Rhodium(I) and Iridium(I) N-Heterocyclic carbene complexes of imidazolium functionalized amino acids and peptides

Article abstract of DOI:10.1016/j.jorganchem.2019.121096

The conjugation of organometallic complexes to peptides is generally achieved through covalent organic linkages of the metal's ligand to the peptide. Examples of direct coordination to metal centers by amino acid side chain residues remain rare. In one such example, side chain methylation of the natural amino acid histidine (His) resulted in an imidazolium functionalized amino acid which was used for the synthesis of rhodium(I), iridium(I), iridium(III), palladium(II) and ruthenium(III) N-heterocyclic carbene (NHC) complexes of the single amino acid and peptides containing this amino acid. Here, we have synthesized two new, non-natural imidazolium functionalized amino acid derivatives, which were used for solid phase peptide synthesis and for the synthesis of [M(COD)(NHC)Cl] (COD = 1,5 cyclooctadiene) complexes of Rh(I) and Ir(I). In total, six new complexes of the single amino acids and four complexes where the amino acids are present in a peptide environment were synthesized. Their characterization provides convincing evidence of conversion of the imidazolium moiety to an NHC ligand and thus the presence of a direct metal-carbon bond between the metal center and the amino acid side chain. Therefore, our compounds represent unique examples of peptide-conjugated complexes that bear the potential to be used for the synthesis of N-heterocyclic carbene complexes conjugated to cancer cell targeting peptides.

Full text of DOI:10.1016/j.jorganchem.2019.121096

Journal Pre-proof
Rhodium(I) and Iridium(I) N-Heterocyclic carbene complexes of imidazolium
functionalized amino acids and peptides
Isabelle Marie Daubit, Jonas Wolf, Nils Metzler-Nolte
PII:
S0022-328X(19)30539-X
DOI:
https://doi.org/10.1016/j.jorganchem.2019.121096
JOM 121096
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 1 November 2019
Revised Date: 20 December 2019
Accepted Date: 21 December 2019
Please cite this article as: I.M. Daubit, J. Wolf, N. Metzler-Nolte, Rhodium(I) and Iridium(I) N-Heterocyclic
carbene complexes of imidazolium functionalized amino acids and peptides, Journal of Organometallic
Chemistry (2020), doi: https://doi.org/10.1016/j.jorganchem.2019.121096.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition
of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of
record. This version will undergo additional copyediting, typesetting and review before it is published
in its final form, but we are providing this version to give early visibility of the article. Please note that,
during the production process, errors may be discovered which could affect the content, and all legal
disclaimers that apply to the journal pertain.
©
2019 Published by Elsevier B.V.

Rhodium(I) and Iridium(I) N-Heterocyclic Carbene Complexes of
Imidazolium Functionalized Amino Acids and Peptides
a
a
a
Isabelle Marie Daubit , Jonas Wolf and Nils-Metzler-Nolte *
Keywords: Bioorganometallic Chemistry, Iridium, Metal Peptide Bioconjugates, Non-natural
amino acids, N-heterocyclic carbene complexes, Rhodium
Abstract
The conjugation of organometallic complexes to peptides is generally achieved through covalent
organic linkages of the metal’s ligand to the peptide. Examples of direct coordination to metal
centers by amino acid side chain residues remain rare. In one such example, side chain
methylation of the natural amino acid histidine (His) resulted in an imidazolium functionalized
amino acid which was used for the synthesis of rhodium(I), iridium(I), iridium(III), palladium(II)
and ruthenium(III) N-heterocyclic carbene (NHC) complexes of the single amino acid and
peptides containing this amino acid. Here, we have synthesized two new, non-natural
imidazolium functionalized amino acid derivatives, which were used for solid phase peptide
synthesis and for the synthesis of [M(COD)(NHC)Cl] (COD=1,5 cyclooctadiene) complexes of Rh(I)
and Ir(I). In total, six new complexes of the single amino acids and four complexes where the amino acids
are present in a peptide environment were synthesized. Their characterization provides convincing
evidence of conversion of the imidazolium moiety to an NHC ligand and thus the presence of a direct
metal-carbon bond between the metal center and the amino acid side chain. Thus, our compounds
represent unique examples of peptide-conjugated complexes that bear the potential to be used for
the synthesis of N-heterocyclic carbene complexes conjugated to cancer cell targeting peptides.
1

Introduction
The discovery of cisplatin inspired the widespread investigation of metal complexes as potential
anti-cancer drug candidates. For a long time, research in this area was limited to metal complexes
without direct metal-carbon bonds, as they were considered too sensitive to oxygen and moisture
to be suitable for an application in biological systems. However, recent advances in the field have
shown a wide range of complexes suitable for this purpose, leading to the birth of medicinal
[
1]
organometallic chemistry. Organometallic complexes of iridium and rhodium were identified as
[
2]
potential anti-cancer compounds as early as 1978. Although in these first examples the
complexes contained a metal center in the oxidation state +I, most of the recently investigated
examples with these late group 8 metals comprise the metal center in the oxidation state +III, as
[
3-8]
these compounds are considered more stable than their lower oxidation state analogues.
A
class of organometallic compounds of rhodium and iridium mainly known for their catalytic
[
9-14]
activities
COD = 1,5-cyclooctadiene). They have only very recently gained attention in the field of
organometallic anti-cancer research. Several examples of this compound class have been
are N-heterocyclic carbene (NHC) complexes of the type [M(COD)(NHC)Cl]
(
[
15-22]
synthesized and their activities against different cancer cell lines have been assessed.
Besides of showing promising cytotoxic activities regarding their IC50 values, they were also
shown to have very distinct mechanisms of action. These involve ligand displacement and
[
22]
[18]
interaction with biomolecules such as DNA
as well as influence on cellular signalling in
[
19-21]
case of [Rh(COD)(NHC)Cl] compounds and proteins for [Ir(COD)(NHC)Cl] compounds.
Their most versatile structural element is the NHC ligand. Due to the possibility to substitute not
only the nitrogen atoms but also the heterocycle backbone, the structure of the ligand can easily
be designed in a way that suits the desired application, a feature which is heavily exploited for
[23-25]
their catalytic applications.
In an attempt to increase the potential in catalytic conversions
for the [Rh(COD)(NHC)Cl] complexes, the natural amino acid histidine (His) was converted to
[
26]
an imidazolium salt by alkylation of both nitrogen atoms. These amino acid derivatives were
then used in the synthesis of palladium(II), rhodium(I) and ruthenium(III) N-heterocyclic carbene
[
27-29]
complexes.
Furthermore, the synthesis and anti-proliferative activity of such metal
[
30]
complexes with Pt(II), Au(I) and Ir(III) was reported. The ability of complex formation was
not only evident for the single, fully protected amino acids, but was retained when the amino acid
[31, 32]
was included into a large, complex peptide scaffold.
This system represents a very unique
2

example of a peptide-conjugated organometallic complex: Instead of covalently attaching the
peptide to a known ligand first, which then in turn coordinates to the metal center, as reported for
[
33]
a similar system , the coordination site in this case is directly included in the peptide chain
without any additional functionality. This concept has recently been adapted for similar
[
34]
[
Ir(COD)(NHC)Cl] complexes and is so far the only reported example of peptide-conjugation
for complexes of the [M(COD)(NHC)Cl] type by a direct metal-carbon bond with a natural
amino acid present in the peptide chain. Herein, we report the synthesis of two new non-natural
imidazolium functionalized amino acid derivatives, their use in peptide synthesis and their ability
to form complexes of the [M(COD)(NHC)Cl] type for iridium and rhodium through the
imidazolium side chain. The new imidazolium functionalized amino acids presented here are not
derived from His, but rather formed from other amino acids and thus extend the synthetic toolbox
for metal-NHC peptide complexes, providing defined anchoring points for the formation of metal
complexes in more complex peptide scaffolds. Additionally, they can potentially be used in the
synthesis of cancer cell-targeting complexes of iridium(I), rhodium(I) as well as several other
[
35]
metals which is an uprising field of research.
Synthesis and Characterization
Synthesis of the amino acid derivatives was performed based on modified literature procedures
starting from Fmoc-Glu(tBu)-OH and Fmoc-Asp(tBu)-OH (scheme 1). After esterification of the
[36]
in situ activated C-terminal carboxylic acid with the respective alcohol,
the side chain
protecting tert-butyl group was removed under acidic conditions. The progress of the reactions
1
13
could be followed by H- and C-NMR, which showed subsequent appearance and
disappearance of the signals for the respective protecting groups (see ESI). Subsequently,
conversion of the carboxylic acid to the respective alcohol was performed by treatment with
isobutylchloroformiate to form the respective anhydride in situ, followed by reduction of the
[37, 38]
anhydride using NaBH
4
.
It is important to note that the yield of the reaction was highly
dependent on the reaction conditions, mainly the solvent and the dilution. In high dilution and a
mixture of THF and water, the reaction proceeded towards the alcohol in moderate to good
1
yields. In low dilution significant amounts of a side product were isolated. H NMR and ESI-MS
revealed the side product to be an amino acid dimer resulting from the reaction of the freshly
3

formed alcohol with the anhydride formed in the previous reaction step. In an attempt to improve
the yield by choosing dry MeOH over water for the reduction step similarly low product yields
were observed together with the reaction product of an esterification between the solvent and the
in situ formed anhydride (see Fig. S1 in the ESI for the respective reaction conditions and side
products).
Once obtained, the alcohols 4a-4d were subjected to iodination by an Appel reaction as reported
[
38]
[19-21, 34]
previously, followed by substitution of iodine by 1-methylimidazole
which led to the
desired amino acid imidazolium salts 6a-6d. The success of the reactions could again readily be
1
13
followed by H and C NMR, which showed appearance of the new γ- and δ-CH group
2
respectively after formation of the alcohol, and most importantly a shift of the respective group
depending on the nature of the adjacent functional group throughout each synthesis step (shown
exemplarily for the series of compounds 2a-6a in Fig. S4 in the ESI).
Scheme 1: Synthesis scheme for the synthesis of amino acid imidazolium salts 6a-6d
In an attempt to increase the yield of the reaction, the amount of 1-methylimidazole used for the
preparation of 6c was increased from 1.3 eq to 2 eq. However, the reaction did not proceed
1
towards the desired product 6c. Instead, H-NMR and ESI-MS confirmed the nature of the
obtained product to be the N-terminally deprotected amino acid 7 (scheme 2). Thus, the outcome
of the reaction can easily be controlled by the amount of nucleophile that is used. With the N-
4

deprotected amino acid 7 in hand, N-terminal Boc protection was carried out with Boc O to yield
2
compound 8.
Scheme 2: Reaction conditions leading to the products 6c and 7 and synthesis of the Boc-protected amino
acid imidazolium salt 8
To obtain the Boc-protected derivative of 6a a different synthetic pathway was chosen. After
initial synthesis of homoserine (Hse) 11 it was N-terminally Boc-protected according to a
[
39-41]
literature known procedure
leading to protected compound 12. The intended C-terminal
methylation with MeI led to an inseparable mixture of the desired compound 13 and the double
methylated side product 14. The mixture was used without further purification to synthesize the
desired amino acid imidazolium salt 16 following the route described in scheme 3.
Scheme 3: Synthesis of the Boc protected amino acid imidazolium salt 16
5

The fully protected amino acid derivatives 6b, 6d, 8 and 16 were used for the preparation of the
respective [M(COD)(NHC)Cl] complexes of rhodium or iridium by the well established Ag O
2
[
9, 19-21, 42]
transmetalation route (scheme 4).
Length of
C-chain n
N-term. protecting
group R1
C-term. protecting
group R2
Metal center
Compound
1
7
1
1
2
1
2
2
Fmoc
Boc
Alloc
Methyl
Methyl
Methyl
Methyl
Alloc
Rh
18a
1
8b
9a
Boc
1
Boc
Ir
19b
Boc
2
0
Fmoc
Scheme 4: Synthesis of [M(COD)(NHC)Cl] amino acid complexes 17-20 by Ag O transmetalation
2
The most significant sign of successful complex formation could be found in the NMR spectra.
They did not only show disappearance of the imidazolium proton of the respective amino acids at
1
around 9.80-9.95 ppm in the H-NMR, but also a significant shift of the imidazolium carbon
atom from around 136-137 ppm in the free amino acids to around 180-182 ppm after
1
3
[43]
complexation in the C-NMR. This confirms that coordination of the amino acid to the metal
center proceeds in the desired manner through the imidazolylidene carbon of the amino acid
obtained by deprotonation of the imidazolium group and not through one of the other functional
groups present in the molecule, which have been reported to be able to coordinate to metal
[
44]
centers in various ways.
Furthermore, it has to be noted that complexation works
independently from the protective groups present in the amino acid. Therefore, the compounds
represent a family of examples of bioconjugated organometallic complexes. The NMR spectra
also show signs of formation of two isomers for the complexes due to the slow rotation around
the metal-carbon bond, a phenomenon that has been reported for the His functionalized
6

[
32]
[
Rh(COD)(NHC)Cl] complexes earlier. In complexes 18 and 19 this can be best observed for
the signal of the C-terminal methyl ester which forms a doublet between 3.69 ppm and 3.76 ppm.
For complexes 17 and 20 the heterocycle methyl group shows two signals between 3.95 ppm and
4
.07 ppm. In comparison, the free ligands only show a singlet for the respective signals in the
same chemical shift area (see NMR spectra in the ESI). Integration of the respective signals of
the two isomers reveals a ratio of almost 1:1.
Going further, the potential of the amino acids to coordinate to metals as part of a larger peptide
scaffold was assessed. To this end, the amino acid imidazolium salts 8 and 16 were C-terminally
saponified by treatment with aqueous NaOH. This resulted in the respective carboxylic acids 21a
and 21b, which were subsequently used for solid phase peptide synthesis (SPPS) based on a
[
34, 45, 46]
literature known procedure
depicted in scheme 5.
to synthesize the peptide imidazolium salts 22a and 22b as
Scheme 5: Synthesis of the carboxylic acids 21a and 21b and their subsequent use in SPPS. SPPS
conditions were as follows for loading: Fmoc-Ala-OH, DCC, DMAP, DCM/DMF o.n., r.t.,
deprotection: 20% Piperidine in DMF, 25 min,r.t., coupling: Fmoc protected amino acid,
TBTU, HOBt, DIPEA, DMF/NMP, 2x 45 min, r.t., final coupling (only 21a and 21b): amino
acid, DCC, HOBT, DMF/NMP, o.n., r.t., cleavage: MeOH/DMF/DIPEA, 50°C, o.n.
2
Peptides 22a and 22b were then used in the complexation of rhodium and iridium by Ag O
[
31, 32, 34]
transmetalation in a similar manner to the fully protected amino acids,
resulting in the
7

peptide complexes 23-24 as depicted in scheme 6. The success of the complexation was proven
by ESI-MS, which confirmed the identity of the obtained complexes, but also by analytical
HPLC which showed a significant shift in the retention time of the metal-peptide complexes in
comparison to the free peptides (see Fig. S5-S8 in the ESI), and additionally established the
purity of the compounds. Similar to the amino acid complexes, disappearance of the imidazolium
1
proton at 8.97 ppm in the H-NMR confirms the formation of a direct metal-carbon bond between
the NHC moiety of the respective peptide and the metal center. In this examples as well, similar
1
to the amino acid complexes, the formation of two isomers could be observed in the H NMR.
Thus, the amino acids 22a and 22b can coordinate to the metals even in the presence of a more
complex peptide environment and, quite remarkably, complexation is not hampered by the
presence of several other functional groups. These peptide-conjugates therefore represent rare
examples of organometallic peptide conjugates of rhodium and iridium.
Scheme 6: Synthesis of [M(COD)NHC)Cl] peptide complexes 23-24 by Ag O transmetalation
2
Conclusion
In summary, we report the successful synthesis of a new set of amino acid imidazolium salts 6a-
6
d, 8 and 16, which contain different combinations of common amino acid protecting groups.
The amino acids 6b, 6d, 8 and 16 were then used for the synthesis of complexes of the
M(COD)(NHC)Cl] type for rhodium and iridium, resulting in six new amino acid complexes 17-
0. The presence of a direct metal-carbon bond between the metal center and the imidazolium
[
2
1
13
moiety of the amino acids could be unambiguously proven by H and C NMR spectroscopy,
thus confirming the nature of the respective compounds as examples of organometallic
complexes conjugated to small biomolecules. Furthermore, the amino acid imidazolium salts 8
8

and 16 were converted to the respective C-terminally deprotected amino acids 21a and 21b
suitable for SPPS and the synthesis of the peptide imidazolium salts 22a and 22b was
successfully performed. Similar to the smaller amino acids, peptides 22a and 22b were used for
the synthesis of [M(COD)(NHC)Cl] complexes of rhodium and iridium resulting in the peptide
conjugated complexes 23 and 24. Identical to the amino acid complexes, the peptide complexes
feature a direct metal-carbon bond between the metal center and the imidazolium moiety which
represents their most unique feature: A coordinative mode of conjugation through a direct bond
with an amino acid side chain. The results show that complexation proceeds through the
imidazolium-derived NHC moiety independently from any other functionality of either the amino
acids or the peptides. This leads to the conclusion that neither the common amino acid protecting
groups (Fmoc, Alloc or Boc) present in the amino acids nor the complex peptide environment
have a negative effect on the complexation reaction. Our results pave the way towards a precise
incorporation of rhodium and iridium into predefined small and medium sized peptides for
therapeutic purposes. In future projects, the potential of the present imidazolium functionalized
amino acids to be used in the synthesis of cancer cell targeting peptides and subsequent synthesis
of cancer cell targeting rhodium and iridium complexes followed by the assessment of their
cytotoxic potential in comparison to their non-peptide-conjugated parent compounds is
envisioned.
Experimental section
General procedures for the main reactions are given in the following. Detailed synthetic
procedures for all of the compounds and for solid phase peptide synthesis with the respective
analytical data can be found in the ESI.
General procedures
C-terminal esterification (2a-2d)
2
In a heated Schlenk flask under N atmosphere, 1 eq of the respective starting material and 1.5 eq
of HOBt were dissolved in 4.5 ml of dry THF per mmol of starting material and cooled to -10°C.
9

In similar dry conditions, 1 eq of DCC was dissolved in 2.5 ml of dry THF per mmol and added
dropwise to the first solution at -10°C. The reaction was stirred for 15-30 min and allowed to
warm to room temperature. Afterwards, 35 eq of the respective alcohol were added dropwise and
the reaction was refluxed over night at 75°C. After evaporation of the solvent under reduced
pressure, the residue was taken up in 13 ml of DCM per mmol of starting material and the
organic phase was extracted three times with saturated NaHCO and brine respectively. The
3
organic phase was separated, dried over MgSO and the solvent was removed under reduced
4
pressure. After Flash column chromatography over silica (n-hexane/EtOAc 1:0 ‰ 7:3), the
product was obtained as a white solid.
tert-Butyl deprotection (3a-3d)
1
eq of the respective starting material was dissolved in 10 ml of a 1:1 mixture of DCM and TFA
per mmol. The solution was stirred at room temperature for 1 h until the gas evolution had
ceased. The solvent was removed under reduced pressure and the oily residue was taken up in as
little DCM as possible and precipitated from hexane, yielding a white precipitate which was
identified as the product.
Carboxylic acid reduction (4a-4d)
In a heated Schlenk Flask under N atmosphere, 1 eq of the respective starting material was
2
dissolved in 65 ml of dry THF per mmol. 4 eq of isobutylchloroformiate were added dropwise,
which resulted in the precipitation of a white solid and the reaction was stirred at room
temperature for 15 min. 6 eq of NaBH were dissolved in 20 ml of H O per mmol and the
4
2
solution was added dropwise to the reaction mixture, resulting in gas evolution and temperature
increase. The reaction was left to stir at room temperature for 15 min, during which time the gas
4
development ceased. After completion, 10 ml of 1 M KHSO per mmol of starting material were
added to the reaction mixture and it was extracted three times with DCM. The combined organic
phases were dried over MgSO and the solvent was removed under reduced pressure. The oily
4
residue was further purified by flash column chromatography over silica (n-hexane/EtOAc 1:0 ‰
0
:1), yielding the product as a clear, slowly crystallizing oil.
1
0

Appel reaction (5a-5d, 15)
In a heated Schlenk flask under N atmosphere, 1.25 eq of PPh and 2.5 eq of imidazole (with
2
3
respect to the starting material) were dissolved in 20 ml of dry THF per mmol of starting
material. 1.3 eq of I (with respect to the starting material) were added and the reaction was
2
stirred for 15 min at room temperature, which led the reaction mixture to turn brown. Under
similarly dry conditions, the respective starting material was dissolved in 12 ml of dry THF per
mmol and the reaction was left to stir at room temperature for 3 h. Afterwards, the reaction
mixture was diluted with 50 ml of EtOAc per mmol of starting material and washed two times
with 10% Na S O to remove the remaining I and two times with brine. The organic layer was
2
2
4
2
4
dried over MgSO and after evaporation of the solvent under reduced pressure, the remaining oily
residue was purified by flash column chromatography over silica (n-hexane/EtOAc 1:0 ‰ 0:1).
The product was obtained as a white solid.
Nucleophilic substitution with 1-methylimidazole (6a-6d, 16)
2
In a heated Schlenk flask under N atmosphere, 1 eq of the respective starting material was
dissolved in 15 ml of dry THF per mmol. 1.3 eq of 1-methylimidazole were added and the
reaction mixture was heated to 50 °C and stirred for 72 h. The solvent was removed under
reduced pressure and the remaining residue was purified by flash column chromatography over
silica (DCM/MeOH 1:0 ‰ 9:1). The product was obtained as a yellowish, foamy solid.
Synthesis of [M(COD)(NHC)Cl] complexes (17-20, 23-24)
2
In a heated Schlenk flask under N atmosphere, 1 eq of the respective imidazolium salt was
dissolved in 5 ml of dry DCM (in case of ligands 6b, 6d, 8 and 16) or dry ACN (in case of
peptides 22a and 22b). The solution was degassed by three consecutive cycles of freeze-pump-
2
thaw. After addition of 0.5 eq of freshly prepared Ag O the solution was left to stir at room
temperature for 1 h in the dark, during which disappearance of the black Ag O could be seen,
2
2
followed by addition of 0.5 eq of [M(COD)Cl] (M=Ir or Rh) leading to a color change to bright
yellow. The solution was then left to stir over night at room temperature. Afterwards the reaction
mixture was filtered through Celite (DCM/MeOH 9:1) and the filtrate was concentrated under
reduced pressure. Purification of the product was carried out by flash column chromatography
over silica (n-hexane/EtOAc 0:1→1:0) yielding a bright yellow oily residue, which was taken up
1
1

in as little EtOAc as possible and precipitated from n-hexane to yield the products as bright
yellow solids.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We kindly acknowledge the work of our in-depth student Philipp Mathes who worked on
the synthesis of complex 20, and of Martin Gartmann, who helped recording the NMR
spectra of all of the new metal-containing compounds.
Affiliations
a
Faculty of Chemisty and Biochemistry, Chair of Inorganic Chemistry I, Ruhr-Universität
Bochum, Universitätsstr. 150, 44801 Bochum, Germany
*
nils.metzler-nolte@rub.de
References
[1] G. Gasser, I. Ott, N. Metzler-Nolte, J. Med. Chem. 54 (2011) 3-25
[2] T. Giraldi, G. Sava, G. Mestroni, G. Zassinovich, D. Stolfa, Chem.-Biol. Interactions 22
(1978) 231-238
[3] Z. Liu, P.J. Sadler, Acc. Chem. Res. 47 (4) (2014) 1174-1185
[4] C.-H. Leung, H.-J. Zhong, D.S.-H. Chan, D.-L. Ma, Coord. Chem. Rev. 257 (11-12) (2013)
1764-1776
[
[
[
[
5] Y. Geldmacher, M. Oleszak, W.S. Sheldrick, Inorg. Chim. Acta 393 (2012) 84-102
6] K.K.-W. Lo, K.Y. Zhang, RSC Adv. 2 (32) (2012) 12069-12083
7] D.-L. Ma, D.S.-H. Chan, C.-H. Leung, Acc. Chem. Res. 47 (12) (2014) 3614-3631
8] D.-L. Ma, M. Wang, Z. Mao, C. Yang, C.-T. Ng, C.-H. Leung, Dalton Trans. 45 (7) (2016)
2762-2771
1
2

[9] G.D. Frey, C.F. Rentzsch, D. von Preysing, T. Scherg, M. Mühlhofer, E. Herdtweck, W.A.
Herrmann, J. Organomet. Chem. 691 (26) (2006) 5725-5738
[
[
[
[
[
[
10] W. Gil, A.M. Trzeciak, Coord. Chem. Rev. 255 (3) (2011) 473-483
11] B. Yiğit, M. Yiğit, İ. Özdemir, Inorg. Chim. Acta 467 (2017) 75-79
12] W.J. Kerr, M. Reid, T. Tuttle, ACS Catal. 5 (1) (2015) 402-410
13] G. Sipos, R. Dorta, Coord. Chem. Rev. 375 (2018) 13-68
14] S. Díez-González, N. Marion, S.P. Nolan, Chem. Rev. 109 (8) (2009) 3612-3676
15] L. Oehninger, H. Alborzinia, S. Ludewig, K. Baumann, S. Wölfl, I. Ott, ChemMedChem 6
(
2011) 2142-2145
16] L. Oehninger, L.N. Kuster, C. Schmidt, A. Munoz-Castro, A. Prokop, I. Ott, Chem. Eur. J.
9 (52) (2013) 17871-17880
[
1
[17] L. Oehninger, R. Rubbiani, I. Ott, Dalton Trans. 42 (2013) 3269-3284
[18] L. Oehninger, S. Spreckelmeyer, P. Holenya, S.M. Meier, S. Can, H. Alborzinia, J. Schur,
B.K. Keppler, S. Wolfl, I. Ott, J. Med. Chem. 58 (24) (2015) 9591-9600
[19] Y. Gothe, Doctoral Thesis, Department of Inorganic Chemistry I, Ruhr-Universität Bochum,
Bochum, 2016
[
20] Y. Gothe, T. Marzo, L. Messori, N. Metzler-Nolte, Chem. Commun. 51 (2015) 3151-3153
21] Y. Gothe, I. Romero-Canelón, T. Marzo, P.J. Sadler, L. Messori, N. Metzler-Nolte, Eur. J.
Inorg. Chem. 2018 (20-21) (2018) 2461-2470
[
[22] J.R. McConnell, D.P. Rananaware, D.M. Ramsey, K.N. Buys, M.L. Cole, S.R. McAlpine,
Bioorg. Med. Chem. Lett. 23 (9) (2013) 2527-2531
[
23] M.N. Hopkinson, C. Richter, M. Schedler, F. Glorius, Nature 510 (7506) (2014) 485-496
24] S.P. Nolan, N-Heterocyclic Carbenes - Effective Tools for Organometallic Synthesis, Wiley
VCH (2015).
[
[
[
[
[
25] N.I. Korotkikh, V.S. Saberov, N.V. Glinyanaya, K.A. Marichev, A.V. Kiselyov, A.V.
Knishevitsky, G.F. Rayenko, O.P. Shvaika, Chem. Heterocycl. Com. 49 (1) (2013) 19-38
26] D. Bregeon, J. Levillain, F. Guillen, J.C. Plaquevent, A.C. Gaumont, Amino acids 35 (1)
(
2008) 175-184
27] A. Monney, E. Alberico, Y. Ortin, H. Muller-Bunz, S. Gladiali, M. Albrecht, Dalton Trans.
1 (29) (2012) 8813-8821
28] F. Hannig, G. Kehr, R. Fröhlich, G. Erker, J. Organomet. Chem. 690 (24-25) (2005) 5959-
972
4
5
1
3

[
29] A. Monney, G. Venkatachalam, M. Albrecht, Dalton Trans. 40 (12) (2011) 2716-2719
30] F. Schmitt, K. Donnelly, J.K. Muenzner, T. Rehm, V. Novohradsky, V. Brabec, J.
Kasparkova, M. Albrecht, R. Schobert, T. Mueller, J. Inorg. Biochem. 163 (2016) 221-228
31] A. Monney, M. Albrecht, Chem. Commun. 48 (89) (2012) 10960-10962
[
[
[
[
[
[
[
32] A. Monney, F. Nastri, M. Albrecht, Dalton Trans. 42 (16) (2013) 5655-5660
33] J. Lemke, N. Metzler-Nolte, Eur. J. Inorg. Chem. (21) (2008) 3359-3366
34] I.M. Daubit, N. Metzler-Nolte, Dalton Trans. 48 (2019) 13662–13673
35] B. Albada, N. Metzler-Nolte, Chem. Rev. 116 (19) (2016) 11797-11839
36] R.N. Murugan, B. Jacob, M. Ahn, E. Hwang, H. Sohn, H.N. Park, E. Lee, J.H. Seo, C.
Cheong, K.Y. Nam, J.K. Hyun, K.W. Jeong, Y. Kim, S.Y. Shin, J.K. Bang, PLOS ONE 8
(11) (2013) e80025
[
37] S. Kocher, J. Rey, J. Bongard, A.N. Tiaden, M. Meltzer, P.J. Richards, M. Ehrmann, M.
Kaiser, Angew Chem Int Ed Engl 56 (29) (2017) 8555-8558
[38] L. Longobardo, N. Cecere, M. DellaGreca, I. de Paola, Amino acids 44 (2) (2013) 443-8
[39] A.J. Ozinskas, G.A. Rosenthal, J. Org. Chem. 51 (26) (1986) 5047-5050
[40] V.P. Prasad, S. Wagner, P. Keul, S. Hermann, B. Levkau, M. Schafers, G. Haufe, Bioorg
Med Chem 22 (19) (2014) 5168-5181
[41] A.G. Jamieson, N. Boutard, K. Beauregard, M.S. Bodas, H. Ong, C. Quiniou, S. Chemtob,
W.D. Lubell, J Am Chem Soc 131 (22) (2009) 7917-7927
[
[
42] Anthony R. Chianese, Xingwei Li, Michael C. Janzen, J. W. Faller, R.H. Crabtree,
Organometallics 22 (2003) 1663-1667
43] A.R. Chianese, X. Li, M.C. Janzen, J.W. Faller, R.H. Crabtree, Organometallics 22 (8)
(2003) 1663-1667
[44] K. Severin, R. Bergs, W. Beck, Angew. Chem. Int. Ed. 37 (1998) 1634-1654
[45] W.R. Abd-Elgaliel, F. Gallazzi, S.Z. Lever, J. Pept. Sci. 13 (7) (2007) 487-492
[46] S.I. Kirin, F. Noor, N. Metzler-Nolte, W. Mier, J. Chem. Educ. 84 (1) (2007) 108-111
1
4

Rhodium(I) and Iridium(I) N-Heterocyclic Carbene Complexes of
Imidazolium-functionalized Amino Acids and Peptides
a
a
a
Isabelle Marie Daubit , Jonas Wolf and Nils-Metzler-Nolte *
Highlights
•
•
•
•
Synthesis of new imidazolium functionalized non-natural amino acids
Use of imidazolium functionalized non-natural amino acids in SPPS
Amino acid and peptide conjugation of iridium(I) and rhodium(I) NHC complexes
Atachment of iridium(I) and rhodium(I) to amino acids and peptides through direct side
chain coordination of imidazolium functionalized amino acids

Rhodium(I) and Iridium(I) N-Heterocyclic Carbene Complexes of
Imidazolium-functionalized Amino Acids and Peptides
a
a
a
Isabelle Marie Daubit , Jonas Wolf and Nils-Metzler-Nolte *
Keywords: Bioorganometallic Chemistry, Iridium, Metal Peptide Bioconjugates, Non-natural
amino acids, N-heterocyclic carbene complexes, Rhodium
Declaration of Interest statement
The authors declare no conflicting interests.