An Organometallic Isostere of an Amino Acid

Article abstract of DOI:10.1021/acs.inorgchem.1c01444

An organometallic complex that mimics an amino acid, also known as an amino acid isostere, can be synthesized from a functionalized bipyridine ligand and a fac-[Re(CO)3]+ center. The reaction of an achiral ligand and metal results in a racemic mixture of

Full text of DOI:10.1021/acs.inorgchem.1c01444

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An Organometallic Isostere of an Amino Acid
Sanjay Gaire, Briana R. Schrage, and Christopher J. Ziegler*
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ABSTRACT: An organometallic complex that mimics an amino acid, also known as an amino acid isostere, can be synthesized from
a functionalized bipyridine ligand and a fac-[Re(CO)3]+ center. The reaction of an achiral ligand and metal results in a racemic
mixture of chiral-at-metal complexes. These metal species have amine and carboxy termini, a side chain type unit that can be varied,
as well as the chiral metal that is analogous to the α carbon of an amino acid. The racemic mixtures can be separated into
enantiomers by chiral chromatography, and the metal complexes can be incorporated into peptides by using solid-phase peptide
synthesis.
Scheme 1. Representation of an Amino Acid (Top Left) and
Isostere Molecule (Top Right). Synthesis of 2a, 2b, 3a, 3b,
4a, and 4b (Bottom)
hiral organometallic complexes are commonly used in
1−6
Capplications ranging from organic synthesis
to
medicinal inorganic chemistry.7−9 Chirality in organometallics
is typically achieved by incorporation of a chiral ligand at a
metal center.10−12 However, transition metal complexes can be
chiral at the metal itself, but this chemistry has not been
expansively investigated.13−19 Rhenium tricarbonyl compounds
can be chiral-at-metal in the presence of asymmetric
coordination geometries, but to date, such chemistry has also
not been explored.20,21 We hypothesized that we could make a
chiral-at-metal fac-Re(CO)3 complex using a simple synthetic
protocol and the resultant compound would act as an isostere
of an amino acid. In this report, we present a strategy for the
straightforward synthesis of fac-Re(CO)3 amino acid isosteres
using a simple bipyridine chelate. Produced from achiral
starting materials, the resultant racemic mixtures can be
separated into enantiomers by chiral chromatography. Addi-
tionally, the complexes can be incorporated into peptides via
solid-phase peptide synthetic methods.
Metal complexes that contain the fac-[Re(CO)3]+ unit and
either three different additional ligands or an asymmetric
chelate are chiral at the metal center.22 In such cases, the
geometry can be considered analogous to a sp3 carbon atom
with different substituents, as shown in Scheme 1.
version, and an fmoc modified system for solid-phase peptide
synthesis.26,29 All three of these ligands react readily with
Re(CO)5X where X = Cl, Br to afford fac-Re(aa-bpy)(CO)3X
complexes. We fully characterized these products, including via
single-crystal X-ray diffraction (Figure 1), and all products are
racemic mixtures. The coordination environments are as
expected for fac-Re(bpy)(CO)3X complexes, which are well-
known in the literature.31,32 In addition to the structures, we
obtained spectroscopic and mass spectrometric data which are
typical for rhenium(I) tricarbonyl compounds. These com-
pounds exhibit distinct spectroscopic features including UV−
This led us to hypothesize that we could use fac-[Re(CO)3]+
to fabricate an isostere, or structural and functional analogue,
of an amino acid.23−25 In such a structure, a bidentate ligand
could incorporate the amine and carboxy termini and the
remaining group of the metal (either a halide or nitrogenous
base) could be considered as the R group. The tricarbonyl unit
would then be structurally equivalent to the α-hydrogen atom
position and the metal as the α-carbon analogue. Using a
similar arrangement as in an amino acid, we can assign the
orientation shown in Scheme 1 as the isostere of an L isomer.
We decided to use 2,2′-bipyridine as our scaffold; a 4,4′-
substituted analogue (amino acid bipyridine, or aa-bpy) can be
readily synthesized as shown in Scheme 1 (the ligand synthesis
scheme is shown in the SI).26−30 We have synthesized three
variants of this ligand: a protected version, a deprotected
Received: May 12, 2021
Published: July 7, 2021
https://doi.org/10.1021/acs.inorgchem.1c01444
© 2021 American Chemical Society
Inorg. Chem. 2021, 60, 10105−10108
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Figure 1. Structures of rac-2a (left), rac-3a (middle), and rac- 4a (right). Hydrogen atoms on the carbon atom positions have been omitted for
clarity.
Figure 2. Chiral HPLC chromatographic separation of compound 2a (inset); CD spectroscopy of the two enantiomers was carried out in DMF.
vis bands due to metal-to-ligand charge transfer transitions and
intense bands between 1885 and 2025 cm−1 in their IR spectra
from carbonyl stretching frequencies.
we hypothesized that we could resolve a racemic tripeptide
mixture using the rhenium center alone. Upon cleavage from
the resin, we purified the peptide using reverse-phase HPLC
and then again by chiral HPLC. As shown in Figure 3, the two
enantiomers were separated via the chirality at the metal, and
we identified the products by high-resolution mass spectrom-
To isolate the “L” isomer of these organometallic isostere
compounds, we turned to chiral chromatography. Using an
HPLC equipped with a 5 μm CHIRALPAK IE (Daicel)
column with a solvent mixture of 60%/40%/0.1%/0.1% n-
hexane/ethanol/trifluoroacetic acid/diethylamine v/v/v, we
were able to separate the two enantiomers for both halide
analogues. Figure 2 shows the chromatograph for the chloride
substituted mixture; the column provides good separation of
the two enantiomers, with the L isomer coming off first. To
confirm separation, we collected circular dichroism spectra of
the two fractions for the chloride substituted species, also
shown in Figure 2. The metal-to-ligand charge transfer bands
are affected by the chiral center for the two enantiomers, and
each one exhibits opposite dichroic behavior as expected. We
were able to carry out the same separation with the bromide
variant, and identical CD spectra were observed for the two
fractions (Supporting Information). After separation, the
enantiomers were stereostable for days in solution.
To probe the utility of these organometallic isosteres, we
decided to incorporate the isostere fac-[Re(bpy)(CO)3]Cl into
a simple tripeptide using solid-phase peptide synthesis (SPPS)
methods.20,33 Using a Rink amide resin with the HBTU
coupling/Fmoc protection strategy, we constructed a gly-
Re(aa-bpy)(CO)3X-gly tripeptide. We chose glycine because
Figure 3. Structure of tripeptide gly-Re(aa-bpy)(CO)3X-gly (top);
chromatographic separation of the two enantiomers (inset) and mass
spectrum of tripeptide.
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etry. The inert fac-[Re(CO)3]+ center is resilient to the
coupling and cleavage conditions of SPPS.
uronium hexafluorophosphate; HPLC, high-performance
liquid chromatography; Fmoc, fluorenylmethyloxycarbonyl
In conclusion, we have synthesized an organometallic
isostere of an amino acid. By using an amine and carboxy
modified bipyridine, we can generate racemic mixtures of fac-
Re(aa-bpy)(CO)3X complexes, which feature a chiral-at-metal
center and a modifiable R group in the form of the halide. We
can separate out the enantiomers, which exhibit dichroism in
their metal-to-ligand charge transfer transitions. Additionally,
we can incorporate these organometallic units into polypep-
tides using SPPS methods. Peptides have long been modified
at the periphery using organometallic units such as fac-
[Re(CO)3]+; in this examples, we can place the metal center in
an α-carbon type position in a peptide backbone. We are
currently modifying these compounds to explore the synthetic
space of the sixth position (the “side chain” group) of our fac-
Re(aa-bpy)(CO)3X complexes.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.inorgchem.1c01444.
■
sı
General information, syntheses, high-resolution ESI
mass spectra, NMR spectra, enantiomeric separation,
CD spectra, X-ray crystal data and structure parameters
(PDF)
Accession Codes
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AUTHOR INFORMATION
Corresponding Author
Christopher J. Ziegler − Department of Chemistry, University
of Akron, Akron, Ohio 44312-3601, United States;
orcid.org/0000-0002-0142-5161; Email: ziegler@
uakron.edu
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Sanjay Gaire − Department of Chemistry, University of Akron,
Akron, Ohio 44312-3601, United States
Briana R. Schrage − Department of Chemistry, University of
Akron, Akron, Ohio 44312-3601, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.inorgchem.1c01444
Funding
National Institutes of Health (1R15GM119030).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
C.Z. acknowledges the National Institute of Health
(1R15GM119030) for funding this research.
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ABBREVIATIONS
CD, circular dichroism; SPPS, solid-phase peptide synthesis;
HBTU, N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)-
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