Aromatic garlands, as new foldamers, to mimic protein secondary structure

Article abstract of DOI:10.1016/j.tet.2012.02.035

Proteins modulate the majority of all biological functions and are composed of highly organized secondary structural elements such as helices, turns, and sheets. Many of these functions are affected by a small number of key structural element, protein-protein interactions. Their mimicry by peptide and non-peptide scaffolds has become a major focus of contemporary research. This paper examines oligomeric system as new foldamers, which either reproduce the local topography of the helix, or project appropriately functionality in a similar manner to residues of an alpha-helix.

Full text of DOI:10.1016/j.tet.2012.02.035

Tetrahedron 68 (2012) 4381e4389
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Aromatic garlands, as new foldamers, to mimic protein secondary structure
a
a
a
a,
Anne Sophie Voisin-Chiret , Gregory Burzicki , Serge Perato , Marcella De Giorgi b, Carlo Franchini b,
ꢀ
a
a,
*
ꢀ
Jana Sopkova-de Oliveira Santos , Sylvain Rault
Universite de Caen Basse-Normandie, Centre d’Etudes et de Recherche sur le Medicament de Normandie (UPRES EA 4258-FR CNRS 3038 INC3M), UFR des Sciences Pharmaceutiques,
a
ꢀ
ꢀ
F-14032 Caen Cedex, France
b
ꢀ
ꢀ
ꢀ
Universite de Bari, Departement de Chimie medicinale, I-70125 Bari, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 October 2011
Received in revised form 10 February 2012
Accepted 14 February 2012
Available online 3 March 2012
Proteins modulate the majority of all biological functions and are composed of highly organized sec-
ondary structural elements such as helices, turns, and sheets. Many of these functions are affected by
a small number of key structural element, proteineprotein interactions. Their mimicry by peptide and
non-peptide scaffolds has become a major focus of contemporary research. This paper examines oligo-
meric system as new foldamers, which either reproduce the local topography of the helix, or project
appropriately functionality in a similar manner to residues of an alpha-helix.
Keywords:
Foldamer
Ó 2012 Elsevier Ltd. All rights reserved.
SuzukieMiyaura cross-coupling
Alpha-helix mimetic
Pyridine
Thiophene
1. Introduction
molecules; (3) a type III mimetic, which represents a topographical
mimetic where positions key functional motifs in an identical
Proteineprotein interactions domains play an important role in
many biological pathways and have been the focus of intense in-
vestigation from structural molecular biology to cell biology for the
majority of the last two decades. More recently, they are emerging
as important targets for pharmaceutical intervention.
Alpha-helix represents the most abundant secondary structural
motif in nature, with a significant proportion of all protein struc-
tures comprising this motif. Unsurprisingly, alpha-helices represent
fundamental recognition elements in many proteineprotein
interactions.
Therefore, alpha-helix offers potential as a template for the
elaboration of ‘rule-based’ small molecule inhibitors, in particular
those based on ‘foldamers’: synthetic non-natural oligomers
that adopt well-defined conformations reminiscent of an alpha-
helix.1
spatial orientation to match those presented by the original alpha-
helix.2
Numerous non-peptide small molecules mimicking alpha-
helices have been published in literature (type III) (Fig. 1).
Early contributions from Hamilton and Jacoby showed that
a terphenyl scaffold was capable of projecting functionality in
a similar manner to the i, iþ3 (or iþ4), and iþ7 residues of an alpha-
helix (Fig. 1, terphenyl and terpyridyl compounds a).3 Then, efforts
have been exerted to decrease overall compound hydrophobicity as
well as reduce the synthetic complexity of teraryl-based alpha-
helix mimetics. This has been accomplished either by increasing
the heteroaromatic nature of the core aryl units (Fig. 1, terpyridyl
scaffold b and e to l) or by replacing some of the covalent character
of the scaffold with a hydrogen-bonding aromatic ring isostere
(Fig. 1, enaminone c and benzoylurea d scaffolds).
Mimicking an alpha-helix can be achieved in three ways: (1)
a type I mimetic, which reproduces the local topography of the
helix, where, for example, covalent constraints are used to stabilize
a conformation closed to alpha-helices; (2) a type II mimetic,
which is a functional mimetic that does not need to mimic the
structure of the original helix. It is typically small natural
The structure of a 5e6e5 imidazoleephenyl-thiazole scaffold
(Fig. 1e)4 bearing additional heteroaromatic functionality has
recently been reported. Rebek and co-workers have also pub-
lished a series of pyridazine-based scaffolds (Fig. 1fej) with a va-
riety of aromatic and heteroaromatic peripheral groups.5
, ,
Additionally, two piperazine-based scaffolds (Fig. 1k,6 l 7) have
been reported: both display functional groups in a manner to
mimic three or four alpha-helical side-chain positions. Otherwise,
it has shown that hydrogen-bonding functional groups such as
an enaminone (Fig. 1d)8 or benzoylurea (Fig. 1c)9 can replace
* Corresponding author. Tel.: þ33 (0)2 31 56 68 01; fax: þ33 (0)2 31 56 68 03;
e-mail address: sylvain.rault@unicaen.fr (S. Rault).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.02.035

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A.S. Voisin-Chiret et al. / Tetrahedron 68 (2012) 4381e4389
Fig. 1. Numerous non-peptide small molecules.
a central six-membered ring, reducing hydrophobicity and syn-
thetic complexity of these types of scaffolds. Recently, McLaughlin
and co-workers presented a facile iterative synthesis of 2,5-
terpyrimidinylenes (Fig. 1m)10 that are structurally analogous to
alpha-helix mimics. In 2011, Hamilton and co-workers have con-
structed a new series of i, iþ3 (or iþ4), iþ7 alpha-helix mimics
based on the enaminone scaffold (Fig. 1n),11 which represent
a step forward in the pursuit of idealized monofacial alpha-helix
mimetics. At the same time, Lee et al. report the design of
a novel pyrrolopyrimidine-based scaffold and developed a facile
solid-phase synthetic route to produce a large library of such
compounds (Fig. 1o).12
Among all of these compounds, we are especially interested in
Jacoby and Hamilton oligophenyl foldamers. At the same time, Che
and Hamilton studied terpyridyl scaffolds and predicted a better
percentage of helicity for terpyridyl than for terphenyl compounds
(Fig. 2).3b,13
Our proposed synthesis of the oligomeric pyridyl system as
peptidomimetics involves three approaches of Jacoby, Hamilton,
and Che and uses the Garlanding concept,14 which allows building
a linear chain from one ring by the implementation of cross-
coupling reactions between boronic species and dihalogenated
compounds. This is a regioselective, flexible, and highly re-
producible approach to introduce various (het)aromatic rings es-
pecially since our laboratory is specialized in the preparation of
boronic species and in the study of their ability to be good coupling
partners.15
We will highlight the subtle role that the conformation of oli-
go(het)arylpyridines can play in adopting helical or elongated
conformations. In parallel, we have just published a study about the
ability of oligopyridyl scaffolds to mimic the alpha-helical twist.
The theoretical as well as experimental studies (X-ray diffraction
and NMR) on conformations of oligopyridines in the function of
substituent and nitrogen pyridine positions were carried out.16
Here, we describe the synthesis of oligopyridyl-, oligophenylpyr-
idyl-, and oligothienylpyridyl-garlands and present preliminary
results suggesting that these compounds could mimic alpha-helix.
2. Results and discussion
2.1. Oligopyridyl foldamers
Our first model considers the pioneering work of Che and
Hamilton about terpyridyl compounds. The preparation of such
compounds was described as long and difficult, using sequential
BohlmanneRahtz heteroannulation reactions.17 To overcome these
difficulties, we have developed an efficient synthesis of oligopyridyl
compounds by the implementation of cross-coupling metal-
locatalyzed SuzukieMiyaura type reactions based on Garlanding
concept.18
We have previously described that the regioselective control of
the formation of the pyridineepyridine linkage requires an efficient
and flexible strategy leading to a selective coupling with the de-
sired halogen when the pyridine bears two or more identical or
different halogens.19
Even if the alpha position of the pyridine ring is more sensitive
to a cross-coupling reaction than the beta one, the inevitable
Fig. 2. Jacoby, Che, and Hamilton approaches.

A.S. Voisin-Chiret et al. / Tetrahedron 68 (2012) 4381e4389
4383
formation of by-products is due to the poor selectivity of the re-
action especially when the two halogens are identical. Faced with
these problems, we reinvestigated the cross-coupling reaction
according to the nature of the halogen and its position on the
pyridine ring. Among halogens, it is known that iodine has a better
reactivity than bromine or chlorine or fluorine. That is why we tried
to increase the selectivity by using iodopyridine instead of bro-
mopyridine ones.
Using these observations, we recently published the synthesis of
the 5,60-dibromo-3,50-dimethyl-[2,30]bipyridine 3a18 from 6-
bromo-5-methylpyridin-3-yl boronic acid 1 and 5-bromo-2-iodo-
3-methylpyridine 2 with 77% yield. We applied a first BreI ex-
change with excellent yield to give iodo compound 3b. Then,
a second SuzukieMiyaura cross-coupling reaction to couple with
boronic acid
1
leads to the 5,600-dibromo-3,50,500-trimethyl-
[2,30,60,300]terpyridine 4a (75%). Then successive BreI exchanges
allow to gain in regioselectivity for subsequent reactions to achieve
the preparation of new quaterpyridines 6a and 6b and sexipyr-
idines 8a and 8b with satisfactory yields (Scheme 1).
Fig. 3. ORTEP view of the crystal structures of 6c (left) and 6d (right).16
In a similar way, we obtained these quaterpyridines 6c and 6d
from bipyridines 3c and 3a (Scheme 2).
Scheme 1. Preparation of compounds 3e8. Reagents and conditions: (a) Na2CO3 2.5 equiv, Pd(PPh3)4 5%, 1,4-dioxane, reflux, 20 h; (a0) Na2CO3 5 equiv, Pd(PPh3)4 10%, 1,4-dioxane,
reflux, 20 h; (b) AcCl 2ꢀ1.5 equiv, NaI 2ꢀ2.5 equiv, CH3CN, reflux, 2ꢀ4 h; (b0) AcCl 2ꢀ2.5 equiv, NaI 2ꢀ3.5 equiv, CH3CN, reflux, 2ꢀ4 h.
Scheme 2. Preparation of compounds 6c and 6d. Reagents and conditions: (a0) Na2CO3
5 equiv, Pd(PPh3)4 10%, 1,4-dioxane, reflux, 20 h.
Suitable crystals for X-ray diffraction studies were obtained by
slow evaporation of a mixture of dichloromethane/ether (9:1). The
solved structures confirmed the absence of eventual rearrange-
ments in the cross-coupling reaction and the ORTEP diagrams of
the 6c and 6d crystal structures are shown in Fig. 3.
A superposition of the X-ray structure of compounds 6c and 6d
on an ideal alanine alpha-helix shows that oligopyridyl scaffolds
can be aligned along the axis of the helix and the positions of
methyl substituents coincide with the positions of Cb atom of the
alanine side chains (Fig. 4) as it is expected for a type III mimetic.
Furthermore, for compound 6d, the two methyl substituents are
positioned in close proximity of the side chains of i and iþ3 resi-
dues. Thus, compound 6d will be able to mimic i and iþ3 side
chains with its substituent groups.13a
Fig. 4. The superposition of the X-ray structure of compound 6c (left) and compound
6d (right) on an alpha-helix.

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A.S. Voisin-Chiret et al. / Tetrahedron 68 (2012) 4381e4389
2.2. Oligophenylpyridyl foldamers
Our second model alternates pyridine and phenyl rings to de-
termine the influence of the phenyl ring instead of the pyridyl one
on the position of substituents with respect to the positions i, iþ3
(or iþ4), iþ7 of an alpha-helix. To date, one example of phenyl-
pyridyl scaffold has been synthesized by Marshall and co-work-
ers13a using iterative Stille cross-coupling reactions with
disadvantages such as numerous protectionedeprotection steps
and tin toxicity. We suggest again using our Garlanding concept
knowledge to obtain efficiently these compounds.
So, the preparation of 50-bromo-30,5-dimethyl-6-(2-methyl-4-
pyridin-3-ylphenyl)-3,20-bipyridine 13 can be achieved from pyr-
idin-3-yl boronic acid 1 and 2-bromo-5-iodotoluene 9.20
We obtained 3-(4-bromo-3-methylphenyl)pyridine 10 with
excellent yield (85%). From compound 10, a lithiumebromine ex-
change was carried out in ether at ꢁ78 ꢂC with n-BuLi followed by
a transmetallation reaction with B(Oi-Pr)3 and a hydrolysis to give
boronic acid 11 (75%). The implementation of a SuzukieMiyaura
cross-coupling reaction between boronic acid 11 and iodo-
bromobipyridine 3b allowed to obtain 50-bromo-30,5-dimethyl-6-
(2-methyl-4-pyridin-3-ylphenyl)-3,20-bipyridine 13 with a very
good yield (74%) (Scheme 3).
Fig. 6. The superposition of the X-ray structure of compound 13 on an alpha-helix.
Scheme 3. Preparation of 50-bromo-30,5-dimethyl-6-(2-methyl-4-pyridin-3-ylphenyl)-3,20-bipyridine 13. Reagents and conditions: (a) Na2CO3 (aq) 2.5 equiv, Pd(PPh3)4 5%, DME,
reflux, 24 h; (b) (1) n-BuLi 1.25 equiv, THFanhyd, ꢁ78 ꢂC, 1 h; (2) B(Oi-Pr)3 1.25 equiv, THFanhyd, ꢁ78 ꢂC, 45 min; (3) hydrolysis; (c) K3PO4 (aq) 2.5 equiv, Pd(PPh3)4 5%, DME, reflux,
20 h.
Suitable crystal for X-ray diffraction studies of 13 were obtained
by slow evaporation of a mixture of dichloromethane/cyclohexane
(1:5) and as above the solved structure is in agreement with
expected one. The ORTEP diagram of the compound 13 crystal
structure is shown in Fig. 5, a disorder is observed on the fourth
ring (on the left).
presence of type III foldamer compounds that would be able to
disrupt the interacting in which a helix engages only one face.
2.3. Oligothienylpyridyl foldamers
In the light of these results and in order to modify the hydro-
phobicity and helicity of such oligomeric systems we decided to
introduce thienyl units in our third model.
Very recently, we described the synthesis of new five-unit thie-
nylpyridyl compounds, obtained from their three-unit congeners
(Fig. 7). We have studied the reactivity of boronic acids and halo-
genated pyridines and/or thiophenes toward the SuzukieMiyaura
cross-coupling reaction in order to obtain bis-thienylpyridines.
Secondly, we have functionalized these compounds by a reaction
of bromination and the resultant bis-bromothienylpyridines have
been engaged in a iterative Pd-catalyzed coupling based on
a pseudo-Garlanding approach with a range of pyridyl boronic acids
to produce a new library of thienylpyridyl oligomers.21
Fig. 5. ORTEP diagram of major conformation of 13.
The superposition of solved X-ray structures with an alpha-helix
shows that methyl groups occupy successively the place of i, iþ4
side chains and the last methyl group is situated midway between
residues iþ3 and iþ6 (Fig. 6). Note also that all the methyl sub-
stituents are really on the same side of the helix.
For example, we first studied the reaction between 3,5-
dibromopyridine 14 and thiophenyl boronic acids 15a and 15b to
produce directly the three-unit thienylpyridyl compounds 16a and
16b (Scheme 4, respectively, 92% and 79%).
The crystal data show that compound 13 is also well able to
distribute the attached functional groups at closed positions of side
chains of an alpha-helix.
Compounds described above, i.e., pyridyl- and phenylpyridyl-
scaffolds, represent a topographical mimetic, which positions key
functional motifs in an identical spatial orientation to match those
presented by the original alpha-helix. Here, we clearly identify the
Secondly, the bromination reaction of 3,5-di(thiophen-2-yl)
pyridine 16a with 3 equiv of N-bromosuccinimide (NBS) gives the
dibrominated compound 17a with excellent yield (92%) (Scheme 5).
When the same reaction was conducted starting from com-
pound 16b by using 3 equiv of NBS, the result was very
different: dibrominated 17b0 (19% of conversion), tribrominated
17b00 (36% of conversion), and tetrabrominated 17b000 (48% of

A.S. Voisin-Chiret et al. / Tetrahedron 68 (2012) 4381e4389
4385
(HO)2B
+
X
X
X
S
S
N
N
R
R
X
X
N
N
S
S
S
S
S
S
X
+
B(OH)2
N
N
N
R=H, Cl, F, OCH3
X=halogen
Fig. 7. Synthesis of five-unit thienylpyridyl compounds.
Fig. 8. ORTEP diagram of crystal majority conformation (76%) of compound 16b.
The superposition of the X-ray structure of 16b with an alpha-
helix shows that this garland aligns well with a turn of alpha-
helix. Each unit fits to a position of one residue in alpha-helix.
For this type of scaffold, three units can cover one helix turn
(3e4 residues) (see Fig. 9). 3,5-(Dithiophen-3-yl)pyridine re-
produces the local topography (backbone mimetic) of an alpha-
helix, which is expected for a type I foldamer.
Scheme 4. Synthesis of 3,5-di(thiophen-2-yl)pyridine 16a and 3,5-di(thiophen-3-yl)
pyridine 16b. Reagents and conditions: Na2CO3 2.5 equiv, Pd(PPh3)4 5%, DME/EtOH,
reflux, 2 h.
Scheme 5. Bromination of compounds 6a and 6b. Reagents and conditions: NBS
(3 equiv), CH2Cl2/AcOH 1:1, rt, 3 h (*ratio of conversion %).
conversion) compounds were obtained due to the mechanism of
the electrophilic substitution which involves the formation of the
carbocation stabilized by the pyridyl ring (Scheme 5).
Finally, brominated compounds were engaged in cross-coupling
reactions to give new five-unit thienylpyridyl compounds 19a and
19d (for example, see Scheme 6).
Fig. 9. A representation of the alignment of the 3,5-(dithiophen-3-yl)pyridine with an
alpha-helix, based on the 16b crystal structure.
Unfortunately, we did not have structural data of a five-unit
thienylpyridyl compound. However, preliminary molecular mod-
eling studies suggest that this structure will be in an elongated
conformation and so mimics the topographical alpha-helix mimetic
as expected in type III foldamer (Fig. 10).
3. Conclusion and future work
An equally important area for the design of surface mimetics is
that of the side chain orientation beyond the CaeCb bonds. Gen-
erally, rotations about the bonds of side chains are close to one of
the three conformations (trans, gaucheþ and gaucheꢁ) in which the
attached atoms are staggered, with the conformation that gives the
greatest separation of the bulkiest groups being favored. Those
preferred side chain conformations are often referred as side chain
rotamers. The variation in the conformer distribution of rotamers
Scheme 6. Reactivity of the compound 17a with pyridylboronic acids 18aed. Pyr-
idylboronic acids 18aed (3.5 equiv), 3,5-di(thiophen-2-yl)pyridine 17a (1 equiv),
Na2CO3 (aq) (4 equiv), Pd(PPh3)4 10%, DME/EtOH, reflux, 24 h.
Then, we studied the behavior of these compounds as mimics of
an alpha-helix and the influence of the introduction of thiophene in
garlands.
Suitable crystal for X-ray diffraction studies were obtained for
compound 16b by slow evaporation of a mixture of dichloro-
methane/cyclohexane (1:1) (Fig. 8). To date, we do not obtain good
crystals for longer chains.
when the CaeCb
bond changes from an sp3esp3 hybridization (in
helix peptide) to an sp2esp3 hybridization (in our oligopyridyl
model) is a phenomenon to evaluate.
Our preliminary calculations16 on bipyridines substituted in
ortho position of the junction bond by the longer chain (i.e., leucine,
isoleucine, and valine) and with the nitrogen atom in meta position

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A.S. Voisin-Chiret et al. / Tetrahedron 68 (2012) 4381e4389
standard for high-resolution procedure, or were performed using
a spectrometer LCeMS Waters alliance 2695 (ESIþ).
Chromatography was carried out on a column using flash silica
gel 60 Merck (0.063e0.200 mm) as the stationary phase. The
eluting solvent, indicated for each purification, was determined by
thin layer chromatography (TLC) performed on 0.2 mm pre coated
plates of silica gel 60F-264 (Merck) and spots were visualized using
an ultraviolet-light lamp.
Elemental analyses for new compounds were performed at the
‘Institut de Recherche en Chimie Organique Fine’ (Rouen). The data
for C, H, and N were within ꢃ0.4 of the theoretical values for all final
compounds.
4.2. 5-Bromo-600-iodo-3,50,500-trimethyl-[2,30;60,300]terpyridine 4b
A
mixture of 885 mg (2.0 mmol) 5,600-dibromo-3,50,500-tri-
methyl-[2,30]terpyridine 4a, sodium iodide 1.1 g (7.1 mmol,
3.5 equiv), and acetyl chloride 361 L (5.1 mmol, 2.5 equiv) in ace-
m
tonitrile (50 mL) was refluxed for 24 h. It was carefully quenched
with water and treated with saturated aqueous solution of NaHCO3
until pH¼8. Product was extracted with ethyl acetate. The organic
layer was dried over MgSO4 and concentrated. The residue was
subjected to above reaction condition again and worked up as
above. Organic extract was washed with saturated aq solution of
NaHSO3, dried over MgSO4, and concentrated. The residue was
chromatographed on silica gel (cyclohexane/ethyl acetate: 9:1) to
afford 860 mg of 5-bromo-600-iodo-3,50,500-trimethyl-[2,30;60,300]
terpyridine 4b as a white solid (88%). Mp: 130 ꢂC. IR (KBr disc) 2916,
1578, 1454, 1384, 1256, 1147, 1111, 1076, 1035, 887, 772, 650,
Fig. 10. A predicted structure of a five-unit thienylpyridyl compound (left) and its
overlay with an alpha-helix (right).
(for substituted pyridine) and in ortho position (for non substituted
one) showed that their potential energy profile is close to the
methyl substituted (i.e., alanine) and one for all three other sub-
stituents (isobutyl for leucine, sec-butyl for isoleucine, and iso-
propyl for valine). As the methyl substituents of our oligopyridines
overlapped with the helix side chains, we can hope that rotamer
distributions for longer side chains on oligopyridyl scaffold will be
closed also to those of alpha-helix one.
Otherwise, we have successfully synthesized compounds whose
substituents attain positions i, iþ3 (or iþ4), iþ7 of an alpha-helix.
Today, we are working on the introduction of substituents, which
resemble more likely to protein residues: the Garlanding approach
is an effective methodology because it is based on potent reactions
and can be applied from reactants bearing various substituents.
These data will furnish valuable information in the context of
the exploration of perturbations of proteineprotein interactions
and consequently with the related biological properties. Further
results will be reported in due time.
523 cmꢁ1
.
1H NMR (CDCl3)
d
8.69 (d, 4J¼1.9 Hz, 1H), 8.62 (d,
4J¼1.9 Hz,1H), 8.40 (d, 4J¼1.9 Hz,1H), 7.82 (d, 4J¼1.9 Hz,1H), 7.80 (d,
4J¼1.9 Hz, 1H), 7.71 (d, 4J¼1.9 Hz, 1H), 2.47 (s, 3H), 2.46 (s, 3H), 2.44
(s, 3H). 13C NMR (CDCl3)
d 154.0, 153.5, 148.5, 147.6, 147.3, 141.1,
139.3, 139.0, 137.3, 135.3, 134.5, 133.1, 131.0, 124.9, 119.8, 26.2, 20.0,
19.9. HRMS (EI) m/z calcd: 478.94939, found: 478.94749. Anal. Calcd
for C18H15BrIN3: C, 45.03; H, 3.15; N, 8.75. Found: C, 45.32; H, 2.98;
N, 8.54.
4.3. 5,6000-Dibromo-3,50,500-trimethyl-[2,30;60,300;600,3000]
quaterpyridine 6a
To a glass vial containing a magnetic stirring bar was added 6-
bromopyridin-3-yl boronic acid 6 408 mg (2.0 mmol, 1.2 equiv) in
1,4-dioxane (40 mL) and the vial was purged with nitrogen. To the
vial was added 5-bromo-600-iodo-3,50,500-trimethyl-[2,30;60,300]ter-
pyridine 4b 810 mg (2.2 mmol). To the vial was added a solution
of tetrakis(triphenylphosphine) palladium(0) 97 mg (0.1 mmol,
0.05 equiv) in 1,4-dioxane (2.0 mL) and sodium carbonate (aq)
447 mg (4.2 mmol, 2.5 equiv), and the vial was once again purged
with nitrogen and the mixture was refluxed for 24 h. The solution
was cooled to room temperature and filtered through a pad of
Celite (washing with dichloromethane) into a flask containing an-
hydrous magnesium sulfate. The solution was dried for 10 min
and filtered through filter paper and the solvent was removed
under reduced pressure to afford the crude product, which was
purified on silica gel column chromatography (cyclohexane/ethyl
acetate: 7:3) to afford 370 mg of 5,6000-dibromo-3,50,500-trimethyl-
[2,30;60,300;600,3000]quaterpyridine 6a as a white solid (43%). Mp:
186 ꢂC. IR (KBr disc) 3049, 2950, 1576, 1445, 1412, 1379, 1091, 992,
Collectively, these and related studies suggest that a large uni-
verse of new foldamers with distinctive structural and functional
properties awaits discovery.
4. Experimental section
4.1. General
Commercial reagents were used as received without additional
€
purification. Melting points (mp) were determined on a Kofler
heating bench.
IR spectra were recorded on a Perkin Elmer BX FT-IR spectro-
photometer. The band positions are given in reciprocal centimeters
(cmꢁ1).
1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were
recorded on a JEOL Lambda 400 spectrometer. The chemical shifts
931, 885, 774, 649 cmꢁ1. 1H NMR (CDCl3)
d
8.79 (d, 4J¼1.9 Hz, 1H),
are given in parts per million (ppm) on the delta scale (
d) and are
8.73 (d, 4J¼1.9 Hz, 1H), 8.64 (d, 4J¼1.9 Hz, 2H), 7.91 (d, 4J¼1.9 Hz,
1H), 7.83 (m, 3H), 7.62 (d, 3J¼8.8 Hz, 1H), 2.53 (s, 3H), 2.48 (s, 3H),
referenced to tetramethylsilane (
in hertz.
d
¼0 ppm) and coupling constants
2.46 (s, 3H). 13C NMR (CDCl3)
d 154.5, 153.8, 153.6, 148.5,147.6,147.3,
Mass spectra were recorded on a JEOL JMS GC Mate spectrom-
eter at ionizing potential of 70 eV (EI) and with PFK as internal
141.8, 141.1, 139.5, 139.3, 135.3, 135.1, 134.4, 133.1, 131.2, 131.1, 127.7,
119.9, 20.1, 20.0, 19.9. HRMS (EI) m/z calcd: 507.99037, found:

A.S. Voisin-Chiret et al. / Tetrahedron 68 (2012) 4381e4389
4387
507.98973. Anal. Calcd for C23H18Br2N4: C, 54.14; H, 3.81; N, 10.49.
Found: C, 54.35; H, 3.81; N, 10.49.
4.6. 30,300,3000,30000-Tetramethyl-[3,20;50,200;500,2000;5000,20000;50000,300000
sexipyridine 8b
]
4.4. 5,6000-Dibromo-3,50,500,5000-tetramethyl-[2,30;60,300;600,3000]
quaterpyridine 6b
To a glass vial containing a magnetic stirring bar was added
pyridin-3-yl boronic acid 206 mg (1.7 mmol, 2.5 equiv) in
7
1,4-dioxane (30 mL) and the vial was purged with nitrogen.
To the vial was added, 5,6000-dibromo-3,50,500,5000-tetramethyl-
[2,30;60,300;600,3000]quaterpyridine 6b 370 mg (0.7 mmol). To the vial
was added a solution of tetrakis(triphenylphosphine) palladium(0)
78 mg (0.07 mmol, 0.05 equiv) in 1,4-dioxane (2.0 mL) and sodium
carbonate (aq) 534 mg (3.3 mmol, 5.0 equiv), and the vial was once
again purged with nitrogen and the mixture was refluxed for 24 h.
The solution was cooled to room temperature and filtered through
a pad of Celite (washing with dichloromethane) into a flask con-
taining anhydrous magnesium sulfate. The solution was dried for
10 min and filtered through filter paper and the solvent was re-
moved under reduced pressure to afford the crude product, which
was purified on silica gel column chromatography (CH2Cl2/MeOH:
To a glass vial containing a magnetic stirring bar was added 6-
bromo-5-methylpyridin-3-yl boronic acid 1 566 mg (2.6 mmol,
1.2 equiv) in 1,4-dioxane (50 mL) and the vial was purged with
nitrogen. To the vial was added 5-bromo-600-iodo-3,50,500-trimethyl-
[2,30;60,300]terpyridine 4b 1.05 g (2.2 mmol). To the vial was added
a solution of tetrakis(triphenylphosphine) palladium(0) 126 mg
(0.1 mmol, 0.05 equiv) in 1,4-dioxane (2.0 mL) and sodium car-
bonate (aq) 580 mg (5.5 mmol, 2.5 equiv), and the vial was once
again purged with nitrogen and the mixture was refluxed for 24 h.
The solution was cooled to room temperature and filtered through
a pad of Celite (washing with dichloromethane) into a flask con-
taining anhydrous magnesium sulfate. The solution was dried for
10 min and filtered through filter paper and the solvent was re-
moved under reduced pressure to afford the crude product, which
was purified on silica gel column chromatography (cyclohexane/
ethyl acetate: 7:3) to afford 623 mg of 5,6000-dibromo-3,50,500,5000-
tetramethyl-[2,30;60,300;600,3000]quaterpyridine 6b as a white solid
(54%). Mp: 186 ꢂC. IR (KBr disc) 3423, 2956, 1585, 1448, 1412, 1380,
98:2, 97:3; 96:4, 95:5 then 93/3) to afford 270 mg of 30,300,3000,30000
-
tetramethyl-[3,20;50,200;500,2000;5000,20000;50000,300000]sexipyridine 8b as
a white solid (76%). Mp: 223 ꢂC. IR (KBr disc) 2949, 1725, 1589, 1392,
1260, 1009, 899, 807, 777, 710 cmꢁ1 1H NMR (CDCl3)
. d 8.92 (d,
4J¼1.9 Hz, 1H), 8.89 (d, 4J¼1.9 Hz, 1H), 8.82 (d, 4J¼1.9 Hz, 4H), 8.69
(d, 4J¼1.9 Hz, 2H), 7.96 (dd, 3J¼7.8 Hz, 4J¼1.9 Hz, 1H), 7.94 (m, 4H),
7.86 (d, 4J¼1.9 Hz,1H), 7.45 (m, 2H), 2.59 (s, 3H), 2.58 (s, 3H), 2.57 (s,
1086,1048, 888, 773, 647 cmꢁ1. 1H NMR (CDCl3)
d
8.78 (d, 4J¼1.9 Hz,
1H), 8.72 (d, 4J¼1.9 Hz, 1H), 8.63 (d, 4J¼1.9 Hz, 1H), 8.44 (d,
4J¼1.9 Hz, 1H), 7.9 (d, 4J¼1.9 Hz, 1H), 7.84 (d, 4J¼1.9 Hz, 1H), 7.82 (d,
3H), 2.50 (s, 3H). 13C NMR (CDCl3)
d 154.9, 154.7, 154.6, 154.5, 149.9,
149.4, 149.1, 148.1, 147.3, 147.4 (2C), 145.7, 139.2, 139.3 (2C), 137.2,
136.5, 135.9,135.0,134.8,134.3, 133.0,132.6,131.5,131.1,131.0,130.8,
128.8, 123.8, 123.1, 20.1, 20.0 (2C), 19.9. HRMS (EI) m/z calcd:
520.23752, found: 520.2351. Anal. Calcd for C34H28N6: C, 78.44; H,
5.42; N, 16.14. Found: C, 78.92; H, 5.33; N, 16.58.
4J¼1.9 Hz, 2H), 2.52 (s, 3H), 2.48 (s, 3H), 2.47 (s, 3H), 2,46 (s, 3H). 13
C
NMR (CDCl3)
d 154.6, 153.8, 153.6, 148.5, 147.4, 147.3, 147.2, 144.3,
141.1, 139.5, 139.4, 139.3, 135.3, 135.1, 135.0, 134.4, 133.2, 131.2, 131.1,
119.9, 22.0, 20.1, 20.0, 19.9. HRMS (EI) m/z calcd: 522.00538, found:
522.0072. Anal. Calcd for C24H20Br2N4: C, 54.99; H, 3.85; N, 10.69.
Found: C, 55.13; H, 3.88; N, 10.75.
4.7. 30-Methyl-[3,20;50,200;500,3000]quaterpyridine 6c
4.5. 300,3000,30000-Trimethyl-[3,20;50,200;500,2000;5000,20000;50000,300000
sexipyridine 8a
]
Starting from pyridin-3-yl boronic acid 7 421 mg (3.4 mmol,
1.25 equiv), 5,60-dibromo-50-methyl-[2,30]bipyridine 3c 450 mg
(1.4 mmol), sodium carbonate 726 mg (6.9 mmol, 2.5 equiv), and
To a glass vial containing a magnetic stirring bar was added
pyridin-3-yl boronic acid 7 102 mg (0.8 mmol, 2.5 equiv) in 1,4-
dioxane (30 mL) and the vial was purged with nitrogen. To the vial
was added, 6000-dibromo-3,50,500-trimethyl-[2,30;60,300;600,3000]qua-
terpyridine 6a 170 mg (0.3 mmol). To the vial was added a solution
of tetrakis(triphenylphosphine) palladium(0) 39 mg (0.03 mmol,
0.05 equiv) in 1,4-dioxane (2.0 mL) and sodium carbonate (aq)
177 mg (1.7 mmol, 5.0 equiv), and the vial was once again purged
with nitrogen and the mixture was refluxed for 24 h. The solution
was cooled to room temperature and filtered through a pad of Celite
(washing with dichloromethane) into a flask containing anhydrous
magnesium sulfate. The solution was dried for 10 min and filtered
through filter paper and the solvent was removed under reduced
pressure to afford the crude product, which was purified on silica gel
column chromatography (cyclohexane/ethyl acetate: 7:3) to afford
40 mg of 300,3000,30000-trimethyl-[3,20;50,200;500,2000;5000,20000;50000,300000]sex-
ipyridine 8a as a white solid (30%). Mp: 184 ꢂC. IR (KBr disc) 3401,
tetrakis(triphenylphosphine)palladium(0)
159 mg
(0.1 mmol,
0.05 equiv) and following the procedure described to obtain sex-
ipyridines 8, the product 6c was obtained as a white solid (324 mg,
73%). Experimental data were found to be identical to that already
described in the literature.19a
4.8. 3,300-Dimethyl-[3,20;50,200;500,3000]quaterpyridine 6d
Starting from pyridin-3-yl boronic acid 7 898 mg (7.3 mmol,
1.25 equiv), 5,60-dibromo-3,50-dimethyl-[2,30]bipyridine 3c 1.0 g
(2.9 mmol), sodium carbonate 1550 mg (14.6 mmol, 2.5 equiv),
and tetrakis(triphenylphosphine)palladium(0) 338 mg (0.3 mmol,
0.05 equiv) and following the procedure described to obtain sex-
ipyridines 8, the product 6d was obtained as a white solid (758 mg,
76%). Experimental data were found to be identical to that already
described in the literature.17a
2956, 2923, 1726, 1590, 1456, 1418, 1379, 1286, 1012, 776, 705 cmꢁ1
.
4.9. 50-Bromo-30,5-dimethyl-6-(2-methyl-4-pyridin-3-
ylphenyl)-3,20-bipyridine 13
1H NMR (CDCl3)
d
9.28 (d, 4J¼1.9 Hz,1H), 9.00 (d, 4J¼1.9 Hz,1H), 8.92
(d, 4J¼1.9 Hz,1H), 8.84 (d, 4J¼1.9 Hz,1H), 8.82 (d, 4J¼1.9 Hz, 2H), 8.70
(d, 3J¼4.9 Hz, 2H), 8.41 (dd, 3J¼7.8 Hz, 4J¼1.9 Hz, 1H), 8.11 (dd,
3J¼7.8 Hz, 4J¼1.9 Hz,1H), 7.95 (m, 3H), 7.91 (d, 3J¼7.8 Hz,1H), 7.87 (d,
4J¼1.9 Hz,1H), 7.46 (d, 3J¼4.9 Hz,1H), 7.44 (d, 3J¼4.9 Hz,1H), 2.58 (s,
To
a stirred solution of 2-methyl-4-(pyridin-3-yl)phenyl-
boronic acid 4b 683 mg (3.20 mmol, 1.25 equiv) in dimethoxy-
ethane (30 mL) under nitrogen were added 50-bromo-30,5-
dimethyl-6-iodo-3,20-bipyridine 3b 1.0 g (2.56 mmol, 1 equiv)
and tetrakis-(triphenylphosphine)palladium(0) 148 mg (0.13
mmol, 0.05 equiv). After 5 min of stirring, aq K3PO4 1.476 g
(6.41 mmol, 2.5 equiv) in 5 mL of water was added. Then the
mixture was heated to 80 ꢂC until the starting material was
consumed (TLC). After cooling down to room temperature, the
3H), 2.56 (s, 3H), 2.54 (s, 3H), 2,46 (s, 3H). 13C NMR (CDCl3)
d 154.7,
154.6, 154.4, 154.1, 150.2, 150.0, 149.4,148.3,148.1, 147.5, 147.4, 145.7,
139.5,139.4,137.6,137.2,134.9,135.0,134.8,134.4,134.3,133.0,132.6,
131.6,131.1,131.0,130.8,123.8,123.6,120.0, 20.1, 20.0 (2C). HRMS (EI)
m/z calcd: 506.22187, found: 506.22384. Anal. Calcd for C33H26N6: C,
78.24; H, 5.17; N, 16.59. Found: C, 78.23; H, 5.79; N, 16.50.

4388
A.S. Voisin-Chiret et al. / Tetrahedron 68 (2012) 4381e4389
mixture was filtered on Celite and washed with CH2Cl2.
The aqueous layer was extracted with EtOAc (2ꢀ50 mL). Com-
bined organic layers were washed with saturated aq solution of
NaCl (50 mL), and dried over MgSO4. Solvent were removed in
vacuo and the crude product was purified by column chroma-
tography, with a gradient of solvent from 8:2 to 5:5 cyclohexane/
EtOAc affording 50-bromo-30,5-dimethyl-6-(2-methyl-4-pyridin-
3-ylphenyl)-3,20-bipyridine 13 as a pale yellow solid (710 mg,
64%). Experimental data were found to be identical to that al-
ready described in the literature.13a
4.13. General procedure for SuzukieMiyaura reaction to
obtain five units 19
To a glass vial containing a magnetic stirring bar was added the
3,5-bis(5-bromothiophen-2-yl)pyridine 17a (1.00 equiv), and the
vial was purged with nitrogen. To the vial was added a solution of
tetrakis(triphenylphosphine) palladium(0) (10 mol %) in dime-
thoxyethane (2.00 mL) and sodium carbonate (aq) (5 equiv), and
the vial was once again purged with nitrogen. The resultant solution
was stirred at room temperature for 5 min when a slurry/solution of
pyridin-3-yl boronic acids 18aed (3.00 equiv) in ethanol (2.00 mL)
was added, the vial was purged with nitrogen and capped, and the
mixture was heated to 90 ꢂC and stirred until the consumption of
the halide (24 h). The solution was cooled to room temperature and
filtered through a pad of Celite (washing with dichloromethane)
into a flask containing anhydrous magnesium sulfate. The solution
was dried for 10 min and filtered through filter paper and the sol-
vent was removed under reduced pressure to afford the crude
product, which was purified on silica gel column chromatography
(cyclohexane/ethyl acetate) to afford compounds 19aed.
4.10. 3,5-Di(thiophen-2-yl)pyridine 16a
To a round bottom flask containing a magnetic stirring bar
was added the 3,5-dibromopyridine 14 370 mg (1.56 mmol),
and the flask was purged with nitrogen. Then a solution of tet-
rakis(triphenylphosphine) palladium(0) 90 mg (0.078 mmol, 0.05
equiv) in dimethoxyethane (2.0 mL) and sodium carbonate
413 mg (aq) (3.90 mmol, 2.50 equiv) was added. The resultant
solution was stirred at room temperature for 5 min when a slurry/
solution of thiophen-2-yl boronic acid 15a 500 mg (3.91 mmol,
2.50 equiv) in ethanol (2.00 mL) was added, the round bottom
flask was purged with nitrogen and capped, and the mixture was
heated to 90 ꢂC and stirred until the consumption of the halide
(2 h). The solution was cooled to room temperature and filtered
through a pad of Celite (washing with dichloromethane) into
a flask containing anhydrous magnesium sulfate. The solution
was dried for 10 min and filtered through filter paper and the
solvent was removed under reduced pressure to afford the crude
product, which was purified on silica gel column chromatography
(cyclohexane/ethyl acetate: 7:3) to afford 3,5-di(thiophen-3-yl)
pyridine 16a as a white solid (350 mg, 92%). Experimental data
were found to be identical to that already described in the
literature.20
4.13.1. 3-(5-(5-(5-(Pyridin-3-yl)thiophen-2-yl)pyridin-3-yl)thio-
phen-2-yl)pyridine 19a. Starting from 3,5-bis(5-bromothiophen-2-
yl)pyridine 17a (1.00 g, 2.49 mmol) and pyridin-3-yl boronic acid
18a (1.07 g, 8.71 mmol) and following the general procedure the
product 19a was obtained as a yellow solid (0.67 g, 68%). Experi-
mental data were found to be identical to that already described in
the literature.20
4.13.2. 2-Chloro-5-(5-(5-(5-(6-chloropyridin-3-yl)thiophen-2-yl)
pyridin-3-yl)thiophen-2-yl)pyridine 19b. Starting from 3,5-bis(5-
bromothiophen-2-yl)pyridine 17a (0.60 g, 1.49 mmol) and 6-
chloropyridin-3-yl boronic acid 18b (0.82 g, 5.21 mmol) and fol-
lowing the general procedure the product 19b was obtained as
a light brown solid (0.35 g, 51%). Experimental data were found to
be identical to that already described in the literature.20
4.11. 3,5-Di(thiophen-3-yl)pyridine 16b
4.13.3. 2-Fluoro-5-(5-(5-(5-(6-fluoropyridin-3-yl)thiophen-2-yl)pyr-
idin-3-yl)thiophen-2-yl)pyridine 19c. Starting from 3,5-bis(5-
bromothiophen-2-yl)pyridine 17a (0.50 g, 1.25 mmol) and 6-
fluoropyridin-3-yl boronic acid 18c (0.62 g, 4.37 mmol) and fol-
lowing the general procedure the product 19c was obtained as
a yellow solid (0.30 g, 55%). Mp: 198e200 ꢂC. Experimental data
were found to be identical to that already described in the
literature.20
Starting from 3,5-dibromopyridine 14 500 mg (2.11 mmol),
tetrakis(triphenylphosphine) palladium(0) 122 mg (0.105 mmol,
0.05 equiv) in dimethoxyethane (2.0 mL), sodium carbonate
559 mg (aq) (5.27 mmol, 2.50 equiv), and thiophen-3-yl boronic
acid 15b 517 mg (5.27 mmol, 2.50 equiv) in ethanol (2.0 mL) and
following the procedure described above, 3,5-di(thiophen-3-yl)
pyridine 16b was obtained as a white solid (400 mg, 79%). Experi-
mental data were found to be identical to that already described in
the literature.20
4.13.4. 2-Methoxy-5-(5-(5-(5-(6-methoxypyridin-3-yl)thiophen-2-
yl)pyridin-3-yl)thiophen-2-yl)pyridine 19d. Starting from 3,5-bis(5-
bromothiophen-2-yl)pyridine 17a (0.46 g, 1.15 mmol) and 6-
methoxypyridin-3-yl boronic acid 18d (0.61 g, 4.01 mmol) and
following the general procedure the product 19d was obtained as
a yellow solid (0.19 g, 33%). Experimental data were found to be
identical to that already described in the literature.20
4.12. Synthesis of brominated compounds 17
To a solution of starting material 16 (1.00 equiv) in a 50:50 (v/v)
mixture of CH2Cl2 and glacial acetic acid was added N-bromo-
succinimide (3.00 equiv). The resultant solution was stirred at
room temperature for 3 h. The solution was washed twice with
NaOH 4% and the organic layers were collected and dried on an-
hydrous magnesium sulfate. After filtration through filter paper,
the solvent was removed under reduced pressure to afford the
crude product, which was purified on silica gel column chroma-
tography (cyclohexane/ethyl acetate 5:5) to afford compounds 17
as stable solids: 17a as a beige solid (0.53 g, 92%), 17b0 as a brown
solid (ratio of conversion: 19%), 17b00 as a brown solid (ratio of
conversion: 36%), and 17b000 as a brown solid (ratio of conversion:
48%).
Acknowledgements
The authors gratefully acknowledge for the financial support
ꢀ
from the ‘Region Basse-Normandie’ and the ‘Ministero dell’Is-
ꢁ
truzione, dell’Universita e della Ricerca Italiana’.
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