Peptide-tethered monodentate and chelating histidylidene metal complexes: Synthesis and application in catalytic hydrosilylation

Article abstract of DOI:10.1039/c3dt50424g

The N_δ,N_ε-dimethylated histidinium salt (His*) was tethered to oligopeptides and metallated to form Ir(iii) and Rh(i) NHC complexes. Peptide-based histidylidene complexes containing only alanine, Ala-Ala-His*-[M] and Ala-Ala-Ala-His*-[M] were synthesised ([M] = Rh(cod)Cl, Ir(Cp*)Cl₂), as well as oligopeptide complexes featuring a potentially chelating methionine and tyrosine residue, Met-Ala-Ala-His*-Rh(cod)Cl and Tyr-Ala-Ala-His*-Rh(cod)Cl. Chelation of the methionine-containing histidylidene ligand was induced by halide abstraction from the rhodium centre, while tyrosine remained non-coordinating under identical conditions. High catalytic activities in hydrosilylation were achieved with all peptide-based rhodium complexes. The cationic S _Met,C_His*-bidentate peptide rhodium catalyst outperformed the monodentate neutral peptide complexes and constitutes one of the most efficient rhodium carbene catalysts for hydrosilylation, providing new opportunities for the use of peptides as N-heterocyclic carbene ligands in catalysis.

Full text of DOI:10.1039/c3dt50424g

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Peptide-tethered monodentate and chelating
histidylidene metal complexes: synthesis and
Cite this: Dalton Trans., 2013, 42, 5655
application in catalytic hydrosilylation†
Angèle Monney,a Flavia Nastrib and Martin Albrecht*a
The Nδ,Nε-dimethylated histidinium salt (His*) was tethered to oligopeptides and metallated to form Ir(III)
and Rh(I) NHC complexes. Peptide-based histidylidene complexes containing only alanine, Ala–Ala–His*–[M]
and Ala–Ala–Ala–His*–[M] were synthesised ([M] = Rh(cod)Cl, Ir(Cp*)Cl2), as well as oligopeptide com-
plexes featuring a potentially chelating methionine and tyrosine residue, Met–Ala–Ala–His*–Rh(cod)Cl and
Tyr–Ala–Ala–His*–Rh(cod)Cl. Chelation of the methionine-containing histidylidene ligand was induced by
halide abstraction from the rhodium centre, while tyrosine remained non-coordinating under identical
conditions. High catalytic activities in hydrosilylation were achieved with all peptide-based rhodium com-
plexes. The cationic SMet,CHis*-bidentate peptide rhodium catalyst outperformed the monodentate neutral
peptide complexes and constitutes one of the most efficient rhodium carbene catalysts for hydrosilylation,
providing new opportunities for the use of peptides as N-heterocyclic carbene ligands in catalysis.
Received 4th November 2012,
Accepted 15th February 2013
DOI: 10.1039/c3dt50424g
www.rsc.org/dalton
involves formation of the heterocycle within the metal coordi-
nation sphere, which precludes the use of histidine as a start-
Introduction
Histidine is ubiquitous in metalloenzymes because its imid- ing material. Alternatively, alkylation of the side-chain
azole side chain is able to coordinate to a vast array of metal nitrogens of histidine constitutes a straightforward process to
centres in various oxidation states.1 Typically, the imidazole is generate NHC derivatives that will not suffer from potential
coordinated through one of its nitrogen atoms, either Nδ or Nε. tautomerisation to the imidazole isomer.7 Such an approach
In addition, imidazole and its substituted derivatives consti- has been used previously to prepare peptide-based imidazol-
tute versatile precursors for the formation of N-heterocyclic (in)ylidene8 and thiazolylidene9 metal complexes. Building on
carbenes (NHCs), a powerful class of spectator ligands for tran- pioneering work by Erker,10 we have developed a synthetic pro-
sition metal chemistry.2 Hence, modification of histidine to tocol to histidylidene (i.e. histidine-derived NHC) complexes as
a NHC precursor provides a straightforward approach to bio- catalyst precursors for transfer hydrogenation and for the cata-
organometallic chemistry,3 as the metal-carbene complex lytic hydrosilylation of ketones.11 The availability of appropri-
enables the exploitation of typical organometallic function ate stereospecific methodologies for the preparation of
such as catalysis, while the peptidic backbone offers opportu- monopeptide organometallic complexes thus allows modifi-
nities for peptidic transformations and hence biochemical cations of the biochemical scaffold to be targeted. Here we
engineering of the hybrid. For example, specific structural report the functionalisation of the histidylidene backbone with
conformations may be induced that affect the organometallic small oligopeptides using peptide coupling and the impact of
site. Peptide-based organometallic conjugates have been suc- these modifications on the (catalytic) activity of the metal
cessfully employed,4 for example for enzyme-controlled enantio- centre.12 This approach provides access to catalytically active
selective catalysis.5
NHC complexes with a peptidic environment around the metal
While protic metal complexes of NH,NH-imidazolylidenes, centre as novel models of metalloenzymes.
i.e. tautomers of imidazole, are known,6 their synthesis often
aSchool of Chemistry and Chemical Biology, University College Dublin, Belfield,
Results and discussion
Dublin 4, Ireland. E-mail: martin.albrecht@ucd.ie; Fax: +353 1716 2501;
Synthesis of alanine-based histidylidene metal complexes
Tel: +353 1716 2504
bDepartment of Chemistry, University Federico II of Napoli, Complesso Universitario
The synthesis of the alanine-containing histidinium ligand
precursors 4a and 4b started from the known13 Nε-methylated
histidine Boc–His(Me)–OMe 1 (Scheme 1). Cleavage of the Boc
Monte S. Angelo, Via Cintia 45, 80126 Napoli, Italy
†Electronic supplementary information (ESI) available: Synthetic procedures for
all new compounds. See DOI: 10.1039/c3dt50424g
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Scheme 1 Synthesis of the histidinium tripeptide 4a and tetrapeptide 4b. Reagents and conditions: (i) HCl/MeOH, reflux; (ii) Boc–Ala–OH, HATU, DIEA, THF, rt; (iii)
HCl/1,4-dioxane, rt; (iv) MeI, MeCN, 40 °C; (v) LiOH, THF/MeOH/H2O, rt, then HCl aq.; (vi) 2, HATU, DIEA, THF, rt.
1
protecting group at the N-terminus was effected with methano- CεH resonances in the H NMR spectrum, e.g. from δH 6.99 to
lic HCl thus providing the dihydrochloride salt H–His(Me)– 7.39 ppm and from δH 7.70 to 8.85 ppm, respectively, for 4b (in
OMe·2HCl 2. Deprotection with TFA was equally successful,14 CD3OD). Both ligand precursors 4a and 4b were highly hygro-
however the obtained trifluoroacetate salt was significantly scopic solids and were obtained as single enantiomers as
more hygroscopic than the chloride salt and hence less easy to demonstrated by the presence of one set of signals in the NMR
handle. The C-protected methyl-histidine 2 was subsequently spectra. They both displayed optical activity, [α]2D0 = −43° and
used for amino acid coupling reactions. These reactions were −37° for 4a and 4b, respectively (c = 1 in MeOH).
all performed using HATU as the coupling agent according to
The histidinium salts 4a–b were successfully metallated
a modified literature procedure.15 Other standard and less using a standard transmetallation procedure via the in situ for-
costly agents such as DCC16 or N-mesyl-benzotriazole17 were mation of a silver carbene intermediate. As described pre-
also evaluated, though these methods failed to give the viously,11 ambient temperature and short reaction times were
desired peptide bond. According to route A (Scheme 1), the crucial for the full retention of the configuration at the
free amine 2 was reacted with commercially available Boc-L- α-carbon of histidine. Subsequent transmetallation with [Ir-
alanine to give the desired dipeptide Boc–Ala–His(Me)–OMe. (Cp*)Cl2]2 or [Rh(cod)Cl]2 afforded the corresponding peptide-
The Boc protecting group was then removed using a solution based histidylidene iridium(III) and rhodium(I) complexes 5a
of HCl in 1,4-dioxane18 and a further alanine residue was intro- and 6a–b, respectively (Scheme 2). Formation of the complexes
duced to give the tripeptide Boc–Ala2–His(Me)–OMe 3a. The was supported by the disappearance of the signal for the Cε-
deprotection-coupling sequence was repeated to synthesise the bound proton in the 1H NMR spectra and by the downfield
tetrapeptide Boc–Ala3–His(Me)–OMe 3b. Successful coupling
was indicated by high-resolution mass spectrometry and by
the presence of three distinct carbonyl signals in the 13C{1H}-
NMR spectrum of 3a in CDCl3 for the two amide functional-
ities and one ester group in the δC 172–173 ppm range, and a
carbamide resonance at δC 155 ppm. Likewise, the tetrapeptide
3b showed three different amide and one ester carbonyl reso-
nances in the δC 173–176 ppm range as well as a carbamide
resonance at higher field (δC 158 ppm, CD3OD solution).
Alternatively, the oligopeptide tether can be synthesised
first (route B). Thus deprotection of the alanine dipeptide
Boc–Ala2–OMe or tripeptide Boc–Ala3–OMe at the C-terminus
using LiOH followed by careful neutralisation and subsequent
coupling to the free amine 2 yielded the oligopeptides 3a–b.
Even though both routes gave the desired oligopeptides 3 in
the same number of steps, route B presents the significant
advantage to be convergent rather than a completely linear
reaction sequence. The imidazole ring was then alkylated by
gently heating 3 with MeI in MeCN to give the Nδ,Nε-dimethyl-
ated histidinium oligopeptides Boc–Alan–His*–OMe 4a (n = 2)
Scheme 2 Synthesis of alanine-containing histidylidene iridium 5 and rhodium
and 4b (n = 3). The formation of the imidazolium salts was
6–7 complexes. Reagents and conditions: (i) Ag2O, [Ir(Cp*)Cl2]2, CH2Cl2, rt; (ii)
indicated by the diagnostic downfield shift of the CδH and Ag2O, [Rh(cod)Cl]2, CH2Cl2, rt; (iii) (S)-Ph-binepine, KPF6, CH2Cl2/H2O, rt.
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shift of the carbene signal in the 13C NMR spectra to δC 156.9, acid residues, the resulting tetrapeptides may adopt a confor-
182.9 and 182.3 ppm for 5a, 6a and 6b, respectively. Of note, mation that is suitable for chelation where the side chain of
the NMR spectra of all three complexes showed the presence the i + 3 residue (i.e. Met/Tyr) is positioned almost eclipsed to
of two rotamers, as expected from the slow rotation about the the metal-bound histidylidene unit.
M–Ccarbene bond.11,19 The resonances attributed to CδH and
Because the side chains of tyrosine comprise a nucleophilic
COOCH3 are most diagnostic and appeared as two sets of phenol group, the imidazole ring of histidine was alkylated
signals each. For example in 6a, two signals for CδH were prior to the coupling with the oligopeptide.11 The Nδ,Nε-
observed at δH 6.56 and 6.60 ppm (1 : 0.9 integral ratio) and dimethylated histidinium salt
8 was deprotected at the
the methylester was resolved at δH 3.67 and 3.70 ppm. The N-terminus using a solution of HCl in 1,4-dioxane, followed by
enantiopurity of the peptidic histidylidene ligand was con- an ion exchange to yield compound 9 in excellent yield
firmed by 31P NMR spectroscopy after coordination of (S)-Ph- (Scheme 3). The N-deprotected histidinium salt was sub-
binepine20 to the rhodium centre in 6a in the presence of sequently coupled to the tripeptides Boc–Tyr–Ala–Ala–OH,
KPF6 (Scheme 2). The resulting cationic phosphine complex 7 which was synthesised in a manner similar to that described
displayed two doublets in a 1 : 0.9 integral ratio in the 31P{1H}- for Boc–Ala3–OH (cf. Scheme 1, route B). This coupling reac-
NMR spectrum, corresponding to the rotamer ratio observed tion afforded the tyrosine-containing histidinium tetrapeptide
for 6a. This pattern is consistent with related enantiopure his- 10 as a highly hygroscopic solid. The formation of the oligo-
tidylidene rhodium complexes.11b In contrast, when the silver peptide was confirmed by high-resolution mass spectrometry,
carbene intermediate was formed using reflux temperature which showed the expected signal for the cationic [M–Cl] frag-
and longer reaction times, the rhodium complex 6a displayed ment at 603.3135 amu (calculated 603.3142 amu). Furthermore
a more complicated 1H NMR spectrum. Four distinct signals the presence of four low field signals for the amide carbonyl
were observed for CδH as well as for the COOCH3 group, which functionalities and the ester in 13C{1H}NMR spectroscopy sup-
is consistent with the presence of two diastereomers (both ported successful coupling. In the 1H NMR spectrum, the
existing as two rotamers) due to partial epimerisation at the signal for the Cε-bound proton appeared at δH 8.79 ppm for
histidylidene α-carbon.
10, which is at slightly higher field than in the deprotected
In addition, single crystals were obtained for the tripeptide monopeptide 9 (δH 9.00 ppm).
iridium complex 5. While the organometallic residue was
Similar to its Met homologue,12 the histidinium tetra-
clearly identified, the Ala–Ala residue was significantly dis- peptide Boc–Tyr–Ala–Ala–His*–OMe was successfully rhodated
ordered and did not allow refinement to converge. Nonetheless, under mild conditions to yield complex 11. The use of freshly
this diffraction analysis supports the formation of the organo- prepared Ag2O22 and the addition of [NEt3Me]I23 as a source of
metallic entity and the presence of a Ir–CNHC bond.
iodide were essential for the successful formation of the silver
carbene intermediate prior to transmetallation with [Rh(cod)-
Cl]2. Analyses by NMR spectroscopy revealed the disappear-
Synthesis of histidylidene complexes containing a remote
potentially coordinating amino acid residue
1
ance of the CεH signal in the H NMR spectra and the appear-
In order to promote chelation, amino acids containing a ance of a low field doublet in the 13C NMR spectra at δC
potentially coordinating functionality in the side chain were 182 ppm (1JRhC = 51 Hz). Two sets of signals were observed,
introduced on the histidylidene ligand. Methionine (Met) and which were attributed to the presence of two rotamers. No epi-
tyrosine (Tyr) were chosen to induce a C,S- and a C,O-bidentate merisation at Cα was observed when the metallation reaction
binding mode of the histidylidene oligopeptide, respectively.12 was carried out at room temperature and for a short time only
An alanine dipeptide linker was placed between the coordi- (1 h).11b
nation sites in order to promote the formation of an α-helix.21
Comparison with model compounds by NMR spectroscopy
Since a complete turn in a peptidic α-helix contains 3.6 amino indicated no spontaneous chelation of the tyrosine residue.
Scheme 3 Synthesis of the peptide-embedded histidylidene-rhodium complex 11 containing a tyrosine residue. Reagents and conditions: (i) HCl/1,4-dioxane, rt,
then ion-exchange resin; (ii) Boc–Tyr–Ala–Ala–OH, HATU, DIEA, THF, rt, then ion-exchange resin; (iii) [NEt3Me]I, Ag2O, [Rh(cod)Cl]2, CH2Cl2, rt.
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for rhodium coordination, which will result in ring-opening of
the metallo-macrocycle in 13, thus entailing an oligopeptide
structure reminiscent of 12. To prevent such ring-opening,
analysis of the chelate tetrapeptide 13 were also performed in
TFE as a non-coordinating and helix-inducing solvent.25 This
solvent change did not have any noticeable impact on the CD
spectrum and the general features of an unordered peptide
structure are still persistent. Introduction of a pronounced
α-helical or β-turn motive therefore requires a longer oligo-
peptide scaffold.
Catalytic hydrosilylation
Based on the established activity of NHC rhodium complexes
such as 14 in hydrosilylation catalysis,11b,26 we investigated the
effect of the peptide scaffold on the catalytic performance of
the rhodium centre. Hydrosilylation of 4-fluoroacetaceto-
phenone as model substrate with Ph2SiH2 using 1 mol% of
catalyst precursor occurred smoothly over 2 h or less. Accord-
1
ing to in situ H and 19F NMR spectroscopy, the silyl ether 15
was formed as the major product along with small quantities
of the enol ether 16 (Table 1).27 Monitoring the course of the
reaction spectroscopically indicated a strong influence of the
peptide scaffold on both the activity and the selectivity of
the catalytically active rhodium centre. Complex 6a containing
two alanine residues bound to the histidylidene ligand dis-
played identical catalytic activity and selectivity towards 15
(within experimental error) as complex 6b comprising three
Ala units (Table 1, entries 1 and 2). With both precursors, 77%
conversion with 94% selectivity was reached within 30 min.
Under the same conditions, the model complex 14 exhibited
higher activity (entry 7), achieving the same conversion level in
only 5 min with similar selectivity. The peptidic backbone in 6
appears to hamper the efficiency of the catalysts, perhaps
because of diffusion limitations due to the bulk imparted by
the oligopeptide moiety. These observations are in line with
Scheme 4 Methionine analogues 12 and 13 featuring a monodentate and
chelating bidentate bonding mode of the histidylidene, respectively.
While with the Met homologue 12, KPF6-mediated chloride
abstraction induced the formation of the macrocyclic chelate
complex 13 (Scheme 4), no signs of phenol binding to the
1
rhodium centre were observed by H NMR spectroscopy when
subjecting 11 to analogous conditions or after addition of
AgPF6 in the presence or absence of DIEA as proton scavenger.
The effect of potentially chelating amino acid residues in
i + 3 position was examined by CD spectroscopy in the far UV
region for the rhodium tetrapeptides 6b, 12, and 13. The CD
spectra of all the complexes in MeCN solution display a strong
negative band at 198 nm and a small positive shoulder at
220 nm (Fig. 1). This typical random coil signature indicates
an unordered secondary structure for all three complexes.24 In
MeCN, the solvent may potentially compete with methionine
Table 1 Hydrosilylation of 4’-fluoroacetophenone with rhodium complexesa
% conversion (% selectivity)b
Entry
[Rh]
5 min
10 min
0.5 h
1 h
84 (90)
83 (91)
86 (90)
2 h
98 (87)
92 (87)
97 (86)
1
2
3
4c
5
6
7
6a
6b
11
11
12
13
14
n/a
n/a
n/a
39 (77)
n/a
56 (83)
77 (90)
n/a
n/a
n/a
64 (73)
n/a
100 (82)
n/a
77 (93)
76 (94)
79 (93)
99 (71)
33 (71)
100 (80)
90 (97)
n/a
n/a
53 (68)
100 (79)
94 (95)
80 (67)
100 (79)
100 (92)
a General conditions: 4′-fluoroacetophenone (1 mmol), diphenylsilane
(2 mmol), and rhodium complex (1 mol%) in CD2Cl2 (1 mL)
at rt; b Conversion (selectivity towards 15 in parentheses) determined by
1H and/or 19F NMR spectroscopy; c With addition of AgOTf (1 mol%).
Fig. 1 CD spectra of complex 6b, 12, and the chelate 13 in MeCN and of 13 in
TFE.
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the previously noted lower catalytic activity of histidylidene an oligopeptide scaffold. Incorporation of an amino acid with
ruthenium and rhodium complexes when compared to their a donor site in the side chain in the i + 3 position allows for
imidazolylidene counterparts with identical first coordination the generation of a bidentate system, mimicking a metallo-
spheres yet lacking the remote amino acid functionality.11
enzyme active site with two coordinated amino acids. Chelation
has a beneficial effect on the catalytic activity of the metal
centre. These principles may be extended to introduce func-
tional sites also at the C-terminus of the oligopeptide and to
eventually engineer a second coordination site by biochemical
methods through incorporation of appropriate amino acids
that induce, for example, α-helical or β-turn conformations.
Such an approach provides active site models in which the his-
tidine is forced to bind via Cε in a carbene binding mode, thus
inducing new reactivity patterns.
Under identical conditions, the tyrosine-containing
rhodium complex 11 showed catalytic activity and selectivity
similar to complexes 6a,b containing only alanine residues,
converting 79% of the ketone in 30 min with 93% selectivity
towards 15 (entry 3). The phenol group present in the side
chain of the tyrosine residue seems to have no impact on the
catalytic properties of the rhodium complex. In contrast, the
methionine side chain in complex 12 is inhibiting catalytic
turnovers (33% conversion after 30 min, entry 5) and decreases
the selectivity from >90% to around 70%. Apparently, the coor-
dinating ability of the thioether side chain efficiently competes
with substrate coordination to the catalytically active centre.
Attempts to enhance the catalytic activity of 11 by inducing
in situ chelation were unsuccessful. For example, addition of
NEtiPr2 (2 mol%) as a base for potentially scavenging HCl from
complex 11 was unfavourable and gave only 57% conversion
after 30 min. However, modification of the rhodium coordi-
nation sphere by abstracting the metal-bound chloride
increased the catalytic activity of the rhodium complexes sub-
stantially. In the presence of a tyrosine side chain, essentially
complete conversion was achieved within 30 min upon acti-
vation of the catalyst precursor with AgOTf (entry 4, cf. 97% con-
version after 2 h with the RhCl unit). Interestingly, though, this
enhanced catalytic activity is accompanied by a loss in selec-
tivity from around 90% towards formation of 15 to only 70%. In
contrast, chloride abstraction from the methionine-containing
oligopeptide rhodium complex 12 and generation of the macro-
cyclic rhodium cation 13 increased the selectivity (entry 6).
Moreover, the activity is markedly higher than that of the
AgOTf-activated complex 11 as full conversion was accom-
plished within 10 min. This activity corresponds to an approxi-
mately four-fold increase of turnover rates, which is presumably
not only induced by the cationic nature of the rhodium centre,
but also by the beneficial effect of methionine coordination.
Since tyrosine chelation was not detected, similar effects due to
intramolecular stabilisation of the metal centre are absent with
complex 11. These results underline the relevance of chelation
and indicate the unique behaviour of the methionine-contain-
ing catalyst. Further optimisation of the peptide scaffold may
thus allow catalyst performance to be further improved.
Acknowledgements
We thank the European Research Council (ERC StG 208561),
the Swiss National Science Foundation, and COST Action
CM1003 for financial support.
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