New ligands bearing chiral bioactive fragments.

Article abstract of DOI:10.1021/ol010058y

[see reaction]. Reliable and practical synthetic routes for the construction of hybrid molecules bearing both a chelating center and a useful biofunction are presented. They comprise the sequential cross-coupling reaction between ethynylated synthons with

Full text of DOI:10.1021/ol010058y

ORGANIC
LETTERS
2001
Vol. 3, No. 12
1857-1860
New Ligands Bearing Chiral Bioactive
Fragments
Abderrahim Khatyr and Raymond Ziessel*
Laboratoire de Chimie, d’Electronique et de Photonique Mole´culaires, Associe´ au
CNRS ESA-7008, Ecole de Chimie, Polyme`res, Mate´riaux de Strasbourg (ECPM), 25
rue Becquerel, 67087 Strasbourg Cedex 02, France
ziessel@chimie.u-strasbg.fr
Received March 30, 2001
ABSTRACT
Reliable and practical synthetic routes for the construction of hybrid molecules bearing both a chelating center and a useful biofunction are
presented. They comprise the sequential cross-coupling reaction between ethynylated synthons with iodo-substituted L-tyrosine derivatives
and provide access to various rationally designed chiral ligands.
For the past three decades, there has been a steady and
progressive interest in the synthesis of oligopyridines, and
an impressive number of such substances are now known.1-3
The interest in the synthesis of metal complexes has driven
research into finding new and improved oligopyridines, and
such complexes figure prominently in historical accounts of
both coordination and analytical chemistry.2 More recently,
metal oligopyridines have been used to construct exotic
molecular architectures,4 to sensitize photoelectrochemical
cells,5 to label biomaterials,6 as the basis for selective
sensors,7 and as magnetic materials.8 In the future oligo-
pyridines will be used in even more applications, especially
as material scientists seek to develop miniaturized devices.9
We have previously argued the case that alkynylated
oligopyridines endow certain metal complexes with special
properties, and this claim is the result of a determined and
sustained effort to produce a comprehensive catalog of
suitably derivatized compounds.2,10 In extrapolating that work
to ligands bearing chiral fragments, the palladium(0)-
catalyzed cross-coupling reaction was utilized as a method
of carbon-carbon bond formation because of the ready
availability of the precursors and the minimal number of side
reactions that occur when a Sonogashira-Hagihara approach
is used.11-13
In the present Letter, we outline a synthetic strategy for
(9) Reed, M. A.; Zhou, C.; Muller, C. J.; Burgin, T. P.; Tour, J. M.
Science 1997, 278, 252. Collier, C. P.; Wong, E. W.; Belohradsky, M.;
Raymo, F. M.; Stoddart, J. F.; Kuekes, P. J.; Williams, R. S.; Heath, J. R.
Science 1999, 285, 391. Collier, C. P.; Mattersteig, G.; Wong, E. W.; Luo,
Y.; Kristen, K.; Sampaio, J.; Raymo, F. M.; Stoddart, J. F.; Heath, J. R.
Science 2000, 289, 1172. Gittins, D.; Bethell, D.; Schiffrin, D. J.; Nichols,
R. J. Nature 2000, 408, 67.
(10) Ziessel, R. J. Chem. Educ. 1997, 74, 673. Harriman, A.; Ziessel,
R. Coord. Chem. ReV. 1998, 171, 331 and references therein.
(11) Sonogashira, K. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, L., Paquette, L. A., Eds.; Pergamon Press: Oxford, 1990; Vol. 3,
pp 545-547.
(1) Munakata, M.; Wu, L. P.; Kuroda-Sowa, T. AdV. Inorg. Chem. 1999,
46, 173.
(2) Ziessel, R. Synthesis 1999, 1839.
(3) Thummel, R. P.; Chamchoumis, C. M. AdV. Nitrogen Heterocycles
2000, 4, 107.
(4) Tschierske, C. Angew. Chem., Int. Ed. 2000, 39, 2454.
(5) Hagfeldt, A.; Gra¨tzel, M. Acc. Chem. Res. 2000, 33, 269.
(6) Evangelista, R. A.; Pollak, A.; Allore, B.; Templeton, E. F.; Morton,
R. C.; Diamandis, E. P. Clin. Biochem. 1988, 21, 173.
(7) Ziessel, R. J. Incl. Phenom. Macro. Chem. 1999, 35, 369.
(8) Ziessel, R. Mol. Cryst. Liq. Cryst. 1995, 273, 101.
10.1021/ol010058y CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/24/2001

the grafting of one or two chiral L-tyrosine fragments to a
variety of different oligopyridines via ethynyl spacers. The
choice of tyrosine as biofragment reflects the thinking that
it would act as an efficient electron relay in model systems,
mimicking the natural water oxidation machinery, but also
act as a possible anchor for binding to oligopeptides or
oligonucleotides.14-16 In natural photosynthesis, light absorp-
tion drives electron transfer from water to carbon dioxide,
producing atmospheric oxygen and providing the biosphere
with an inexhaustible amount of reducing power. Light-
driven oxidation of water is catayzed by a reaction center,
the so-called photosystem II (PS II), which is composed of
arrays of chlorophyll molecules (e.g., P680), electron acceptors
(quinones), and donors (tyrosines). In brief, the oxidized P680
retrieves an electron by oxidation of a nearby tyrosine residue
which then forms a neutral radical. This radical in its turn
oxidizes a tetranuclear Mn cluster bound to PS II. After four
consecutive turnovers, two water molecules are oxidized and
one oxygen molecule is produced. In short, one of the key
steps is the electron-transfer retrieval from the tyrosine.
The aim of the present work is to construct artificial
systems able to mimic part of the electron-transfer reaction
in PS II. The synthetic routes have been adapted to ensure
that various protecting groups, such as benzoyl, can be
attached either to the amine or to the amine and phenol
fragments and to provide a means by which to tune the
electron-transfer process in subsequent photophysical experi-
ments.
temperature conditions. The synthesis of 1 requires special
conditions and is prone to low yield in the presence of an
excess of acid chloride or base as well as at higher
temperature. Indeed, the diprotected compound 2 is prepared
with 2 equiv of benzoyl chloride and excess base. The
tyrosine-grafted monotopic bipy and terpy ligands 3a/b and
4a/b are readily synthesized via a Sonogashira-Hagihara
cross-coupling reaction between respectively 4′-ethynyl-
2,2′:6′,6′′-terpyridine18 and 5-ethynyl-2,2′-bipyridine18 and
iodo-functionalized L-tyrosine compound 1 or 2 (Scheme 2).
Scheme 2a
Access to this family of ligands requires the synthesis of
the key building blocks 1 and 2, which have been prepared
from the esterified tyrosine salt17 (Scheme 1), using a
methodology commonly and widely used in amino acid/
peptide chemistry.
Scheme 1a
a (a) 4′-Ethynyl-2,2′:6′,6′′-terpyridine (1 equiv), [Pd(PPh3)2Cl2]
(6 mol %), CuI (6 mol %), THF, iPr2NH, rt, 42% for 3a and 49%
for 3b; (b) 5-ethynyl-2,2′-bipyridine (1 equiv), [Pd(PPh3)2Cl2] (6
mol %), CuI (6 mol %), THF, iPr2NH, rt, 57% for 4a and 60% for
4b.
This is a convenient and versatile method for the connec-
tion step because of the required mild conditions and the
tolerance of various functions such as an amide, an ester,
and/or a phenol. In fact, the Pd(0) catalyst precursor was
prepared in situ from Pd(II) and Cu(I) salts and a large excess
of a secondary base was needed to quench the nascent acid.
It was soon established that the phenol-protected tyrosine
derivative 2 also reacted smoothly under similar conditions
(12) Ziessel, R.; Suffert, J.; Youinou, M.-T. J. Org. Chem. 1996, 61,
6535.
(13) Tour, J. M. Chem. ReV. 1996, 96, 537 and references therein.
(14) Barber, J.; Andersson, B. Nature 1994, 370, 31 and references
therein.
a (a) Benzoyl chloride (1 equiv), triethylamine (2 equiv), rt, 89%;
(b) benzoyl chloride (2 equiv), triethylamine (6 equiv), rt, 73%.
(15) Magnuson, A.; Berglund, H.; Korall, P.; Hammarstro¨m, L.; Aker-
mark, B.; Styring, S.; Sun, L. J. Am. Chem. Soc. 1997, 119, 10720.
(16) Hurley, D. J.; Tor, Y. J. Am. Chem. Soc. 1998, 120, 2194.
(17) Jung, M. E.; Rohloff, J. C. J. Org. Chem. 1985, 50, 4909.
(18) Grosshenny, V.; Romero, F. M.; Ziessel, R. J. Org. Chem. 1997,
62, 1491.
Quite selective formation of the amide-protected com-
pound 1 could be achieved in the presence of 2 equiv of
base and equimolar amounts of benzoyl chloride under mild
1858
Org. Lett., Vol. 3, No. 12, 2001

with the bipy- and terpy-alkyne functionalized cores provid-
ing ligands 3b and 4b in acceptable yields (Scheme 2). It is
worth noting that these doubly protected compounds are also
conveniently prepared from derivatives 3a and 4a by reaction
of benzoyl chloride in excess triethylamine. Molecules 3b
and 4b will be important test compounds in subsequent
photophysical experiments in which electron transfer from
the phenolic moiety to, for example, a ruthenium triplet
excited state is expected to be strongly inhibited in contrast
to the related derivatives 3a and 4a.
Consequently, the success achieved in the palladium-
catalyzed coupling reaction with tyrosine fragments prompted
us to investigate the functionalization of dibromo-substituted
starting materials. The synthesis of the chiral di-tyrosine
ligands 5 and 6 could be achieved in good yields under
similar conditions starting respectively from 5,5′-diethynyl-
2,2′-bipyridine18 and 2′′,6-diethynyl-2,2′:6′,6′′-terpyridine
(Scheme 3).
The diethynyl-terpy building block is prepared by taking
advantage of well-established protocols18 from 2′′,6-dibromo-
2,2′:6′,6′′-terpyridine19 and propargylic alcohol. The resulting
2′′,6-diethynyl-2,2′:6′,6′′-terpyridine (70%) is completely
deprotected in refluxing toluene under basic conditions
(NaOH pellets), affording the bis-terminal alkyne in good
yield (89%). It is worth pointing out that quite selective
monodeprotection could be provided by varying the experi-
mental procedure. According to previous observations with
1,4-(2-methyl-3-butyn-2-ol)-2,5-didodecyloxybenzene,20 se-
lective monodeprotection was achieved by heating the
reaction to reflux in benzene under basic conditions for
relatively short reaction times. During the grafting of the
tyrosine residue, the formation of a side product assigned as
the monosubstituted derivatives could not be prevented
entirely despite varying the experimental conditions, includ-
ing a large excess of derivatives 1 or 2. It is surmized that
the deactivation of the Pd catalyst is possibly due to chelation
of the polypyridine fragment to the metal center, a process
which had not been envisaged in previous experiments. One
other possibility is that the coupling of one tyrosine residue
to the bipy or terpy skeleton deactivates the compound with
respect to further reaction. It is worth pointing out that
addition of another 6 mol % of [Pd(PPh3)2Cl2] and CuI during
the course of the reaction does not significantly improve the
final yields of the target derivatives.
Scheme 3a
A further synthetic application of the present reaction is
demonstrated by the cross-coupling reaction of the pivotal
intermediates 1 and 2 with the ethynyl-functionalized ditopic
module 7, itself prepared by a multistep and linear procedure
from 5,5′-dibromo-2,2′-bipyridine and 5-ethynyl-2,2′-bipy-
ridine (Scheme 4).21
Scheme 4a
a (a) 2′′,6-Dibromo-2,2′:6′,6′′-terpyridine, HCtC(CH3)2OH (2.5
equiv), [Pd0(PPh3)4] (6 mol %), PrNH2, 60 °C, 70%; (b) NaOH
(excess), toluene, 100 °C, 89%; (c) 2′′,6-diethynyl-2,2′:6′,6′′-
n
i
a (a) [Pd(PPh3)4] (6 mol %), benzene, Pr2NH, 80 °C, 74%; (b)
terpyridine (0.5 equiv), [Pd(PPh3)2Cl2] (6 mol %), CuI (6 mol %),
THF, Pr2NH, rt, 70% for 5a and 72% for 5b; (d) 5,5′-diethynyl-
TMSCtCH, [Pd(PPh3)2Cl2] (6 mol %), CuI (10 mol %), THF,
i
iPr2NH, rt, 60%; (c) K2CO3, CH3OH, rt, 89%; (d) 1 or 2 (1 equiv),
i
2,2′-bipyridine (0.5 quiv), [Pd(PPh3)2Cl2] (6 mol %), CuI (6 mol
[Pd(PPh3)2Cl2] (6 mol %), CuI (6 mol %), THF, Pr2NH, rt, 49%
i
%), THF, Pr2NH, rt, 76% for 6a and 74% for 6b.
for 8a and 50% for 8b.
Org. Lett., Vol. 3, No. 12, 2001
1859

Here, the relatively low yields of the final coupling
reaction providing compounds 8a/b could be due to the
sparingly soluble ethynyl starting material and/or to the
presence of a strong σ-withdrawing effect22 of the alkyne
spacer spanning the two bipy modules. Complexation of both
bipy subunits in ligands 8a and 8b will increase the charge
density of the luminophoric label (4+ vs 2+ for the others
derivatives), and it is anticipated that interaction with
anionically charged microstructures such as DNA, micelles,
dendrimers, or polyelectrolytes will be significantly strength-
ened.23
to the ruthenium triplet excited state. It is forseen that the
triple bond will serve as an efficient conduit for channelling
the electron. The development of these new chiral photo-
sensitizers would expand the opportunities for applications
in the field of sensors and bioactive chromophores. The study
of these scaffoldings is currently underway, and the results
will be disclosed in the near future.
Acknowledgment. This work was supported by the
Centre National de la Recherche Scientifique and by the
Engineering School of Chemistry (ECPM). We thank Dr.
Muriel Hissler for many helpful discussions and advice
concerning the synthesis of the ditopic ligand and Dr. Lo¨ıc
Charbonnie`re for a critical reading of the present manuscript.
The next phase of this work is to complex the empty
coordination sites with ruthenium(II) precursors and to study
the efficiency of electron transfer from the tyrosine moieties
(19) Burstall, F. H. J. Chem. Soc. 1938, 1662. Uchida, Y.; Okabe, M.;
Kobayashi, H.; Oae, S. Synthesis 1995, 939.
(20) Khatyr, A.; Ziessel, R. J. Org. Chem. 2000, 65, 3126.
(21) Khatyr, A.; Ziessel, R. J. Org. Chem. 2000, 65, 7814.
(22) Eastmond, R.; Johson, T. R.; Walton, D. R. M.J. Organomet. Chem.
1973, 50, 87.
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(23) Turo, N. J.; Barton, J. K.; Tomalia, D. A. Acc. Chem. Res. 1991,
24, 332 and references therein.
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