Synthesis of a new metal chelating amino acid: Terpyridyl-alanine

Article abstract of DOI:10.1016/j.tetlet.2019.02.037

In past years, terpyridine-containing substances have been found useful in polynucleotide chemistry and enzymatic engineering applications. Therefore, the construction of a noncanonical amino acid with a terpyridine side chain may offer promising features for in vitro and in vivo applications, such as the direct bio-expression of proteins with these substances as building blocks. The first step towards these goals is to establish a synthetic protocol for a terpyridine analog bearing an amino acid moiety. Here, we demonstrate the synthesis of terpyridyl-alanine for the first time in five steps and an overall yield of 50%. A metal complex with Fe(II) ions was prepared by crystallization of a protected terpyridyl-alanine derivative and analyzed by X-ray crystallography. Complex formation in aqueous solution was studied by ¹H-NMR, UV/Vis and fluorescence spectroscopy. The comparison of five transition metal ions revealed a metal dependent shift in the UV-absorption and a strong fluorescence in the presence of Zn(II) ions.

Full text of DOI:10.1016/j.tetlet.2019.02.037

Accepted Manuscript
Synthesis of a new metal chelating amino acid: Terpyridyl-alanine
Tobias Schneider, Ivana Gavrilova, Nediljko Budisa
PII:
S0040-4039(19)30182-0
https://doi.org/10.1016/j.tetlet.2019.02.037
TETL 50631
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
6 December 2018
18 February 2019
21 February 2019
Please cite this article as: Schneider, T., Gavrilova, I., Budisa, N., Synthesis of a new metal chelating amino acid:
Terpyridyl-alanine, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.02.037
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Graphical Abstract
Synthesis of a new metal chelating amino acid:
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Terpyridyl-alanine
Tobias Schneider, Ivana Gavrilova, and Nediljko Budisa

1
Tetrahedron Letters
Synthesis of a new metal chelating amino acid: Terpyridyl-alanine
Tobias Schneidera, Ivana Gavrilovaa, and Nediljko Budisaa,b
aInstitute of Chemistry, Technical University of Berlin, Müller-Breslau-Str. 10, Berlin, 10623, Germany
bDepartment of Chemistry, University of Manitoba, 144 Dysart Rd, 360 Parker Building, R3T 2N2 Winnipeg, MB, Canada
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
In past years, terpyridine-containing substances have been found useful in polynucleotide
chemistry and enzymatic engineering applications. Therefore, the construction of a noncanonical
amino acid with a terpyridine side chain may offer promising features for in vitro and in vivo
applications, such as the direct bio-expression of proteins with these substances as building
blocks. The first step towards these goals is to establish a synthetic protocol for a terpyridine
analog bearing an amino acid moiety. Here, we demonstrate the synthesis of terpyridyl-alanine
for the first time in 5 steps and an overall yield of 50%. A metal complex with Fe(II) ions was
prepared by crystallization of a protected terpyridyl-alanine derivative and analyzed by X-ray
Available online
Keywords:
Amino acids
Terpyridine
Metal complexes
UV/Vis spectra
1
crystallography. Complex formation in aqueous solution was studied by H-NMR, UV/Vis and
fluorescence spectroscopy. The comparison of 5 transition metal ions revealed a metal
dependent shift in the UV-absorption and a strong fluorescence in the presence of Zn(II) ions.
2009 Elsevier Ltd. All rights reserved.
———
 Corresponding author. Tel.: +49-30-314-28960; fax: +49-30-314-28279; e-mail: budisa@chem.tu-berlin.de

2
Tetrahedron
1. Introduction
Terpyridines are a class of nitrogen-containing heterocycles
consisting of three monocyclic pyridine rings. The most
prominent terpyridine is 2,2’:6’,2”-terpyridine (terpy), which has
attracted attention as promising functional moiety, particularly as
tool for introducing many new chemical reactions and functions
into biological systems. For example, the use of terpyridine
derivatives as tridentate ligands for transition metals has been
well documented in numerous studies1. Particular attention was
paid to the catalytic properties of terpyridine-metal complexes
2
especially to Ru(II) complexes , which act as photo- or electro-
catalysts in economically important reactions like water
oxidation3 and CO2 reduction4, artificial photosynthesis5 as well
as in photodynamic therapy6. Additionally, terpy complexes are
often used as a structural unit in the formation of artificial
supramolecular frameworks.7
Figure 2. Genetically encoded amino acids (1-4) and terpyridyl-
alanine (5)
This approach can be extended to terpy as a side chain of
amino acids. The use of the above-mentioned, much-explored
catalytic and functional properties of terpy-complexes in different
protein scaffolds would allow us to expand the toolkit of
genetically encoded amino acids for further applications (e.g.
development of biocompatible catalysis) in complex protein
structures.[25] In addition, it should offer an option to sustainably
alter the chemical composition of whole cells and their structures,
especially those that are not readily available for classical
chemical modifications. The first step in this direction is certainly
the reliable synthetic path for a terpyridine-containing amino
acid. In this context, the aim of this work is to establish a
synthetic protocol for the synthesis of terpyridylalanine (5) to
support further microbiological and cell biological studies.
Figure 1. Applications of terpyridine-metal complexes
Complexes with a large variety of transition metal cations
have been synthesized, some of which can be used as catalysts in
reactions like [3+2]-cycloaddition, cyclopropanations (both
Cu(II)8) and hydrosylilations (Fe(II)9). Furthermore, some
complexes are known for their luminescent properties.10
Many applications of terpyridine-based complexes are found
in (poly)nucleotide chemistry. A terpyridine based Zn(II)
complex has been demonstrated to act as a catalyst for adenosine
triphosphate (ATP) hydrolysis11. Zn-terpy complexes can be used
as detectors for pyrophosphate by change in their fluorescence
spectra.12 Other complexes are potent RNA cleavage13 and DNA
binding agents14. For example, complexes with Ru(II)15 and
Pt(II)16 were used to bind to DNA fragments and enable its
detection due to shifts in their UV/Vis-absorption and
luminescent properties.
2. Results and discussion
To achieve the synthesis of terpyridyl-alanine (5) we
envisioned the following synthetic strategy.
In recent years, numerous studies have exploited terpy
compatibility with biological systems for the production of
artificial metalloenzymes, and remarkable results have been
reported.17 In the course of these experiments a terpy analogue
was incorporated into a protein scaffold by means of strain-
promoted azide-alkyne cycloaddition and was subsequently used
as an enantioselective catalyst.18 However, this method requires
the use of a bulky linker, which might impair the formation of a
defined binding pocket in those proteins.
Scheme 1. Retrosynthetic approach for the synthesis of 5
The amino acid moiety should be constructed by hydrolysis of
the diethylacetamidomalonate group in 6. The introduction of
this group is commonly achieved by nucleophilic substitution,
which requires a leaving group at the 4’-CH2 position. The
leaving group should be installed by conversion of alcohol 7.
Remarkably, we were not able to find a synthetic protocol for this
compound. Therefore, we aimed to produce 7 from by reduction
of acid 8.
An alternative to this approach would be a direct incorporation
by orthogonalized protein translation19, which uses non-canonical
amino acids to directly integrate them into the amino acid
sequence during ribosomal synthesis.20 This approach has a great
advantage of being efficient in living cells (in vivo) and avoids
the use of linkers, as well as post-translational modifications.
Orthogonalized translation has already enabled the in vivo
incorporation of a small number of amino acids with metal
chelating side chains without affecting the vitality and growth of
the host cells. In particular, two derivatives of 8-
hydroxyquinoline (121 and 222), bipyridine (3)23 and a pyrazole
modified tyrosine (4)24 were inserted into various functional
proteins during in vivo biosynthesis.
Carboxylic acid
8 was synthesized according to well
established procedures described in the literature.26 Alkylation to
methyl ester 9 was performed in order to make the subsequent
reduction more facile. The reaction was achieved using

3
SOCl2/MeOH in a good yield. Reduction of 9 to alcohol 7 proved
difficult at first. Attempts with LiAlH4 in THF gave a green
solution, which turned orange during workup and produced
heterogeneous product with no significant amount of 7 present.
Racemic terpyridyl-alanine 5 was then produced by acidic
hydrolysis of 6 (32% HCl, reflux, 4h) and purified by isoelectric
precipitation. The amino acid was produced on a one gram scale
with an overall yield of 50%.
NaBH4 is usually regarded as unsuitable for the reduction of
esters but is known to be able to react with electron deficient
esters.27 Interestingly, under mild conditions NaBH4 in ethanol
only led to transesterification to the ethyl ester 10 (see scheme 2).
Additionally, the synthesis of the enantiomericaly pure (S)-
terpyridyl-alanine was attempted starting from the partial
hydrolysis of 6. Basic hydrolysis of the ethyl esters followed by
decarboxylation under acidic conditions gave racemic N-acetyl
amino acid 13. Unfortunately, enzymatic resolution of this
compound with acylase I from A. melleus and porcine kidney
acylase was unsuccessful.
Scheme 2. Reagents & conditions (a) NaBH4 (1 equiv), EtOH,
57%
Scheme 4. Reagents & conditions (a) KOH, EtOH, H2O, not
isolated (b) 0.2 M HCl, 62%, (c) amino acylases, H2O (pH 8)
Refluxing 9 with 3 equiv. NaBH4 in EtOH for several hours
led to partial conversion to alcohol 7, while addition of LiCl to
the mixture proved to be superior, producing alcohol 7 in
excellent yields (Scheme 3).
Possibly, the binding pocket of these enzymes might be
simply unsuitable for compound 13. However, amino acylases
are known to use metal cofactors (usually Zn2+) and to be
inhibited by metal-chelating agents.29 Nonetheless, even the
addition of 0.5, 1 and 2 equiv. of ZnBr2 into the reaction mixture
did not improve enzyme activity.
PBr3 was then used to convert alcohol 7 to bromide 11. When
anhydrous DCM was used as a solvent the reaction mixture
turned blue and precipitation was observed. The desired product
was detected after workup, albeit in a low yield (< 30%). The
addition of water to the reaction mixture significantly improved
this result and gave bromide 11 in a good yield of 83%. Addition
of water produces HBr in the mixture due to its reaction with
PBr3. This will lead to the protonation of the nitrogen atoms in 7.
We suspect that this is necessary to suppress nucleophilic
substitution on the freshly produced bromide. Therefore,
insufficient amounts of acid will lead to multimers with N-alkyl-
pyridinium units. These are known to show absorbance in the
visible part of the electromagnetic spectrum28, which would
explain our observation of a deep blue color.
The solubility of racemic terpyridyl alanine in water is
relatively low; we determined the value of 56±8 µmol/L at pH 7.
However, the solubility can be greatly increased by addition of
acid or base, as well as suitable transition metal ions like Fe(II)
or Ni(II) as a result of complex formation.
In
addition,
we
have
synthesized
rac-N-
acetyltepyridylalanine-methylester 14 to perform crystallization
of this compound with a small number of transition metal salts.
Acetyl and methyl protective groups at the amino acid moiety
were installed to suppress its metal complexation and to create a
peptide-like environment. We were able to obtain X-ray
crystallographic data from crystals of 14 and of 14 with Fe(II)
ions.
In the next step of our planned strategy, the reaction of
bromide 11 with diethyl acetamidomalonate proceeded as
anticipated to give compound 6 in a good yield (Scheme 3).
Single crystals of this compound were prepared and analyzed
using X-ray crystallography and confirmed our presumed
structure (See supporting information).
Scheme 5. Reagents & conditions (a) SOCl2, MeOH, 59% (b)
Metal salts, H2O/MeCN
Scheme 3. Reagents & conditions (a) SOCl2, MeOH, 89%; (b)
NaBH4, LiCl, EtOH, 96%; (c) PBr3, H2O, DCM, 83%; (d) Diethyl
acetamidomalonate, NaH, DMF, 79% (e) 32% HCl, 90%

4
Tetrahedron
Scheme 6. Subsequent formation of [(14)2-Zn]2+ and [(14)-Zn]2+
by addition of Zn(II) ions.
Equivalents of Zn(II)
Compound
0.2
61% 20%
0% 0%
0.4
0.5
0%
0%
0.6
0%
0.8
0%
1.0
0%
1.5
0%
Free 14
[(14)Zn]2
10% 22% 31% 39%
[(14)2Zn]2+ 39% 80% 100% 90% 78% 69% 61%
Table 1. Relative signal intensity of 14 in unbound state, bound in
[(14)Zn]2+and [(14)2Zn]2+ with increasing concentration of Zn(II)
1
ions determined by H-NMR spectroscopy in a 1:1 D2O:MeCN-d3
mixture. This data is consistent with previous values collected for
other terpyridines.[30]
Figure 3. X-ray crystal structures for compound 14 A) and its
Fe(II) complex (B). Carbon – grey; hydrogen – white; oxygen –
red; nitrogen – blue; iron – brown. Sulfate (counter ion) and
solvent molecules are not shown in B.
We recorded UV/Vis spectra of 5 and 14 with a small
selection of transition metal ions to study the optical properties of
the formed complexes. Previous studies reported a metal
dependent absorbance of terpyridine complexes31, which was
fully confirmed in our experiments as well.
Co-crystallization of 14 with FeSO4 ∙ 7 H2O led to dark red
needles. As expected, a mononuclear bis complex was formed;
the Fe(II) atom is coordinated by a distorted octahedral
arrangement of six nitrogen atoms from two terpyridyl side
chains. Additionally, we obtained light-brown needles when we
co-crystallized 14 with Ni(NO3)2 ∙ 6 H2O or Co(NO3)2 ∙ 6 H2O.
The general structure of those complexes is very similar to the
Fe(II) complex. However, their structures were not completely
resolved (see supporting information).
We followed the stepwise addition of Zn(II) into a solution of
14 by 1H-NMR spectroscopy. When less than 0.5 equiv. of Zn(II)
were added, new signals for the bis complex ([(14)2Zn]2+) were
detected without concurrent observation of signals for a mono-
complex([(14)Zn]2+). When more than 0.5 equiv. of Zn(II) were
added, a set of signals for a mono-complex emerged and gained
intensity with rising Zn(II) concentration. This assignment was
further affirmed by additional DOSY experiments. The relative
signal intensity of 14, [(14)Zn]2+ and [(14)2Zn]2+ with varying
Zn(II)-concentration is shown in table 1.

5
experiments, which is required to form a bis complex, can be
attributed to the lower absolute concentration, which disfavors
1
complex assembly (50 µM in UV/Vis vs. 2.2 mM in H-NMR).
A further increase in concentration did not significantly alter the
absorption curves, which suggests that the absorption profiles of
[(14)Zn]2+and [(14)2Zn]2+ are fairly similar. Fe(II) and Hg(II)
showed an analogous behavior to Zn(II), while Ni(II) absorption
profiles already seized to change when a 25µM concentration
was reached. However, for Cu(II), this process took up to 50µM
(for more information see SI). All measurements were also
performed with 5 and gave similar results.
Figure 5. UV/Vis absorbance spectra of compound 14 with
varying concentration of Zn(II) ions. Spectra show no significant
changes after a Zn(II) concentration of 30 µM is exceeded.
Figure 4. UV/Vis absorbance spectra of compound 14 alone and
with addition of 5 transition metal ions recorded in 50/50 (v %)
MeCN/aqueous phosphate buffer (pH 7). Ligand and metal ion
concentration = 5∙10-5 mol/L. (A) Spectrum from 200 nm - 700 nm
(B) Enlarged section between 250 nm - 350 nm
We also found that samples of 5 and 14 show fluorescent
properties when Zn(II) ions are added, which has been reported
for other types of terpyridines as well.[12] This property could be
of particular importance for noninvasive biological imaging in
various microscopic settings. In particular, when exited at
275 nm, emission-maxima were detected at 342 and 355 nm. On
the other hand, no fluorescence was observed for other metal ions
under the identical experimental conditions. However, addition
of Cu(II) ions to a solution of 5 and Zn(II) instantly led to a
complete suppression of fluorescence. When Ni(II) was added
instead of Cu(II), the fluorescence decreased at a slower pace,
resulting in complete suppression after 1 hour.
Addition of Fe(II) ions produced a deep purple color with a
maximum absorption in the visible region at 555 nm (see figure 4
A), which is a well described reaction of terpyridines with Fe(II)
ions and has been used for the colorimetric detection of ferrous-
ions.32 The addition of Ni(II), Cu(II), Zn(II) and Hg(II) did not
lead to absorbance in the visible region. However, in contrast to
the free ligand, they exhibit one or multiple local absorbance
maxima between 310 nm and 340 nm (See figure 4 B). For a
given metal, the wavelength of these maxima was identical for
compounds 14 and 5 (see supporting information). Metal specific
shifts in absorbance were also observed in the spectral regions
below 310 nm.
The recording of UV/Vis spectra with different metal:ligand
ratios enabled us to qualitatively follow the complex formation
by observing the gradual change in the absorbance profile. The
concentration of 14 was held fixed at 50 µM, while the
concentration of metal ions was raised progressively. We found
that spectra with all metal cations continued to change from 0
µM to 25 µM. For Zn(II), there was only little change associated
with the addition of more metal salt, which suggests the complete
formation of a bis complex at a 2:1 ratio in solution (see Figure
5), which is consistent with our 1H-NMR experiments. The
slightly higher ratio of Zn(II) ions to 14 in the UV/Vis

6
Tetrahedron
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1
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Declarations of interest: none

7
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8
Tetrahedron
Tetrahedron Letters
Synthesis of a new metal chelating amino
acid: Terpyridyl-alanine
Tobias Schneidera, Ivana Gavrilovaa, and Nediljko
Budisaa,b
aInstitute of Chemistry, Technical University of Berlin, Müller-Breslau-Str.
10, Berlin, 10623, Germany
bDepartment of Chemistry, University of Manitoba, 144 Dysart Rd, 360
Parker Building, R3T 2N2 Winnipeg, MB, Canada
Highlights:
Terpyridine-containing compounds have higher
compatibility with living cells
Amino acids with terpyridine side chains are
potentially useful tools for the design of
metalloenzymes
Reliable synthesis of terpyridyl-alanine for the
first time in 5 steps and an overall yield of 50%
is achieved
Various terpyridyl-alanine metal complexes are
analyzed structurally and spectroscopically
———
 Corresponding author. Tel.: +49-30-314-28960; fax: +49-30-314-
28279; e-mail: budisa@chem.tu-berlin.de