the protein target.
* Corresponding author. Tel.: +1 858 784 2250; fax: +1 858 784 2876.
E-mail address: jrebek@scripps.edu (J. Rebek).
Figure 1. Orientation of the i, i + 4, i + 8, i + 11 residues in an idealized a-helix.
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.06.074

5910
P. Restorp, J. Rebek / Bioorg. Med. Chem. Lett. 18 (2008) 5909–5911
Figure 2. Examples of
a-helix mimetics: Hamilton’s terphenyl scaffold A, König’s
1,4-dipiperazino benzenes B, and the oxazole-pyridazine-based scaffold C.
standard amide-bond forming conditions afforded amide 3, which
was subsequently transformed into keto-piperazine 4.10 Saponifi-
cation of 4 using LiOH followed by a Curtius rearrangement deliv-
ered aniline 5, possessing a handle for further functionalization.
Figure 3. Minimized representations of
a-helix mimetic 7a and an idealized
alanine -helix (Hyper Chem 7.0 semi-empirical, AM1).
a
11
enolysis of the phenolic protecting group yielded the mimetics 7 in
excellent yields.
Reduction of 5 with LiAlH4 resulted in partial deprotection of
the benzyloxy ether. This problem could be circumvented by using
BH3 DMS as reductant, which delivered amine 6 in high yield.
Reaction of 6 with iPrNCO or BnNCO followed by catalytic hydrog-
Figure 3 shows a minimized representation of 7a along with an
idealized
a-helix consisting of alanine a-amino acids. The dis-
Scheme 1. Reagents and conditions: (a) R-CH(NH2)CO2H, CuI, K2CO3, DMF, 100 °C , 70% (R = iPr), 75% (R = Bn), (b) 4-(benzyloxy)-2-methylaniline, EDCI, HOBt, CH2Cl2, rt, 75%
(R = iPr), 82% (R = Bn), (c) bromo-acetylbromide, NaHCO3(aq), EtOAc, rt, (d) CsCO3, DMF, 0 °C, 72% (2 steps, R = iPr), 61% (2 steps, R = Bn), (e) LiOH, THF:H2O, rt, 88% (R = iPr),
92% (R = Bn), (f) DPPA, NEt3, DMF, rt ? 100 °C 74% (R = iPr), 68% (R = Bn), (g) BH3 DMS, THF, reflux, 91% (R = iPr), 82% (R = Bn), (h) R0-NCO, CH2Cl2, rt, (i) Pd-black, H2 (1 atm),
THF:MeOH, 95% (R = iPr, R0 = iPr), 89% (R = iPr, R0 = 97), X% (R = Bn, R0 = iPr), 91% (R = Bn, R0 = Bn).

P. Restorp, J. Rebek / Bioorg. Med. Chem. Lett. 18 (2008) 5909–5911
5911
tances between the substituents in the key positions of 7a [i to i + 4
= 5.3 Å, i + 4 to i + 8 = 6.2 Å, i to i + 8 = 9.8 Å, i + 4 to i + 11 = 9.0 Å,
and i + 8 to i + 11 = 5.1 Å] compares favorably to those of an ideal-
Dr. Dariush Ajami for his assistance with the computations and
modeling.
ized alanine
a-helix: [i to i + 4 = 6.3 Å, i + 4 to i + 8 = 6.2 Å, i to
References
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in few synthetic steps, which mimics the i, i + 4, i + 8, i + 11 resi-
dues of an -helix. The synthetic methodology reported in this let-
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We are grateful to the Skaggs Institute for support. P.R. is a
Swedish Knut and Alice Wallenberg post-doctoral fellow. We thank
Dr. Craig Turner and Dr. Lionel Moisan for helpful discussions and