Synthesis of a 'propeller-like' oligoheteroaryl with alternating pyridine and oxazole motifs

Article abstract of DOI:10.1055/s-0034-1379549

The molecular architecture of oligomeric pyridyl-oxazole compounds is key to determining their mode of interaction with G-quadruplex DNA structures, which is a family of prominent anticancer biomolecular targets. We report herein an efficient synthetic route that begins with chelidamic acid and affords, in just seven steps, an unusual 'propeller-like' pyridyl-oxazole architecture with alternating pyridine and oxazole rings, that has not been yet validated as a G-quadruplex binder. The synthesis employs Van Leusen chemistry for the construction of oxazole rings from aldehydes, and two Pd(II)/Cu(I)-mediated cross-coupling reactions involving C-H activation of oxazoles for the formation of C-C bonds between bromopyridine intermediates and oxazole fragments. This modular synthesis was designed to be amenable to the construction of analogues.

Full text of DOI:10.1055/s-0034-1379549

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Synthesis of a ‘Propeller-Like’ Oligoheteroaryl with Alternating
Pyridine and Oxazole Motifs
Savvas N. Georgiades*
Natalia Rizeq
N
O
Department of Chemistry, University of Cyprus, 1 Panepistimiou Ave.,
via C–H
activation/
C–C cross-
coupling
7 steps
⋅H2O
OH
Aglandjia, Nicosia 2109, Cyprus
georgiades.savvas@ucy.ac.cy
+
3
5
7
2
(
2
8
)
9
5
4
5
6
N
O
HO
N
H
O
O
N
O
N
N
O
N
N
Received: 14.10.2014
Accepted after revision: 24.10.2014
Published online: 08.01.2015
DOI: 10.1055/s-0034-1379549; Art ID: st-2014-d0863-l
Abstract The molecular architecture of oligomeric pyridyl-oxazole
compounds is key to determining their mode of interaction with G-qua-
druplex DNA structures, which is a family of prominent anticancer bio-
molecular targets. We report herein an efficient synthetic route that
begins with chelidamic acid and affords, in just seven steps, an unusual
‘propeller-like’ pyridyl-oxazole architecture with alternating pyridine
and oxazole rings, that has not been yet validated as a G-quadruplex
binder. The synthesis employs Van Leusen chemistry for the construc-
tion of oxazole rings from aldehydes, and two Pd(II)/Cu(I)-mediated
cross-coupling reactions involving C–H activation of oxazoles for the
formation of C–C bonds between bromopyridine intermediates and ox-
azole fragments. This modular synthesis was designed to be amenable
to the construction of analogues.
Savvas N. Georgiades (left) was born in Nicosia, Cyprus (1977). He ob-
tained his B.Sc. in Chemistry from University of Cyprus (2001) and his
Ph.D. in Organic Chemistry/Chemical Biology from Harvard University
(2006). After postdoctoral appointments at the Scripps Research Insti-
tute-La Jolla, California (2006-2007) and Imperial College London
(2007-2010), Dr. Georgiades worked for one year as Lecturer in Phar-
macy and Chemistry at Kingston University (UK), before joining Univer-
sity of Cyprus as Lecturer in Organic and Medicinal Chemistry (2011).
His research interests include: (a) Development of new DNA G-quadru-
plex binders as a basis for new anti-cancer treatments; (b) Synthesis and
biological evaluation of small-molecule modulators of cellular signaling
pathways, relevant to cancer and neurodegenerative diseases; (c) De-
velopment of novel synthetic methodologies.
Key words anticancer, oligoheteroaryl, propeller architecture, C-H ac-
tivation, G-quadruplex
Oligoheteroaryl compounds that incorporate in their
structure several oxazole rings have become a focal point of
recent synthetic efforts, inspired by the unique natural
product telomestatin1 (Figure 1 A, i). Telomestatin is a mac-
rocycle of bacterial origin, made up of seven oxazoles and
one thiazoline, all connected in a cyclic head-to-tail ar-
rangement. The interest in this molecule derives from its
ability to specifically bind the DNA G-quadruplex helix
formed within the guanine-rich single-stranded sequence
of the human telomeres (H-telo).2 Telomestatin binding
causes G-quadruplex stabilization, which stalls the elonga-
tion of the telomere by the enzyme telomerase, a process
responsible for rendering cancer cells ‘immortal’. Telomer-
ase inhibition eventually triggers apoptosis. While the ex-
act nature of telomestatin interaction with H-telo is not
fully understood, it is believed that it involves π-π stacking
of the macrocycle on the terminal planar surfaces of the
Natalia Rizeq (right) was born in Larnaca, Cyprus (1990). In 2012, she
obtained her B.Sc. in Chemistry from Aristotle University of Thessaloniki
(Greece). She is currently a M.Sc. student at the Department of Chemis-
try, University of Cyprus, carrying out her research on novel binders for
DNA G-quadruplexes under the supervision of Dr. Savvas N. Georgiades.
quadruplex (the most exposed guanine tetrads),2 probably
reinforced by additional contacts of the oxazoles to other
quadruplex binding elements (Figure 1 B, i).
Early synthetic examples of telomestatin analogues
(e.g., Figure 1 A, ii), as well as synthetic precursors to telo-
mestatin itself, have been peptide-like, in that they include
some amide bonds as part of their macrocyclic periphery,
and originate from amino acid building blocks.3 More re-
cently, focus has shifted to macrocyclic systems whose pe-
riphery
combines
both
pyridine
and
oxazole
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of G-quadruplexes in these regions by small molecules has
been shown to down-regulate the expression of the corre-
sponding oncogenes, which also acts in an anticancer ca-
pacity.6
Recognizing the potential of the pyridyl-oxazole moiety
to serve as a privileged motif in the design of selective G-
quadruplex binders, Hamon et al. went on to report on non-
cyclic pyridyl-oxazole counterparts (e.g., Figure 1 A, iv),
which were surprisingly found to discriminate between
two different G-quadruplex folds of the human telomeric
sequence.7 Moreover, the same group described cationic
pyridyl-oxadiazole systems that exhibit the opposite pref-
erence towards the same two variants of the H-telo quadru-
plex.8 Such non-cyclic pyridyl-oxa(dia)zole compounds
represent a different mode of binding (Figure 1 B, ii), which
resembles groove binding in duplex DNA. This is consistent
with the crescent-like shape of the molecules. Since the
grooves differ significantly between diverse G-quadruplex-
es, they offer unique opportunities as sites of selective rec-
ognition by small molecules.
Branched pyridyl-oxazoles, in which all the branches
are oxazole-pyridine oligomers, have not been previously
reported or evaluated for binding to G-quadruplex DNA. In
the current communication, we describe the development
of a versatile and efficient synthetic method that allows
easy access to pyridyl-oxazoles of propeller-like architec-
ture. The synthesis has been exemplified with the prepara-
tion of a model compound (Figure 2). This type of structure
deviates from the classical crescent-like one, in that it intro-
duces a third branching point on the central pyridine moi-
ety. With appropriate selection of a substituted pyridyl
early precursor, three oxazoles can occupy positions 2, 4,
and 6 of the central pyridine ring and offer sites for further
outward extension. This type of molecule is designed to
have rotational flexibility at the aryl–aryl connections and
the ability to randomly test different modes of binding be-
fore settling for a preferred one, depending on which G-
quadruplex it is called to interact with and which branches
it uses. In case it acts as groove binder, the third branch
could, in principle, allow contacts with more flexible do-
mains of the quadruplexes (e.g., loop domains), which are
located away from the grooves and which have so far re-
mained unexploited.
Figure 1 (A) Telomestatin (i) and examples of previously reported syn-
thetic polyoxazoles (ii–iv), inspired from telomestatin. (B) Proposed
mode of binding for macrocyclic telomestatin-like (blue) vs. non-cyclic
(orange) pyridyl-oxazole ligands onto a DNA G-quadruplex (each gray
rectangle represents one guanine base)
heteroaromatic rings (e.g., Figure 1 A, iii),4 which facilitates
synthesis and increases versatility when it comes to chemi-
cal functionalization. Biological evaluation of all these mol-
ecules suggests that they successfully mimic the binding of
telomestatin to H-telo and hence are also considered poten-
tial anticancer lead structures.
Identifying promising new molecules that can distin-
guish between different G-quadruplexes remains a major
challenge, especially in light of the fact that G-rich sequenc-
es with potential of folding into quadruplex are found not
only in the telomeres, but all across the human genome, in-
cluding several oncogene promoter regions.5 Stabilization
Our synthesis began from commercially available cheli-
damic acid (1), which offers three positions for modifica-
tion around its heterocyclic ring (Scheme 1). The 2- and 6-
carboxylate positions were both modified as ethyl esters to
afford 29 in excellent yield (98%), by using thionyl chloride
in EtOH.10 The esters served as protecting groups in the ear-
ly stages and could be converted into desirable functional-
ities later in the synthesis.
The 4-hydroxy group of 2 was subsequently replaced by
bromide in high yield (92%), upon treatment with PBr5
(neat) at 95 °C,10 to furnish compound 3.11 The bromide was
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S. N. Georgiades, N. Rizeq
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O
OH
⋅H2O
OH
N
HO
EtO
OEt
N
H
N
a.
b.
N
O
O
O
O
O
2
1
N
O
N
N
O
N
Br
N
N
N
N
N
O
O
c.
4
Figure 2 Structure of the propeller-like pyridyl-oxazole compound syn-
thesized in this study
EtO
OEt
N
O
O
3
EtO
OEt
needed to serve as a handle for carrying out a C–C coupling
reaction, which allowed us to introduce the third branching
point.
N
O
N
O
5
Pyridyl-oxazole 4,12 which was prepared in-house from
2-pyridine carboxaldehyde in 98% yield as described in the
supporting information, was introduced onto the 4-posi-
tion of the pyridine ring of compound 3, in a transformation
that involved a palladium/copper cocatalyzed C–H activa-
tion of the oxazole. The reaction, which afforded intermedi-
ate 513 in 51% yield after chromatographic purification, was
a modification of previous protocols describing C–C cross-
couplings of 5-aryloxazoles directly on aryl bromides,14 and
made use of the reaction conditions employed by Hamon et
al.7 in their assembly of crescent-like pyridyl-oxazoles. Spe-
cifically, the cross-coupling was carried out in 1,4-dioxane,
with Pd(OAc)2 and CuI as cocatalysts, Cs2CO3 as base, and
P(Cy)3·HBF4 as an additive. In our case, the bromopyridine
involved (3) is more substituted and the success of the reac-
tion demonstrates that it is tolerant to ester functionalities.
However, its usefulness in constructing bis-aryl pyridyl-ox-
azole systems is somewhat limited by the formation of un-
desired side-products, which were not fully characterized.
Attempts to replace 1,4-dioxane with higher boiling point
solvents, such as DMF and NMP, typically led to lower yields
and problematic isolation of the desired product.
N
N
N
O
O
d.
e.
f.
H
H
N
N
OH
OH
O
O
7
6
N
N
N
Br
N
O
N
O
9
g.
N
N
N
N
N
N
O
O
O
O
10
8
A stepwise reduction-reoxidation approach was applied
on 5 to obtain a dialdehyde. Our initial efforts for direct
conversion of 5 into a dialdehyde by using sterically hin-
dered aluminum reagents, such as DIBAL-H and Red-Al,
only led to incomplete reductions and mixtures of products,
which may be attributed to the tendency of the substrate to
coordinate to the metal. Therefore, we turned to a method
that employs NaBH4 in anhydrous MeOH15 for the full re-
duction of diester 5 to the diol. Diol 616 was obtained clean
after simple aqueous workup, without any need for chro-
matographic purification, in 76% yield.
N
N
Scheme 1 Synthetic route for the preparation of a model propeller-like
tris-oxazole substituted pyridyl compound 10, from chelidamic acid (1).
Reagents and conditions: (a) EtOH, SOCl2, 0 °C, then r.t. for 18 h, then
reflux for 2 h, 98%; (b) PBr5 (neat), 95 °C, 3.5 h, then CHCl3, EtOH, 0 °C,
3 h, 92%; (c) 1,4-dioxane, Pd(OAc)2, CuI, Cs2CO3, P(Cy)3·HBF4, 130 °C,
24 h, 51%; (d) MeOH, NaBH4, 0 °C, then r.t. for 18 h, 76%; (e) DMSO,
IBX, r.t., 10 h, 56% (f) MeOH, TosMIC, K2CO3, reflux, 4 h, 77%; (g) 1,4-
dioxane, Pd(OAc)2, CuI, Cs2CO3, P(Cy)3·HBF4, 130 °C, 24 h, 54%.
pared batches of IBX19 behaved in our hands more repro-
ducibly than SeO2 or MnO2, the performance of which
varied significantly between batches, giving dialdehyde 7 in
56% yield.
Diol 6 was subsequently oxidized to dialdehyde 717 by
using hypervalent iodine reagent 2-iodoxybenzoic acid
(IBX) as the oxidant, in anhydrous DMSO.18 Freshly pre-
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A 1,3-dipolar cycloaddition carried out on the two alde-
hyde moieties of 7 by the reagent tosylmethyl isocyanide
(TosMIC), upon its deprotonation by K2CO3 in MeOH heated
to reflux (Van Leusen reaction),20 assured an efficient con-
version of 7 into the tris-oxazole system 821 (77% yield).
Tris-oxazole adducts with this pattern of oxazole connec-
tivity to a central pyridine ring represent a new family of
compounds and could prove to be useful synthetic interme-
diates in many applications, including biologicals and mate-
rials.
In our case, the two terminal oxazoles allowed for yet
another C–C cross-coupling step, under the same condi-
tions as the previous one,7 but this time with 2-bromopyri-
dine (9) as the coupling partner, to introduce one additional
pyridine ring on each of the two termini and extend the re-
spective branches. The use of excess 2-bromopyridine (3
equiv) was key to driving the valuable intermediate 8 to the
corresponding bis-pyridinylated product 1022 (54% yield).
We anticipate that the same reaction can be applied to
modified/substituted 2-bromopyridines and could lead to
even more extended oligomers with the same architecture,
some of which would make good candidates for targeting
G-quadruplexes.
M.; Shin-ya, K.; Takahashi, T. Org. Lett. 2006, 8, 4165. (e) Minhas,
G. S.; Pilch, D. S.; Kerrigan, J. E.; LaVoie, E. J.; Rice, J. E. Bioorg.
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Rice, J. E. Bioorg. Med. Chem. Lett. 2008, 18, 913.
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33, 2908. (b) Todd, A. K. Methods 2007, 43, 246. (c) Todd, A. K.;
Haider, S. M.; Parkinson, G. N.; Neidle, S. Nucleic Acids Res. 2007,
35, 5799. (d) Huppert, J. L.; Balasubramanian, S. Nucleic Acids
Res. 2007, 35, 406.
(6) Du, Z.; Zhao, Y.; Li, N. Genome Res. 2008, 18, 233.
(7) Hamon, F.; Largy, E.; Guédin-Beaurepaire, A.; Rouchon-Dagois,
M.; Sidibe, A.; Monchaud, D.; Mergny, J.-L.; Riou, J.-F.; Nguyen,
C.-H.; Teulade-Fichou, M.-P. Angew. Chem. Int. Ed. 2011, 50,
8745.
(8) Petenzi, M.; Verga, D.; Largy, E.; Hamon, F.; Doria, F.; Teulade-
Fichou, M.-P.; Guédin, A.; Mergny, J.-L.; Mella, M.; Freccero, M.
Chem. Eur. J. 2012, 18, 14487.
(9) Data for compound 2: 1H NMR (CDCl3): δ = 1.41 (t, J = 7.1 Hz, 6
H), 4.46 (q, J = 7.1 Hz, 4 H), 7.35 (s, 2 H). 13C NMR (CDCl3 + trace
DMSO-d6): δ = 13.6, 61.6, 115.6, 148.1, 163.9, 167.1. MS (ESI):
m/z = 238.08 (calcd 238.07 [M – H]–), 261.06 (calcd 261.06, [M +
Na – H]–).
(10) Cooper, C. G. F.; MacDonald, J. C.; Soto, E.; McGimpsey, W. E.
J. Am. Chem. Soc. 2004, 126, 1032.
In summary, we have described an expedient method
leading to the generation of a model propeller-like pyridyl-
oxazole compound 10, with three branches and alternating
pyridine and oxazole rings in each branch. This is a novel
architecture with potential interest for anticancer research.
Several analogues of model compound 10 are being pre-
pared in our laboratory by variations of this method, and
their evaluation for G-quadruplex binding is underway and
will be reported in due course.
(11) Data for compound 3: 1H NMR (CDCl3): δ = 1.45 (t, J = 7.2 Hz,
6 H), 4.49 (q, J = 7.2 Hz, 4 H), 8.42 (s, 2 H). 13C NMR (CDCl3): δ =
14.1, 62.7, 131.0, 134.9, 149.5, 163.5. MS (ESI): m/z = 302.01
(calcd 302.00, [M + H]+).
(12) Data for compound 4: 1H NMR (CDCl3): δ = 7.13 (t, J =7.0 Hz,
1 H), 7.55 (d, J = 7.0 Hz, 1 H), 7.61 (s, 1 H), 7.65 (t, J = 7.0 Hz,
1 H), 7.89 (s, 1 H), 8.53 (d, J = 7.0 Hz, 1 H). 13C NMR (CDCl3): δ =
119.0, 122.7, 124.5, 136.6, 146.7, 149.5, 150.7, 150.8. MS (ESI):
m/z = 147.06 (calcd 147.06, [M + H]+).
(13) Data for compound 5: 1H NMR (CDCl3): δ = 1.46 (t, J = 7.2 Hz,
6 H), 4.51 (q, J = 7.2 Hz, 4 H), 7.29 (td, J1 = 5.5 Hz, J2=2.8 Hz, 1 H),
Acknowledgment
7.80–7.82 (m, 2 H, overlapping), 7.90 (s, 1 H), 8.65 (dt, J1
=
4.7 Hz, J2 = 1.5 Hz, 1 H), 8.87 (s, 2 H). 13C NMR (CDCl3): δ = 14.1,
62.5, 119.7, 123.6, 123.8, 127.6, 136.5, 137.0, 146.2, 149.6,
150.0, 152.5, 158.0, 164.0. MS (ESI): m/z = 368.12 (calcd 368.13,
[M + H]+).
We thank the University of Cyprus for a New Faculty Startup Grant to
SNG.
(14) (a) Zificsak, C. A.; Hlasta, D. J. Tetrahedron 2004, 60, 8991.
(b) Besselièvre, F.; Mahuteau-Betzer, F.; Grierson, D. S.; Piguel,
S. J. Org. Chem. 2008, 73, 3278. (c) Besselièvre, F.; Lebrequier, S.;
Mahuteau-Betzer, F.; Piguel, S. Synthesis 2009, 3511.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379549.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
(15) (a) Seregin, I. V.; Schammel, A. W.; Gevorgyan, V. Org. Lett. 2007,
9, 3433. (b) Seregin, I. V.; Schammel, A. W.; Gevorgyan, V. Tetra-
hedron 2008, 64, 6876.
References and Notes
(16) Data for compound 6: 1H NMR (DMSO-d6): δ = 4.63 (d, J =
6.1 Hz, 4 H), 5.63 (t, J = 6.1 Hz, 2 H), 7.44 (t, J = 5.8 Hz, 1 H),
7.96–7.98 (m, 4 H, overlapping), 8.06 (s, 1 H), 8.69 (d, J = 5.0 Hz,
1 H). 13C NMR (DMSO-d6): δ = 64.1, 114.2, 119.9, 123.9, 127.4,
134.4, 137.6, 146.1, 150.1, 151.5, 159.7, 162.8. MS (ESI): m/z =
282.10 (calcd 282.09, [M – H]–).
(1) Shin-ya, K.; Wierzba, K.; Matsuo, K.-L.; Ohtani, T.; Yamada, Y.;
Furihata, K.; Hayakawa, Y.; Seto, H. J. Am. Chem. Soc. 2001, 123,
1262.
(2) Kim, M.-Y.; Vankayalapati, H.; Shin-ya, K.; Wierzba, K.; Hurley,
L. H. J. Am. Chem. Soc. 2002, 124, 2098.
(3) (a) Yamada, S.; Shigeno, K.; Kitagawa, K.; Okajima, S.; Asao, T.
(Taiho Pharmaceutical Co. Ltd., Sosei Co. Ltd.) 200248153, 2002;
Chem. Abstr. 2002, 137, 47050 (b) Endoh, N.; Tsuboi, K.; Kim, R.;
Yonezawa, Y.; Shin, C. Heterocycles 2003, 60, 1567. (c) Deeley, J.;
Pattenden, G. Chem. Commun. 2005, 797. (d) Doi, T.; Yoshida,
(17) Data for compound 7: 1H NMR (CDCl3): δ = 7.30 (t, J = 5.6 Hz,
1 H), 7.80–7.84 (m, 2 H, overlapping), 7.91 (s, 1 H), 8.66 (d, J =
4.7 Hz, 1 H), 8.76 (s, 2 H), 10.20 (s, 2 H). 13C NMR (CDCl3): δ =
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S. N. Georgiades, N. Rizeq
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120.3, 121.5, 124.1, 128.4, 136.7, 138.0, 145.6, 149.7, 152.0,
153.9, 158.1, 191.6. MS (ESI): m/z = 280.06 (calcd 280.07, [M +
H]+).
CD3OD): δ = 114.0, 114.8, 119.9, 123.6, 126.3, 127.5, 131.4,
136.1, 137.2, 146.5, 148.3, 150.1, 152.2, 158.9. MS (ESI): m/z =
358.10 (calcd 358.10, [M + H]+).
(18) Georgiades, S. N.; Clardy, J. Bioorg. Med. Chem. Lett. 2008, 18,
3117.
(19) Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64,
4537.
(22) Data for compound 10: 1H NMR (CDCl3): δ = 7.33 (dd, J1 =7.9, J2 =
4.9 Hz, 1 H), 7.45 (dd, J1 = 7.9, J2 = 4.9 Hz, 2 H), 7.85–7.95 (m,
3 H, overlaid), 7.95 (d, J = 6.5 Hz, 1 H), 7.96 (s, 1 H), 8.08 (s, 2 H),
8.30 (d, J = 7.9 Hz, 2 H), 8.49 (s, 2 H), 8.72 (d, J = 4.9 Hz, 1 H),
8.83 (d, J = 4.1 Hz, 2 H). 13C NMR (CDCl3): δ = 115.1, 120.0, 122.7,
123.6, 125.1, 127.6, 128.8, 136.2, 137.0, 137.2, 145.8, 146.7,
148.3, 149.0, 150.2, 151.2, 152.5, 159.1, 161.2. MS (ESI): m/z =
512.14 (calcd 512.15, [M + H]+).
(20) Leusen, D. V.; Leusen, A. M. V. Synthetic Uses of Tosylmethyl Iso-
cyanide (TosMIC), In Organic Reactions; Vol. 57; Wiley-VCH:
Weinheim, 2004, 417.
(21) Data for compound 8: 1H NMR (CDCl3): δ = 7.31 (t, J = 5.6 Hz,
1 H), 7.83–7.87 (m, 4 H, overlapping), 7.93 (s, 1 H), 8.05 (s, 2 H),
8.26 (s, 2 H), 8.69 (d, J = 4.5 Hz, 1 H). 13C NMR (CDCl3 + trace
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 489–493