Synthesis and structure of 1,4-dipiperazino benzenes: Chiral terphenyl-type peptide helix mimetics

Article abstract of DOI:10.1021/ol8002749

(Chemical Equation Presented) The terphenyl structure has been proven to be an ideal scaffold mimicking side-chain functionalities of peptidic α-helices. The synthesis of 1,4-dipiperazino benzenes, using stepwise transition metal-catalyzed N-arylation of chiral piperazines to a central benzene core is reported. The structure determination by X-ray crystallography reveals a geometrical arrangement of the hydrophobic side chains resembling the orientation of key i, i + 3, and i + 7 positions in a peptidic α-helix or in terphenyl helix mimetics.

Full text of DOI:10.1021/ol8002749

ORGANIC
LETTERS
2008
Vol. 10, No. 7
1473-1476
Synthesis and Structure of
1,4-Dipiperazino Benzenes: Chiral
Terphenyl-type Peptide Helix Mimetics
Prantik Maity and Burkhard Ko1nig*
Institut fu¨r Organische Chemie, UniVersita¨t Regensburg,
D-93040 Regensburg, Germany
burkhard.koenig@chemie.uni-regensburg.de
Received February 6, 2008
ABSTRACT
The terphenyl structure has been proven to be an ideal scaffold mimicking side-chain functionalities of peptidic
r-helices. The synthesis of
1,4-dipiperazino benzenes, using stepwise transition metal-catalyzed N-arylation of chiral piperazines to a central benzene core is reported.
The structure determination by X-ray crystallography reveals a geometrical arrangement of the hydrophobic side chains resembling the orientation
of key i, i
+ 3, and i + 7 positions in a peptidic r-helix or in terphenyl helix mimetics.
The R-helix is one of the most common structural motifs in
protein secondary structures1 and is of particular importance
for protein-protein, protein-DNA, and protein-RNA in-
teractions.2 However, studying or intercepting such interac-
tions using peptides is difficult because they are flexible and
proteolytically unstable. Therefore, structural mimetics3 have
been developed that display side-chain functionalities with
similar distance and angular relationships to those found in
R-helices. Important functional groups are typically found
along one ‘face’ of a peptide helix involving side chains from
the i, i + 3 or i + 4, i + 7, and i + 11 amino acids.4 Reported
helix mimetics are based on a variety of molecular struc-
tures: Kahne5 reported a pentasaccharide scaffold as an
R-helix mimic presenting multiple charged groups that
selectively bind the minor grove of DNA and not RNA.
â-Peptides have been used by Gellman6 and Schepartz7 to
mimic an R-helix. Recently, Hamilton and co-workers8 have
(3) (a) Hagihara, M.; Anthony, N. J.; Stout, T. J.; Clardy, J.; Schreiber,
S. L. J. Am. Chem. Soc. 1992, 114, 6568-6570. (b) Gennari, G.; Salom,
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Tetrahedron Lett. 1996, 37, 8589-8592. (d) Cho, C. Y.; Moran, E. J.;
Cherry, S. R.; Stephans, J. C.; Fodor, S. P. A.; Adams, C. L.; Sundaram,
A.; Jacobs, J. W.; Schultz, P. G. Science 1993, 261, 1303-1305. (e) Hamuro,
Y.; Geib, S. J.; Hamilton, A. D. J. Am. Chem. Soc. 1996, 118, 7529-7541.
(f) Nowick, J. S.; Mahrus, S.; Smith, E. M.; Ziller, J. W. J. Am. Chem.
Soc. 1996, 118, 1066-1072. (g) Lokey, R. S.; Iverson, B. L. Nature 1995,
375, 303-305. (h) Murray, T. J.; Zimmerman, S. C. J. Am. Chem. Soc.
1992, 114, 4010-4011. (i) Antuch, W.; Menon, S.; Chen, Q.-Z.; Lu, Y.;
Sakamuri, S.; Beck, B.; Schauer-Vukasinovic, V.; Agarwal, S.; Hess, S.;
Domling, A. Bioorg. Med. Chem. Lett. 2006, 16, 1740-1743. For reviews
on R-helix mimetics, see: (j) Yin, H.; Hamilton, A. D. Angew. Chem., Int.
Ed. 2005, 44, 4130-4163. (k) Maity, P.; Ko¨nig, B. Pept. Sci. 2008, 90,
8-27. (l) Davis, J. M.; Tsou, L. K.; Hamilton, A. D. Chem. Soc. Rev. 2007,
36, 326-334. See also: (m) Cummings, M. D.; Schubert, C.; Parks, D. J.;
Calvo, R. R.; Lafrance, L. V.; Lattanze, J.; Milkiewicz, K. L.; Tianbao, L.
Chem. Biol. Drug Des. 2006, 67, 201-205. (n) Ahn, J.-M.; Han, S.-Y.
Tetrahedron Lett. 2007, 48, 3543-3547. (o) Walensky, L. D.; Kung, A.
L.; Escher, I.; Malia, T. J.; Barbuto, S.; Wright, R. D.; Wagner, G.; Verdine,
G. L.; Korsmeyer, S. J. Science 2004, 305, 1466-1470.
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(2) (a) Cochran, A. G. Chem. Biol. 2000, 7, 85-89. (b) Cochran, A. G.
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10.1021/ol8002749 CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/12/2008

developed mimetics of the hydrophobic face of an R-helix
using the terphenyl scaffold. The tris-ortho-substituted ter-
phenyl can mimic the i, i + 4, and i + 7 residues of the
R-helix by adopting a staggered conformation that closely
reproduces the angular orientation of the peripheral func-
tionalities on the helical surface. Synthetic foldamers mim-
icking extended R-helices are accessible using benzoylurea
oligomers.9 Rebek recently reported the synthesis of small
libraries of low-molecular-weight R-helix mimetics having
a pyridazine ring in the central position.10 Such terphenyl-
type compounds effectively mimic the geometrical arrange-
ment of amino acid side chains along one face of a peptide
helix. However, most of the compounds lack chirality.
We describe here the synthesis of chiral piperazines
bearing hydrophobic side chains and their transition metal-
catalyzed assembly into helix mimetics of the terphenyl type.
The new compounds keep the relative orientation of the key
side chain functionalities as in terphenyl-type helix mimetics.
Figure 1 shows the structure of the most stable conformer11
We follow a previously reported general route13 to syn-
thesize enantiomerically pure monosubstituted piperazines
(Scheme 1) starting from chiral amino acids. The amino
Scheme 1. Synthesis of Protected Chiral Piperazines 4a-c
and 7a-b
esters 1 were treated with ClCH2COCl and NaHCO3 in a
mixture of water and benzene, which gave the products 2a-c
in high purity and good yields. The crude products were
subsequently reacted with benzylamine in methanol yielding
diketopiperazines 3a-c in good yield through a 1,5-cyclo-
condensation reaction.14 The diketopiperazines were reduced
by LiAlH4 to give monosubstituted piperazines 4a-c bearing
a Bn protecting group on nitrogen atom 4. A series of
deprotection and reprotection steps leads to piperazines 7a-b
which are Bn protected at nitrogen atom 1.
Figure 1. Orientation of residues in an idealized R-helix and in
substituted 1,4-dipiperazino benzene
of a methyl-substituted 1,4-dipiperazino benzene and its
relation to the R-helix structure. In addition, they are water
soluble and chiral, which will facilitate the study of stereo-
chemical effects in helix binding.12
(4) (a) Fairlie, D. P.; West, M. L.; Wong, A. K. Curr. Med. Chem. 1998,
5, 29-62. (b) Jain, R.; Ernst, J. T.; Kutzuki, O.; Park, H. S.; Hamilton, A.
D. Mol. DiVersity 2004, 8, 89-100. (c) Zutshi, R.; Brickner, M.;
Chmielewski, J. Curr. Opin. Chem. Biol. 1998, 2, 62-66. (d) Berg, T.
Angew. Chem., Int. Ed. 2003, 42, 2462-2481.
The synthesis of 1, 4-dipiperazino benzene starts from
2-bromo-5-iodotoluene (8) and (S)-1-benzyl-3-alkylpipera-
zine (4a-c). The preferred substitution of the iodo-substitu-
ent is expected in transition metal-catalyzed N-arylation
reactions. Several ligands have been introduced to promote
copper-catalyzed N-arylation of aliphatic secondary amines,
most notably N,N-diethylsalicylamide,15 amino acids,16 and
(5) Xuereb, H.; Maletic, M.; Glidersleeve, J.; Pelczer, I.; Kahne, D. J.
Am. Chem. Soc. 2000, 122, 1883-1884.
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2005, 7, 5405-5408. (g) Kim, I. C.; Hamilton, A. D. Org. Lett. 2006, 8,
1751-1754.
(12) Protein helices derived from natural amino acids are chiral. Many
examples from medicinal chemistry show that the interaction of proteins
with chiral molecules significantly depends on their chirality: Chirality in
Drug Research; Francotte, E., Lindner, W., Eds.; Wiley: New York, 2007;
Vol. 33. Methods and Principles in Medicinal Chemistry; Mannhold,
R., Kubinyi, H., Folkers, G., Eds.; Wiley-VCH: Weinheim, 2006. 1,4-
Dipiperazino benzene helix mimetics with different chirality are therefore
expected to interact differently with helix-binding proteins.
(13) Liu, B.; Xu, G.-Y.; Yang, C.-H.; Wu, X.-H.; Xie, Y.-Y. Syn.
Commun. 2004, 34, 4111-4118.
(14) Daugan, A. C.-M. (ICOS Corp.). Tetracyclic derivs., process of
preparation and use. EP 0740668.
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Cai, Q.; Zhu, W.; Zhang, H.; Zhang, Y.; Ma, D. Synthesis 2005, 496-499.
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Application in drug synthesis: Egger, M.; Li, X.; Mu¨ller, C.; Bernhardt,
G.; Buschauer, A.; Ko¨nig, B. Eur. J. Org. Chem. 2007, 2643-2649.
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8614-8617.
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J. C.; Rebek, J., Jr. Bio. Med. Chem. Lett. 2007, 17, 4641-4645.
(11) Spartan ’06, Wavefunction, Inc. AM1 semi-empirical geometry
optimization.
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Org. Lett., Vol. 10, No. 7, 2008

amino alcohols.17 Wan and co-workers reported copper
powder/rac-BINOL or (copper + CuI)/rac-BINOL as cata-
lytic system, but the N-arylation requires elevated temper-
atures of 90-125 °C.18 Recently, Buchwald and co-workers
developed a highly selective room-temperature copper-
catalyzed N-aryl coupling reaction using CuI and a cyclic
â-diketone as the catalytic system and Cs2CO3 as base.19
Jiang and co-workers reported room-temperature copper-
catalyzed Caryl-N coupling using CuBr/ rac-BINOL as the
catalytic system.20 The number of reported examples of
room-temperature coupling reactions of aryl-iodides and
ortho-substituted cyclic secondary amines is still small.21 We
used the inexpensive and readily available catalytic system
consisting of CuBr, racemic BINOL (1,1′-binapthyl-2,2′-diol)
and Cs2CO3 as base to achieve the formation of Caryl-N
(ortho-substituted piperazine) bonds at room temperature.
The reaction conditions were optimized (Table 1) with (S)-
gave the highest yields and 90% of the racemic BINOL was
recovered. The yields of the N-arylation depend on the
piperazine substituent and decreases with increasing steric
bulk of the alkyl side chain.
The X-ray diffraction analysis of compound 9b (Figure
2) reveals a flattened chair conformation of the piperazine
Figure 2. Structure of compound 9b in the solid state determined
by X-ray diffraction analysis. For clarity all H atoms are omitted.
Table 1. Optimization of Reaction Conditions for the
Copper-Catalyzed Caryl-N Bond Formation of
2-Bromo-5-iodotoluene (8) and (S)-1-Benzyl-3-alkylpiperazine
(4a-c) to Give Compound 9
ring in the solid state. The i-Bu substituent occupies an axial
position.
The second Caryl-N bond formation was accomplished by
a palladium-catalyzed reaction (Table 2). Palladium-catalyzed
amination of aryl halides has been shown to be a general
Table 2. Optimization of the Reaction Conditions for the
Palladium-Catalyzed Caryl-N Bond Formation of Compounds
9a-c and (S)-1-Benzyl-2-alkylpiperazine (7a,b) Giving
Compounds 10
ligand
base
solvent
R
yield (%)
A
A
A
B
K3PO4
K3PO4
DMF
DMSO
DMF
DMSO
DMF
DMF
DMF
DMF
DMF
CH3
CH3
CH3
CH3
CH3
CH3
CH3
iBu
10
7
16
0
30
40
60
48
54
Cs2CO3
Cs2CO3
K3PO4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
C (20%)
C (20%)
C (30%)
C (30%)
C (30%)
Bn
ligand
R1
R2
yield (%)
1-benzyl-3-methylpiperazine (4a) and 2-bromo-5-iodotoluene
(8). 2-Isobutyrylcyclohexanone, L-proline, and racemic BINOL
as ligands were reacted in DMF or DMSO with 20 mol %
CuBr and Cs2CO3 as the base. Racemic BINOL (30 mol %)
D
E
F
F
F
CH3
CH3
CH3
iBu
iBu
CH3
CH3
CH3
iBu
Bn
0
5
75
70
72
(17) (a) Lu, Z.; Twieg, R. J.; Huang, S. D. Tetrahedron Lett. 2003, 44,
6289-6292. (b) Lu, Z.; Twieg, R. J. Tetrahedron 2005, 61, 903-918.
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A: Chem. 2006, 256, 256-260.
(19) Shafir, A.; Buchwald, S. J. Am. Chem. Soc. 2006, 128, 8742-8743.
(20) Jiang, D.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2007, 72, 672-
674.
method for the formation of aromatic carbon-nitrogen
bonds.22 More recently, Buchwald and co-workers23 reported
substituted and unsubstituted biaryl monophosphine ligands
(D), which are very effective in Caryl-N bond forming
(21) Marinetti, A.; Hubert, P.; Genet, J.-P. Eur. J. Org. Chem. 2000,
1815-1820
Org. Lett., Vol. 10, No. 7, 2008
1475

processes. We have tested the three ligands D, E, and F for
the formation of the second Caryl-N bond in compounds 9.
In all cases, Pd2(dba)3‚CHCl3/L* (D/E/F) was used as the
catalyst, NaOtBu as the base, and toluene as solvent. Racemic
BINAP (F) gave the highest reaction yield (up to 75%) at
125-128 °C for this reaction in our hand (Table 2).
The dibenzyl protected compounds 10a-c were depro-
tected by Pd-C/H2 conditions (Scheme 2) to afford com-
pounds 11a-c which show good water solubility.
Scheme 2. 1,4-Dipiperazino Benzene
Figure 3. (a) Idealized alanine R-helix structure, (b) structure of
compound 11a in the solid state as determined by X-ray analysis,
and (c) superposition of the structure of Hamiltons methyl-
substituted terphenyl with the structure of compound 11a; both
X-ray analyses.
on the concentration of 11b: With increasing concentration,
the signal intensity decreases, which indicates an increasing
aggregation induced by the hydrophobic substituents. Changes
in the proton NMR coupling pattern (see Supporting
Information for data) in aqueous solutions at concentrations
higher than 10 µmol/L support this interpretation.
The distances between the substituents in the key position
[i to i + 3 ) 5.55 Å, i + 3 to i + 7 ) 6.22 Å, i to i + 7)
8.89 Å] were calculated from the X-ray diffraction structure
(Figure 3b). The values are similar to those found in an
idealized alanine R-helix [i to i + 3 ) 5.6 Å, i + 3 to i +
7 ) 6.3 Å, i to i + 7) 10.6 Å]. A comparison of the structure
of compound 11a with the reported structure of Hamilton’s
methyl-substitued terphenyl compound9a shows a striking
similarity of the arrangement of the methyl substituents in
space.
A circular dichroism (CD) spectrum of compound 11b was
measured at 21 °C between 200 and 300 nm in water (see
Supporting Information for experimental details and CD
spectrum). The CD spectrum shows a signal in the range of
245-255 nm arising from the aromatic chromophore in its
chiral environment. The intensity of the CD signal depends
To conclude, 1,4-dipiperazino benzenes have been pre-
pared as a new class of inherently chiral R-helix structural
mimetics. Protected piperazines as the key synthetic inter-
mediates were synthesized from chiral amino acids. Subse-
quent copper- and palladium-catalyzed Carly-N coupling
reactions lead to the target products in good yields. Racemic
BINAP proved to be the best ligand for both reactions. The
compounds aggregate in aqueous solution at concentrations
exceeding 10 µmol/L, as indicated by CD and NMR. The
X-ray structure analysis of 1,4-dipiperazino benzene 11a
reveals a geometrical arrangement of the key substituents,
which is similar to an idealized R-helical structure and
matches the structure of terphenyl R-helix mimetics. Being
structurally similar, but chiral, 1,4-dipiperazino benzenes will
allow the investigation of stereochemical aspects of protein-
helix mimetic recognition. Work in this direction is in
progress.
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Acknowledgment. We thank the Fonds der Chemischen
Industrie, the Deutsche Forschungsgemeinschaft (GRK 760),
and the University of Regensburg for support of this work.
Supporting Information Available: Synthetic procedures
and characterization data of all new compounds; CD and
NMR spectra of compound 11b in aqueous solution at
different concentrations; X-ray analyses data for compounds
9a, 9b, and 11a. This material is available free of charge
via the Internet at http://pubs.acs.org.
(23) (a) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc.
1998, 120, 9722-9723. (b) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin,
J.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1158-1174. (c) Charles, M.
D.; Schultz, P.; Buchwald, S. L. Org. Lett. 2005, 7, 3965-3968. (d)
Anderson, K. W.; Tundel, R. E.; Ikawa, T.; Altman, R. A.; Buchwald, S.
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