Design of stable β-sheet-based cyclic peptide assemblies assisted by metal coordination: Selective homo- and heterodimer formation

Article abstract of DOI:10.1002/chem.201203213

Metal-directed supramolecular construction represents one of the most powerful tools to prepare a large variety of structures and functions. The ability of metals to organize different numbers and types of ligands with a variety of geometries (linear, trigonal, octahedral, etc.) expands the supramolecular synthetic architecture. We describe here the precise construction of homo- and heterodimeric cyclic peptide entities through coordination of a metal (Pd, Au) and to β-sheet-type hydrogen-bonding interactions. The selective coordination properties of the appropriate metal allow control over the cross-strand interaction between the two-peptide strands. Metal tweezers: The self-assembling properties of α,γ-cyclic peptides are reinforced by metal coordination to precisely construct homo- and heterodimeric complexes. The metal coordination is able to shift the equilibrium from several nonequivalent dimers to one single ensemble (see scheme). Copyright

Full text of DOI:10.1002/chem.201203213

DOI: 10.1002/chem.201203213
Design of Stable b-Sheet-Based Cyclic Peptide Assemblies Assisted by Metal
Coordination: Selective Homo- and Heterodimer Formation
Michele Panciera, Manuel Amorꢀn,* Luis Castedo, and Juan R. Granja*[a]
Abstract: Metal-directed supramolecu-
lar construction represents one of the
most powerful tools to prepare a large
variety of structures and functions. The
ability of metals to organize different
numbers and types of ligands with a va-
riety of geometries (linear, trigonal, oc-
tahedral, etc.) expands the supramolec-
ular synthetic architecture. We describe
here the precise construction of homo-
and heterodimeric cyclic peptide enti-
ties through coordination of a metal
(Pd, Au) and to b-sheet-type hydrogen-
bonding interactions. The selective co-
ordination properties of the appropri-
ate metal allow control over the cross-
strand interaction between the two-
peptide strands.
Keywords:
cyclic peptides
·
dimers · gold · metal tweezers ·
self-assembly
Organometallic and coordination complexes have become
established as very versatile tools—not only as a catalyst but
also for their potential applications in molecular electronics
and materials science.[1,2] Metal alkynyl derivatives are
amongst the most intriguing of these complexes and gold
acetylides are perhaps the most appealing to their lumines-
cent properties and their geometrical and electronic proper-
ties.[3] In addition to the interest in gold complexes due to
their novel catalytic properties,[4] gold acetylides have also
aroused great interest in supramolecular construction[5] and
sensing due to the combination of the linear coordination
geometry, the linearity of the acetylene moiety, and the
known tendency of gold to interact with itself (aurophilia).[6]
Gold(I) compounds also have several potential roles in bio-
logically related chemistry, due to their relatively low toxici-
ty and its lability.[7] Finally, peptides that carry functional or-
ganometallics are envisioned to provide novel systems in
which biological and metal-related properties are combined
to create useful assembly components for the preparation of
supramolecular functional materials. However, only a few
works on this aspect have been currently reported.[8]
species in a controlled way.[11] b-sheet-based structures have
become a powerful tool in supramolecular chemistry, biolo-
gy, and nanotechnology since chemists learned to control
the formation of multiple aggregates and to tailor the solu-
bility.[12] However, further understanding of the b-sheet for-
mation process and structure must be achieved to address
medical problems, such as Alzheimerꢀs and Parkinsonꢀs dis-
eases, amongst others.[13] Part of our program is devoted to
understanding the structural basis of the nanotube interac-
tions in an effort to control precisely the nanotube structure,
a possibility that would allow the development of further
applications. We envisaged that metal–ligand interactions
would be a useful tool not only to control and induce the su-
pramolecular process of nanotube formation, but also to
modulate the electronic and spectroscopic properties.[14] We
present a one-step route aimed at the precise b-sheet regis-
ter control based on a metal-directed assembly process that
induces the exclusive formation of homo- and/or heterodi-
meric entities with precise interpeptide arrangements.
In our preliminary studies we showed that cyclic peptides
that lack Cn symmetry form several (n) nonequivalent
dimers—such as hexapeptide CP1, which forms three
In recent years we have been interested in the preparation
of biocompatible supramolecular ensembles, such as peptide
nanotubes.[9,10] For this reason, we started a program for the
development of cyclic peptides that assemble through b-
sheet-type interactions to form homo- and/or heterodimeric
(Acw)1, and D(S)1 (Scheme 1).[15,16] Al-
dimers DACTHUNTRGENNUG(Accw)1, DACHUTNGTRENNGUN
though backbone–backbone interactions in the dimers are
almost identical, they can be distinguished by the different
cross-strand pairwise relationship between the a-amino acid
components of the cyclic monomers. The dimer ratios
depend on several factors, such as side-chain substitution,
backbone skeleton, and so on. For example, CP1, a 3-amino-
cyclohexanecarboxylic acid (g-Ach)-based cyclic peptide
that contains one serine, forms the three nonequivalent
dimers in 1:1:2 ratios. The major supramolecular diaster-
eomer is the one in which the serines are in register. Al-
though we initially attributed this finding to the formation
of an additional hydrogen-bonding interaction between the
hydroxyl groups of serines, other CPs that contain this
amino acid, such as the 3-aminocyclopentanecarboxylic acid
[a] M. Panciera, Prof. Dr. M. Amorꢁn, Prof. Dr. L. Castedo,
Prof. Dr. J. R. Granja
Departamento de Quꢁmica Orgꢂnica y
Unidad Asociada al CSIC, Centro singular de investigaciꢃn
en Quꢁmica Biolꢃgica y Materiales Moleculares (CIQUS)
Campus Vida, Universidad de Santiago de Compostela
15782 Santiago de Compostela (Spain)
Fax : (+34)881815704
E-mail: manuel.amorin@usc.es
juanr.granja@usc.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203213.
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FULL PAPER
Results and Discussion
Cyclic peptides CP4–6 were
prepared and these bear ortho-
or para-substituted diphenyl-
phosphinobenzoate
moieties
linked to a Ser or Lys side
chain. The peptides were pre-
pared from CP1 by reaction
with the corresponding (o,p)-
phosphinobenzoic acids in the
presence of N’-(3-dimethylami-
nopropyl)-N-ethylcarbodiimide
(EDC),
1-hydroxybenzotri-
azole (HOBt), and 1-hydroxy-
benzotriazole (DMAP) in di-
chloromethane and CP3 by re-
action with the corresponding
o-phosphinobenzoic acids in
the presence of N,N-diisopro-
pylethylamine (DIEA) and [O-
(7-azabenzotriazol-1-yl)-
N,N,N’,N’-tetramethyluronium
hexafluorophosphate] (HATU)
in dichloromethane. In nonpo-
lar solvents these peptides exit
as a mixture of three nonequi-
valent dimers in almost equi-
molecular ratios (D
ACHTUNGTRENN(UNG A,S)4, D-
Scheme 1. Cyclic peptides containing g-Ach (CP1, CP3–6) and g-Acp (CP2 and CP7) residues and model of
the three nonequivalent dimers (D(Accw)n, D(Acw)n, and D(S)n in which n is 1 to 7) formed by these non-C3
G
ACHTUNGTRENNUNG
N
ACHTUNGTRENNUNG
denced by the appearance of
several peaks between d=8.00
and 8.80 ppm corresponding to
the three amide protons in-
volved in hydrogen-bonding in-
symmetric peptides. At the bottom, top view of the schematic representation of the three nonequivalent
dimers derived with the nomenclature proposed for these systems and schematic representation of metal che-
lating properties of syn-dimer (D(S)n).
(g-Acp)-based CP2, did not show any special preference for
being on register. CP2 forms the three corresponding
dimers (DACHTUNGTRENNUNG(Accw)2, DAHCTUNGTRENN(UNG Acw)2, and D(S)2) in an almost equi-
teractions that are forming three nonequivalent dimers. For
example, CP4 showed nine doublets (see Figure 1 or the
Supporting Information for other peptides). In this case, the
three dimers are not formed in an equimolecular ratio, with
the less abundant dimer apparently the one in which both
phosphine-bearing side chains are in register (D(S)4). In
principle, only one of the three dimers, the syn form, can co-
ordinate metals as supramolecular bidentate ligands and
metal coordination should therefore restrict the interdimer
equilibria towards this form (Scheme 1).
This hypothesis was initially tested with the formation of
palladium complexes. Thus, addition of palladium acetate to
a deutorochloroform solution of CP4 (Figure 1) immediately
led to the formation of a single dimer, signified by the ap-
pearance of three new doublets in the NMR spectrum at
d=8.71, 8.66, and 8.04 ppm and the shift of the aromatic
proton signal from d=7.94 to 7.85 ppm. In addition, other
signals—such as the three methyl groups, which now appear
as one singlet per methyl group (d=3.17, 2.49, and
2.45 ppm)—also provide clear evidence of the formation of
the new complex. Addition of only 0.5 equivalents of metal
with respect to CP concentration (1.0 equiv per dimer) was
molecular ratio. Diastereoisomer control was recently ach-
ieved by means of salt-bridged interactions in CPs that con-
tain one Lys and Glu.[16b] Interestingly, the equilibrium can
be shifted to any other dimeric form through the addition of
an external chemical signal, such as divalent anions or cati-
ons. Unfortunately, these groups are not sensitive enough to
the addition of one equivalent of a specific metal and there-
fore cannot be used in sensing or other such applications.
Based on these results we believe that the use of improved
metal ligands, such as phosphines or alkynes, covalently
linked to the CP could bring additional sensitivity to this
equilibrium (Scheme 1) along with additional structural and
chemical information and complexity towards nanotechno-
logical applications. In an effort to learn about the organo-
metallic and supramolecular properties of this system we de-
cided to study complex formation on dimeric models, paying
attention not only to the formation of homomeric but also
heteromeric aggregates.[17]
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M. Amorꢁn, J. R. Granja et al.
On the other hand, CP5, which has the para-oriented
phosphine moiety, does not form the same type of complex.
Upon addition of palladium the distribution of aromatic
1
protons in the H NMR spectrum, together with the phos-
phorus NMR spectrum (in which the signal at d=À7.5 ppm
disappears as a new signal is formed at d=25.8 ppm), sug-
gests some changes at the phosphine moiety, which initially
we associated to metal coordination. In contrast to the pre-
vious discussed isomer, neither the NH proton signals nor
N-methyl groups change in ratio or shift upon addition of
palladium. One additional feature of the para-derivative
ligand is the appearance of a new peak in the mass spectrum
(1103, [M+16]+) which corresponds to the oxidized phos-
phine. This rapid oxidation precludes coordination to the
palladium and hence the interdimer equilibrium cannot be
restricted. Thus, whereas the Pd complex of ortho-oriented
derivatives (CP4 and CP6) can be stored at room tempera-
ture for several hours without evidence of oxidation, the
para-oriented analogue is oxidized in a few seconds even on
using degased solvents. These results confirm the equilibri-
um control through metal coordination with homodimers,
with only one complex formed on addition of the metal pro-
vided that the supramolecular bidentate ligand has the ap-
propriate geometry to coordinate the metal.
Figure 1. Homodimer equilibrium of CP4 to form one single dimer
(D(S)4[Pd]) directed by palladium coordination and 1H NMR spectro-
scopy upon addition of a) 0.0, b) 0.5, c) 1.0, and d) 2.0 equivalents of pal-
ladium acetate per dimer, respectively.
The above-mentioned properties of gold acetylide com-
plexes motivated us to prepare a new peptide bearing a ter-
minal alkyne (CP7). We envisaged that this CP could be
used in the supramolecular construction of both homo- and
heterodimeric complexes. As expected, in nonpolar solvents,
such as deuterochloroform, CP7 forms three nonequivalent
enough to shift completely the equilibrium towards the
dimer D(S)4[Pd] (Figure 1). Phosphorus NMR spectra
showed the downfield shift of phosphorous signal upon the
addition of palladium (form d=À6.0 to 11.1 ppm, see
Figure 1 in the Supporting Information). Further addition of
Pd (more than two equivalents) did not lead to any change
in the NMR spectrum, thus confirming the stability of the
chelate complex. Tetracoordination of palladium must occur
by simultaneous interaction of the metal with both the car-
bonyl and phosphine of each 2-phosphinobenzoate moiety.
On the other hand, the lysine-derived CP6, which has a
longer spacer between the phosphine moiety and the CP
skeleton, was also treated with palladium acetate (see Fig-
ure S2 in the Supporting Information). Initial addition of
one equivalent of palladium with respect to the dimer led to
the appearance of a new species, with the preferred forma-
tion of a single dimer, probably D(S)6[Pd], which is indicat-
ed by the doublet at d=8.70 ppm. It should be pointed out
that, in contrast with CP4, the formation of this dimer re-
quired several hours. Further addition of palladium gave
rise to the formation of new, different complexes, as evi-
denced by proton NMR spectra. The 31P NMR spectrum
contained only one signal (at d=29.9 ppm) after addition of
one equivalent of Pd per dimer. At least two nonequivalent
dimers can be differentiated, as shown by the three doublets
in the NH region for each dimer (d=8.80, 8.75, and
8.18 ppm for one dimer, and d=8.72, 8.69, and 8.25 ppm for
the other one). These two dimers could correspond to the
dimers (DACHTUNTRGENN(UG Accw)7, DACHTUNTGREN(NUNG Acw)7, and D(S)7) in almost equimolec-
ular ratio. We envisaged that gold acetylides would coordi-
nate to bidentate ligands, such as 1,2-bis(diphenylphosphi-
no)ethane (dppe) with two gold acetylides oriented towards
the same direction, perhaps assisted by gold–gold interac-
tions.[7] To this end, we added CP7 to a THF/MeOH (3:2)
solution of gold chloride in the presence of base (triethyla-
mine) to give a precipitate of the acetylide complex
AHCTUNGTRENNUNG
(CP7[Au])n.[18] Addition of this precipitate to a chloroform
solution of dppe induces the solubilization of the gold com-
plex and the formation of dimer D(S)7[Au]dppe (Scheme 2
and Figure S3 in the Supporting Information), in which the
phosphorus atoms are coordinated to the gold atoms of
each CP in the dimer. The formation of this dimer is clearly
evidenced by the simplification of amide signals (d=8.38,
8.25 and 8.21 ppm) in the NMR spectrum. Phosphorus
NMR spectra showed one new signal at d=19.7 ppm and
this confirms the existence of only one type of phosphorus
and its coordination to the metal. On the other hand, addi-
tion of triphenylphosphine to a suspension of gold complex
AHCTUNGTRENNUNG
a
G
ACHTUNGTRENNUNG
1
Scheme 2). The H NMR spectrum of this complex is similar
to the one observed for the dppe derivative
(D(S)7[Au]dppe; see Figure S4 in the Supporting Informa-
tion), but careful evaluation of amide proton signals sug-
gests the formation of at least two dimers. The number and
DACHTUNGTRENNUNG(Accw)6 and DACHTUNGTRENNUNG(Acw)6 forms, in which each phosphine is co-
ordinated to one palladium atom. The absence of D(S)6
could be attributed to the flexibility of the CP/phosphine
spacer, which reduces its chelating properties.
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Design of Stable b-Sheet-Based Cyclic Peptide Assemblies
FULL PAPER
Scheme 2. Homo and hetero-inter-dimer equilibrium of CP7 based on the formation of gold acetylide complexes. For simplicity most of the a-amino acid
side chains have been removed, the three nonequivalent dimers of triphenylphosphine complex are represented with the R group as an isopropyl or an
acetylene moiety (bottom-center). Inset: hetorodimeric gold complex formed before the addition of triethylamine, in which gold chloride is coordinated
to the phosphine moiety, the lack of interaction with the complementary CP (CP4 or CP6) allow the formation of the three nonequivalent dimers, denot-
ed by an R group that could be the phenyl or the acetylide moieties.
ratio of dimers could not be established; although it appears
that the two dimers are those in which gold complexes are
gold.[21] The stability of the gold complex is remarkable; it
can be purified by HPLC and stored at room temperature
for several weeks without detectable decomposition. The
heterodimeric gold derivative can also be formed in situ
simply by mixing the two peptides (CP6 and CP7) with gold
chloride in the presence of base (triethylamine). The forma-
tion of the complex was followed by H NMR spectroscopic
experiments (see Figure 2 and Figure S6 in the Supporting
Information). The initial mixture of the two peptides gave a
not in register (D
CATHGNUTRNEU(NGN Accw)7[Au]AHCTNUTREGG(NNNU PPh3)2 and DCATHNUGTREN(NUNG Acw)7[Au]-
ACHTUNGTRENNUNG
tions are not playing an important role in stabilizing the S
form, perhaps due to the steric repulsion of triphenylphos-
phine moieties or to the existence of some geometrical con-
straints.[19]
1
One of the special features of self-assembling cyclic pepti-
des that contain g-amino acids is their tendency to form, in
addition to homodimers, heterodimers that are more stable
than the corresponding homoderivatives.[17] This versatile
equilibrium, which is similar to that in natural systems,
opens the opportunity to create new molecular tools and ap-
plications.[20] Encouraged by this special feature, we decided
to evaluate the formation of heterodimers in which the
metal would be coordinated to two different ligands, such as
an alkyne and a phosphine. We envisaged that to achieve
the optimal linear gold coordination it would be necessary
to use the cyclic peptide with the longest spacer between
peptide backbone and the phosphine moiety (Figure 2).
Thus, we began by evaluating CP6, which solubilized the
gold complex precipitate
(ACTHNGUETRUNN(G CP7[Au])n) immediately on
1
mixing. The H NMR spectrum showed the formation of a
new dimer that was identified as the gold complex hetero-
dimer (Figure 2c and Figure S5 in the Supporting Informa-
tion). The amide signals at d=8.69 and 8.61 ppm were as-
signed for Leu and d=8.42 ppm for Phe residues; thus con-
firming the exclusive formation of D(S)6–7[Au]. The
31P NMR spectrum showed one signal at d=40.1 ppm that
was attributed to the phosphine coordinating the gold ion
(Figure S5 in the Supporting Information). The mass spec-
trum contained a peak (m/z: 2128.8, [M+Ag]+) that coin-
cides with the heterodimeric complex coordinated to
Figure 2. 1H NMR spectra showing the formation of different dimers as a
consequence of the equilibrium between CP6 and
(A,S)6, b) after the addition of 0.25 equivalents of (CP7[Au])n (mixture
of D(A,S)6 and D(S)6–7[Au]), c) after the addition of 1.0 equivalents of
(CP7[Au])n to form D(S)6–7[Au], d) mixture of CP6 and CP7
(0.9 equiv) forming D(A,S)6–7, e) after addition of AuCl·SMe2 to give D-
(A,S)6–7[AuCl], and f) after addition of 3.0 equivalents of Et3N to form
(A,S)6–7[Au]. The amide protons of lysine side chain (NHLys) are de-
ACHTUNGTRNE(NUNG CP7[Au])n: a) D-
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
DACHTUNGTRENNUNG
noted in the figure, which allows us to visualize the formation of different
dimers in each mixture.
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M. Amorꢁn, J. R. Granja et al.
complex NMR spectrum with multiple NH signals (Fig-
ure 2d), which in some cases did not overlap with any of the
signals of the corresponding homodimers, which suggests
the main formation of the three nonequivalent heterodimers
triethylamine. In this case formation of the complex takes
longer and several equivalents of amine are required. To
achieve the formation of T-shaped D(S)4–7[Au] (Scheme 3)
by avoiding the removal of the acetylene proton, we re-
(DACHTUNGTRENNUNG(A,S)6–7). This complex
NMR spectrum did not allow
an accurate estimate of the
dimer ratios, although it can be
inferred on the basis of preced-
ing examples that correspond
to an equimolecular mixture of
the three nonequivalent heter-
odimers. Interestingly, addition
of one equivalent of gold
chloride led to changes in the
aromatic signals of phosphine
moieties (31P NMR showed a
new signal at d=29.5 ppm
compared with d=À11.5 ppm
for the starting heterodimer D-
ACHTUNGTRENNUNG(A,S)6–7), although the finger-
print signals of the amide pro-
tons still showed the existence
of a complex mixture of the
three nonequivalent dimers
(Figure 2e). The lack of infor-
Scheme 3. Structure of the expected T-shaped gold complex (T-shaped D(S)4–7[Au]) and the observed homo-
dimer D(S)4[Au] resulting of mixing CP4 and CP7 with gold(I) followed by addition of silver hexafluoroan-
timonate.
mation transfer between the two peptides suggests that the
alkyne moiety does not interact with the metal, which must
remain coordinated to the chloride. Under these conditions
gold-complex dimeric structure must exist as a mixture of
placed triethylamine with a silver salt. Under these condi-
tions, the formation of a new dimer was observed, see Fig-
ure S8 in the Supporting Information. Firstly, the CPs and
gold were mixed and the formation of the three nonequiva-
lent heterodimers was confirmed by NMR spectroscopy (see
Figure S8d in the Supporting Information). One equivalent
of silver hexafluoroantimonate was then added and a precip-
itate was formed and a dramatic change was observed in the
NMR spectrum of the mixture (Figure S8e in the Supporting
Information). The NH region of the newly formed complex
is very simple, with only one set of signals corresponding to
three amide protons of a single peptide. None of the signals
corresponding to CP7 appear in the NMR spectrum, which
must precipitate as a silver acetylide, whereas the phos-
phine-bearing CP (CP4) apparently forms a single isomer,
to which we have attributed the structure D(S)4[Au]
the three nonequivalent dimers (DACHTUNTRGENN(UG A,S)6–7CAHTUNGTERN[NUGN AuCl]) in an
equimolecular ratio as can be inferred by the three triplets
at d=6.80, 6.74, and 6.68 ppm that correspond to the amide
proton of lysine side chains of each dimer. Addition of trie-
thylamine (three equivalents) removed the terminal alkyne
proton and led to the formation the gold acetylide (Sche-
me 2f and Figure S6 in the Supporting Information), the
NMR spectra (1H and 31P) of which are identical to that ob-
tained through the gold-acetylide preformation method.
The good results obtained with CP6 led us to investigate
heterodimer formation involving the ligand with the shorter
spacer (CP4). The addition of ACHTNUGTRENUNG(CP7[Au])n to a chloroform
solution of CP4 gave linear gold complex D(S)4–7[Au]
(Scheme 2), as indicated by the simplification of the NH sig-
nals (see Figure S7 in the Supporting Information) in the
NMR spectra and confirmed by mass spectrometry (m/z:
2087.8, [M+Ag]+).[21] This result was quite surprising be-
cause we believed that the spacer between CP and the phos-
phine moiety was too short to accommodate the linear coor-
dination of gold. We were interested in observing the forma-
tion of the gold p-complex as a straightforward route to vi-
nylidenemetal complexes.[22] In this T-shaped gold complex
the metal is h2-bonded to the alkyne, through which the re-
action mechanism is generally thought to proceed,[23] but
such complexes have not yet been well-characterized. Fur-
thermore, D(S)4–7[Au] can also be formed in one step by
mixing both CPs with gold chloride followed by addition of
(Scheme 3). Mass spectrometry (m/z: 1186.0242 [M+H]2+
)
supports the formation of D(S)4[Au] and this was con-
firmed by mixing CP4 with gold chloride followed by treat-
ment with AgSbF6, a process that gave rise to the same com-
plex (see Figure S9 in the Supporting Information). The
silver derivative (D(S)4[Ag]) was discarded because the
treatment of CP4 with the silver salt did not give a com-
pound with the same characteristics as those from the previ-
ous experiments (Figure S9b in the Supporting Information).
The behavior of CP with phosphine-derived Lys (CP6) is
quite different with respect to silver salt addition. Under
similar conditions, the treatment of CP7 and CP6 (gold
chloride followed by addition of AgSbF6) led to the forma-
tion of a complex mixture of compounds that could not be
characterized.
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Design of Stable b-Sheet-Based Cyclic Peptide Assemblies
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To further assess the relative stability of homo- and heter-
odimer complexes, the homodimer D(S)7[Au]dppe was
treated with one equivalent of CP6 and the formation of
heterodimer D(S)6–7[Au] as a single product was observed
immediately. Thus, the heterodimer between the CPs CP6
and CP7 make the interaction between the gold acetylide
and phosphine moiety more stable than the homodimer in
which two gold acetylide phosphine interactions are present.
On the other hand, when this heterodimer was treated with
an excess of the dppe ligand (see Figure S10 in the Support-
ing Information), a shift in the equilibrium towards the cor-
responding homodimer did not occur. Similarly, the addition
of dppe to the Ser-derived heterodimer (D(S)4–7[Au])
or Au, the dimers behaved as chelating ligands to coordinate
with the metal. This coordination restricted the interdimer
equilibria to the form in which the amino acids that contain
the phosphine moieties in each CP are hydrogen-bonded. In
addition, selective heterodimer formation can be achieved
by forming gold acetylide complexes. These complexes can
form stable homodimers by coordination with bidentate
phosphines (dppe) or heterodimers by addition of a phos-
phine-containing CP. In all of these examples, metal coordi-
nation restricts the b-sheet register to allow the metal to co-
ordinate to both peptides. The length of the spacer between
the CP skeleton and the phosphine moiety modifies the sta-
bility of the complexes.
drove
the
equilibrium
towards
the
homodimer
D(S)7[Au]dppe. These experiments again confirm the
higher stability of the Lys-derived heterodimer in compari-
son to D(S)4–7[Au], which is even less stable than the dppe
homodimer.
Experimental Section
Materials and methods: See the Supporting Information
Finally, these complexes can also be used for carbon–
carbon bond-forming processes. For example, a Sonoga-
shira-type reaction occurred when gold complex D(S)6–
7[Au] was treated with 4-iodoanisole in boiling chloroform
for 24 h. This reaction gave CP8 although the yield was not
high (15%).[24] Better results were obtained when catalytic
amounts (1.2%) of palladium dibenzylideneacetone ([Pd2-
Peptide synthesis: Synthesis of amino acids (Acp and Ach) and hexapep-
tides were prepared by following a similar synthetic strategy previously
described elsewhere.[11,17]
c-[l-Ser(Bn)-d-MeN-g-Ach-(l-Phe-d-MeN-g-Ach-)2]: A solution of Boc-(l-
Phe-d-MeN-g-Ach-)2l-Ser(Bn)-d-MeN-g-Ach-OFm
(tert-butoxycarbonyl,
332 mg, 0.28 mmol) in 20% piperidine in CH2Cl2 (2.8 mL) was stirred at
RT for 30 min. After removal of the solvent, the residue was dissolved in
CH2Cl2 (40 mL) and washed with HCl (5%), dried over Na2SO4, filtered,
and concentrated. The resulting material was dissolved in TFA/CH2Cl2
(1:1, 2.5 mL) and stirred at RT for 10 min. The solvent was removed and
the residue was dried under high vacuum for 3 h and used without fur-
ther purification. The linear peptide was dissolved in CH2Cl2 (280 mL)
and treated with TBTU (1-[bis(dimethylamino)methylene]-1H-benzotria-
zolium tetrafluoroborate 3-oxide) (99 mg, 0.31 mmol), followed by drop-
wise addition of DIEA (290 mL, 1.70 mmol). After 12 h, the solvent was
removed under reduced pressure, and the crude was purified by flash
chromatography (0–7% MeOH/CH2Cl2) to afford 204 mg of c-[l-
Ser(Bn)-d-MeN-g-Ach-(l-Phe-d-MeN-g-Ach-)2] as a white solid (82%, Rf =
ACHTUNGTRENNUNG(dba)3]·CHCl3) were also added, in which case the cross-cou-
pling process gave a higher yield (35%) in a shorter reaction
time. The reaction was also carried out with derivative
D(S)7[Au]dppe and CP8 was also obtained in 45% yield.
Finally, the process can be carried out by using catalytic
amounts of gold chloride, palladium, and phosphine (CP6)
in the presence of base (Et3N) to give CP8 in similar yields
(Scheme 4).
1
0.60 (5% MeOH/CH2Cl2)). H NMR (500 MHz, CDCl3, 258C, TMS): d=
8.82 (d, 3J(H,H)=9.2 Hz, 0.36H; NHPhe), 8.78 (d, 3J
ACTHNUGTRENNUGN ACHTUNGTRENNNUG
0.38H; NHPhe), 8.76 (d, 3J
(H,H)=9.3 Hz, 0.30H; NHPhe), 8.63 (d, J
8.59 (d, 3J(H,H)=8.9 Hz, 0.32H; NHPhe), 8.54 (d, 3J
0.35H; NHSer), 8.50 (d, 3J(H,H)=9.4 Hz, 0.35H; NHSer), 8.31 (d, 3J-
(H,H)=9.3 Hz, 0.30H; NHSer), 7.25 (m, 15H; Ar), 5.54 (m, 1H; HaSer),
ACHTUNGTRENNUNG
3
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
5.36 (m, 2H; HaPhe), 4.79–4.30 (m, 5H; HgAch, CHbBn), 3.86–3.33 (m, 2H;
HbSer), 3.24–2.75 (m, 7H; HbPhe, HaAch), 3.10 (s, 2H; Me-N), 3.07 (s, 1H;
Me-N), 2.58 ppm (s, 6H; Me-N); FTIR (293 K, CaF2 Pellet): n˜ =3303
(amide A), 2932, 2861, 1671 (amide III), 1625 (amide I), 1525 cmÀ1
(amide II); MS (ESI): m/z (%): 912 (58) [M+Na]+, 890 (100) [M+H]+;
HRMS (ESI): m/z: calcd for C52H69N6O7: 889.5222; found: 889.5218.
c-[l-Lys(Z)-d-MeN-g-Ach-(l-Phe-d-MeN-g-Ach-)2]: The mentioned cyclic
peptide was prepared from Boc-(l-Phe-d-MeN-g-Ach-)2l-Lys(Z)-d-MeN-g-
Ach-OFm (180 mg, 0.14 mmol) by following a similar procedure descri-
bed for c-[l-Ser(Bn)-d-MeN-g-Ach-(l-Phe-d-MeN-g-Ach-)2] to afford, after
purification by flash chromatography (2–7% MeOH/CH2Cl2), 67 mg of
expected CP as a white solid (48%, Rf =0.60 (5% MeOH/CH2Cl2)).
Scheme 4. Sonogashira cross-coupling studies carried out with peptide–
gold complexes to form CP8.
1H NMR (500 MHz, CDCl3, 258C, TMS): d=8.76 (d, 3J
0.33H; NHPhe), 8.75 (d, 3J(H,H)=9.2 Hz, 0.33H; NHPhe), 8.68 (d, 3J-
(H,H)=8.6 Hz, 0.33H; NHPhe), 8.67 (d, J
8.60 (d, 3J(H,H)=9.0 Hz, 0.33H; NHPhe), 8.59 (d, 3J
0.33H; NHPhe), 8.42 (d, 3J(H,H)=9.4 Hz, 0.33H; NHLys), 8.37 (d, 3J-
(H,H)=9.4 Hz, 0.33H; NHLys), 8.24 (d, 3J
(H,H)=9.4 Hz, 0.33H; NHLys),
7.23 (m, 15H; Ar), 5.28 (m, 2H; HaPhe), 5.16–4.81 (m, 3H; HaLys, CH2Bn),
4.54 (m, 3H; HgAch), 3.14–2.70 (m, 9H; HaAch, HbPhe, HdLys), 2.99 (m,
3H; Me-N), 2.54, 2.51, 2.50, 2.49, 2.48 ppm (5 s, 6H; Me-N); FTIR
(293 K, CaF2 Pellet): n˜ =3302 (amide A), 3001, 2931, 2860, 1716, 1666
ACHTUNGTREN(NUNG H,H)=9.1 Hz,
AHCTUNGTRENNUNG
Conclusion
3
G
ACHTUNGTRENNUNG
E
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
We have described how the use of metal coordination can
allow the selective formation of a single dimer. The peptides
designed for this purpose self-assemble through b-sheet-type
interactions and contain phosphine moieties attached to an
amino acid side chain. In the presence of metals, such as Pd
R
ACHTUNGTRENNUNG
Chem. Eur. J. 2013, 19, 4826 – 4834
ꢄ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4831

M. Amorꢁn, J. R. Granja et al.
(amide III), 1624 (amide I), 1525 cmÀ1 (amide II); MS (ESI): m/z (%):
997 (100) [M+Na]+, 975 (43) [M+H]+; HRMS (ESI): m/z: calcd for
C56H75N7NaO8: 996.5569; found: 996.5576.
NHLys), 7.55 (brs, 0.6H; Ar2-DPPBA), 7.44 (brs, 0.35H; Ar2-DPPBA), 7.36–7.10
(m, 22H; ArPhe, Ar2ÀDPPBA), 6.91 (s, 1H; Ar2ÀDPPBA), 6.48 (s, 0.35H;
NHwLys), 6.05 (s, 0.30H; NHwLys), 5.30 (m, 2H; HaPhe), 5.11 (m, 0.60H;
HaLys), 5.04 (m, 0.40H; HaLys), 4.54 (m, 3H; HgAch), 3.19–2.73 (m, 9H;
HaAch, HbPhe, HdLys), 2.99 (s, 3H; Me-N), 2.55, 2.53, 2.52, 2.51, 2.50,
2.48 ppm (6 s, 6H; Me-N); 31P NMR (121 MHz, CDCl3, 258C): d=
À11.4 ppm; FTIR (293 K, CaF2 Pellet): n˜ =3303 (amide A), 3002, 2932,
2861, 1657 (amida III), 1624 (amide I), 1528 cmÀ1 (amide II); MS (ESI):
c-[l-Ser
ACHTUNGTRENNUNG
tion of
56 mmol) in Pd(OH)2 (10 mg, 20% wt.) in EtOH (630 mL) was stirred at
RT for 5 h under a hydrogen atmosphere (balloon pressure). The result-
ing mixture was filtered through a Celite pad, the residue was washed
with ethanol, and the combined filtrates and washings were concentrated
under reduced pressure. The resulting material was dissolved in CH2Cl2
(270 mL) and treated with 2-(diphenylphosphino)benzoic acid (2-DPPBA,
12.6 mg, 41 mmol), HOBt (8.4 mg, 60 mmol), EDC·HCl (12 mg, 60 mmol),
and DMAP (7.6 mg, 60 mmol). After 3 h the solvent was removed under
reduced pressure. The residue was purified by flash chromatography (2–
6% MeOH/CH2Cl2) to afford 31 mg of CP4 as a white solid (69%, Rf =
m/z (%): 1151 (6) [M+Na]+, 1129 (100) [M+H]+, 565 (92) [M+H]2+
;
HRMS (ESI): m/z: calcd for C67H83N7O7P: 1128.6086; found: 1128.6061.
c-[l-Prg-d-MeN-g-Acp-(l-Leu-d-MeN-g-Acp-)2] (CP7): The mentioned
cyclic peptide was prepared from Boc-(l-Leu-d-MeN-g-Acp-)2l-Prg-
d-MeN-g-Acp-OFm (188 mg, 0.19 mmol) by following a similar procedure
described for c-[l-Ser(Bn)-d-MeN-g-Ach-(l-Phe-d-MeN-g-Ach-)2] to
afford, after purification by flash chromatography (2–7% MeOH/
CH2Cl2), 110 mg of CP7 as a white solid (84%, Rf =0.6 (5% MeOH/
CH2Cl2)). 1H NMR (500 MHz, CDCl3, 258C, TMS): d=8.35 (d,
1
0.50 (5% MeOH/CH2Cl2)). H NMR (500 MHz, CDCl3, 258C, TMS): d=
8.76 (d, 3J(H,H)=9.2 Hz, 0.40H; NHPhe), 8.73 (d, 3J
ACHTUNGTRENNUNG ACHTUNGTRENNUNG
3J
NHPrg), 8.22 (d, 3J
3J(H,H)=8.3 Hz, 0.50H; NHLeu), 5.35 (q, 3J
ACHTUNGTRENNUNG
N
ACHTUNGTRENNUNG
0.30H; NHPhe), 8.69 (d, 3J
3J
ACHTUNGTRENNUNG
E
,
N
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
5.17 (m, 2H; HaLeu), 4.94–4.69 (m, 3H; HgAcp), 3.10 (s, 3H; Me-N), 3.07
(s, 6H; Me-N), 2.92 ppm (m, 3H; HaAcp); FTIR (293 K, CaF2 Pellet): n˜ =
3300 (amide A), 2956, 1672 (amide III), 1618 (amide I), 1533 cmÀ1 (amide
II); MS (ESI): m/z (%): 719 (78) [M+Na]+, 698 (100) [M+H]+; HRMS
(ESI): m/z: calcd for C38H61N6O6: 697.4647; found: 697.4637.
AHCTUNGTRENNUNG
(brs, 1H; Ar2-DPPBA), 7.22 (m, 22H; ArPhe, Ar2-DPPBA), 6.89 (brs, 1H;
Ar2-DPPBA), 5.51 (brs, 1H; HaSer), 5.33 (m, 2H; HaPhe), 4.53 (m, 3.75H; 3
HgAch, 0.75 HbSer), 4.38 (dd, 3J
ACHTUNGTRENNUNG
(m, 0.75H; HbSer), 4.11 (dd, 3J
ACHTUNGTRENNUNG
c-[l-Prg(4-methoxyphenyl)-d-MeN-g-Acp-(l-Leu-d-MeN-g-Acp-)2] (CP8):
In a screw-cap sealed tube a mixture of CP7 (5.0 mg, 6.95 nmol), 4-iodoa-
nisole (3.4 mg, 14.5 nmol), AuCl·SMe2 (2.1 mg, 71.3 nmol), CP6 (8.1 mg,
71.9 nmol), and Et3N (6 mL) were dissolved in CHCl3 (2.5 mL) and [Pd2-
2.97 (2 s, 2.30H; Me-N), 2.90 (s, 0.70H; Me-N), 2.54, 2.53, 2.51, 2.50,
2.49 ppm (5 s, 6H; Me-N); 31P NMR (121 MHz, CDCl3, 258C): d=
À6.0 ppm; FTIR (293 K, CaF2 Pellet): n˜ =3307 (amide A), 3001, 2931,
2860, 1718, 1670 (amide III), 1626 (amide I), 1523 cmÀ1 (amide II); MS
(ESI): m/z (%): 1088 (100) [M+H]+; HRMS (ESI): m/z: calcd for
C64H76N6O8P: 1087.5457; found: 1087.5453.
AHCTUNTGREGUN(NN dba)3]·CHCl3 (1.2 mol%, 0.76 mg, 0.083 nmol) was added. The tube was
sealed and heated at 408C for 24 h. After cooling down, the mixture was
purified by HPLC (Rt =15.0 min, 5–15% MeOH/CH2Cl2, Phenomenex,
5 m, 250ꢅ10.00 mm, 5 micron) to afford 2 mg of CP8 as a yellow oil
c-[l-SerACHTUNGTRENNUNG
(4-DPPBA)-d-MeN-g-Ach-(l-Phe-d-MeN-g-Ach-)2] (CP5): Pre-
pared from c-[l-Ser(Bn)-d-MeN-g-Ach-(l-Phe-d-MeN-g-Ach-)2] (21.7 mg,
24 mmol) in the same way as CP4 to yield, after HPLC purification (Rt =
(35%). 1H NMR (500 MHz, CDCl3, 258C, TMS): d=8.38 (d, 3J
ACHTUNGTRENNUNG
6.4 Hz, 1H; NHPrg), 8.23 (d, 3J
Ar), 6.80 (d, 3J
ACHTUNGTRENNUNG
17.3 min, 1–15% MeOH/CH2Cl2, Phenomenex, 5 m, 250ꢅ10.0 mm,
5
N
ACHTUNGTRENNUNG
micron), 18.5 mg of CP5 as a white solid (71%, Rf =0.50 (5% MeOH/
CH2Cl2)). 1H NMR (500 MHz, CDCl3, 258C, TMS): d=8.76 (d,
HaPrg), 5.17 (s, 2H; HaLeu), 4.95–4.72 (m, 3H; HgAcp), 3.79 (s, 3H; Me-
O), 3.13 (s, 3H; Me-N), 3.08 (s, 6H; Me-N), 2.95 ppm (m, 3H; HaAcp);
FTIR (293 K, CaF2 Pellet): n˜ =3300 (amide A), 2957, 2872, 1672 (amide
III), 1622 (amide I), 1531 cmÀ1 (amide II); MS (ESI): m/z (%): 1607 (10)
[M+H]2+, 826 (54) [M+Na]+, 804 (100) [M+H]+; HRMS (ESI): m/z:
calcd for C45H67N6O7: 803.5066; found: 803.5078.
3J
NHPhe), 8.68 (d, 3J
8.6 Hz, 0.35H; NHPhe), 8.36 (d, 3J
3J(H,H)=7.9 Hz, 0.30H; NHSer), 8.31 (d, 3J
NHSer), 7.83 (d, 3J
(H,H)=7.7 Hz, 2H; CH-Ar2-DPPBA), 7.25 (m, 22H;
ACHTUNGTRENNUNG ACHTUNGTRENNUNG
(H,H)=9.1 Hz, 0.60H; NHPhe), 8.72 (d, 3J
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
c-[l-Prg[Au]-d-MeN-g-Acp-(l-Leu-d-MeN-g-Acp-)2] (CP7[Au])n: A solu-
tion of CP7 (8.0 mg, 9.96 nmol) and Et3N (10 mL, 71.9 nmol) in THF
(750 mL) was added to a solution of AuCl·SMe2 (3.4 mg, 11.54 nmol) in
THF (750 mL) and MeOH (560 mL). After having been stirred at RT for
30 min the solid was isolated by filtration, washed successively with THF,
MeOH, and Et2O to afford, after high vacuum drying, 8.1 mg of
CH-ArPhe, CH-Ar2-DPPBA), 5.61 (m, 1H; HaSer), 5.31 (m, 2H; HaPhe), 4.70–
4.24 (m, 5H; HgAch, HbSer), 3.13–2.75 (m, 7H; HbPhe, HaAch), 3.10, 3.09,
3.08 (3s, 3H; Me-N), 2.53, 2.52, 2.51, 2.50 ppm (4s, 6H; Me-N);
31P NMR (121 MHz, CDCl3, 258C): d=À7.5 ppm; FTIR (293 K, CaF2
Pellet): n˜ =3307 (amide A), 2929, 2858, 1730, 1670 (amide III), 1624
(amide I), 1522 cmÀ1 (amide II); MS (ESI): m/z (%): 1110 (64) [M+Na]+,
1088 (79) [M+H]+, 544 (100) [M+H]2+; HRMS (ESI): m/z: calcd for
C64H76N6O8P: 1087.5457; found: 1087.5449.
AHCTUNGTREG(NNNU CP7[Au])n (79%). The peptide was stored in the refrigerator and pro-
tected from light and used without further characterization.[18]
c-[l-LysACHTUNGTRENNUNG
(2-DPPBA)-l-MeN-g-Ach-(l-Phe-d-MeN-g-Ach-)2] (CP6): A solu-
D(S)4–7[Au]: Procedure A: Peptide CP4 (4.9 mg, 4.5 nmol) was dis-
solved in CDCl3 (500 mL) in a NMR tube and portions (0.25, 0.50, 0.75,
tion of c-[l-Lys(Z)-l-MeN-g-Ach-(l-Phe-d-MeN-g-Ach-)2] (33.3 mg,
34 mmol) in Pd/C (6.7 mg, 10% in wt.) in MeOH (2.2 mL) was stirred at
RT for 5 h under hydrogen atmosphere (balloon pressure). The resulting
mixture was filtered through a Celite pad, the residue was washed with
methanol, and the combined filtrates and washings were concentrated
under reduced pressure. The resulting material was dissolved in CH2Cl2
(340 mL) and treated with 2-DPPBA (10.5 mg, 34 mmol) and HATU
(14.2 mg, 37 mmol), followed by the dropwise addition of DIEA (35 mL,
0.204 mmol). After 3 h the solvent was removed under reduced pressure.
The crude was purified by flash chromatography (0–6% MeOH/CH2Cl2)
to afford 19.0 mg of CP6 as a white solid (50%, Rf =0.50 (5% MeOH/
and 1.0 equiv) of
dimer formation. 1H NMR (500 MHz, CDCl3, 258C, TMS): d=8.73 (d,
3J(H,H)=9.6 Hz, 1H; NHLeu), 8.65 (d, 3J
(H,H)=9.4 Hz, 1H; NHLeu),
8.46 (d, 3J(H,H)=9.5 Hz, 1H; NHSer), 8.43 (d, 3J
(H,H)=9.5 Hz, 1H;
NHPhe), 8.42 (d, 3J(H,H)=9.4 Hz, 1H; NHPhe), 8.04 (d, 3J
(H,H)=6.3 Hz,
1H; NHPrg), 7.82 (m, 1H; Ar2-DPPBA), 7.55–7.44 (m, 6H; Ar), 7.43–7.34
(m, 6H; Ar), 7.29–7.11 (m, 10H; ArPhe), 6.86 (dd, 3J
(H,H)=10.3, 8.3 Hz,
ACHTUNGTRNE(NUNG CP7[Au])n (4.5 mg, 4.5 nmol) were added for hetero-
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
1H; Ar2-DPPBA), 5.50 (m, 1H; HaSer), 5.24 (m, 2H; HaLeu, HaPhe), 5.18 (m,
2H; HaLeu, HaPhe), 5.00 (m, 3H; HgAcp), 4.86 (brs, 1H; HaPrg), 4.71 (dd,
3
3J
C
G
1
3
CH2Cl2). H NMR (500 MHz, CDCl3, 258C, TMS): d=8.77 (d, J
9.4 Hz, 0.35H; NHPhe), 8.75 (d, 3J
(H,H)=9.4 Hz, 0.35H; NHPhe), 8.69 (d,
3J(H,H)=8.8 Hz, 0.35H; NHPhe), 8.67 (d, 3J
(H,H)=8.8 Hz, 0.35H;
NHPhe), 8.61 (d, 3J(H,H)=8.4 Hz, 0.35H; NHPhe), 8.59 (d, 3J
(H,H)=
8.4 Hz, 0.35H; NHPhe), 8.45 (d, 3J
(H,H)=9.3 Hz, 0.30H; NHLys), 8.40 (d,
3J(H,H)=9.6 Hz, 0.30H; NHLys), 8.26 (d, 3J
(H,H)=9.4 Hz, 0.36H;
ACHTUNGTRNE(NUNG H,H)=
4.37 (m, 3H; HgAch), 3.25 (m, 2H; HbPrg, HaAcp), 3.11 (s, 3H; Me-N),
G
3.09 (s, 3H; Me-N), 2.98 (s, 3H; Me-N), 2.98 (s, 3H; Me-N), 2.81 (d,
E
R
3J
ACTHNGUTREN(NUG H,H)=17.0 Hz, 1H; HbPrg), 2.72 (m, 2H; HaAcp, HaAch), 2.58 (s, 3H;
G
A
Me-N), 2.56 (s, 3H; Me-N), 2.72 (m, 2H; HaAch), 2.34–2.03 (m, 2H;
HaAcp), 0.90 ppm (overlapped doublets, 12H; MeLeu); 31P NMR
(121 MHz, CDCl3, 258C): d=40.9 ppm; FTIR (293 K, CHCl3): n˜ =3302
AHCTUNGTRENNUNG
R
ACHTUNGTRENNUNG
4832
www.chemeurj.org
ꢄ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 4826 – 4834

Design of Stable b-Sheet-Based Cyclic Peptide Assemblies
FULL PAPER
(amide A), 2999, 2958, 2933, 2862, 1670 (amide III), 1624 (amide I),
P.1; c) V. W.-W. Yam, S. W. K. Choi, K. K. Cheung, Organometallics
1996, 15, 1734–1739; d) J. Li, P. Pyykkç, Chem. Phys. Lett. 1992,
197, 586–590; e) H. Schmidbaur, Chem. Soc. Rev. 1995, 24, 391–
400; f) P. Pyykkç, Angew. Chem. 2004, 116, 4512–4557; Angew.
Chem. Int. Ed. 2004, 43, 4412–4456.
1531 cmÀ1 (amide II); MS-MALDI-TOF: m/z (%): 2088 (100) [M+Ag]+.
D(s)6–7[Au]: Procedure B: Peptide CP6 (4.9 mg, 4.3 nmol), CP7
(3.0 mg, 4.3 nmol), and AuCl·SMe2 (1.3 mg, 4.3 nmol) were dissolved in
CDCl3 (500 mL) in a NMR tube and portions (1.0, 2.0 and 3.0 equiv) of
triethylamine (1.8 mL, 13.0 nmol) were added to form the mentioned het-
erodimeric gold complex. 1H NMR (500 MHz, CDCl3, 258C, TMS): d=
[7] H. E. Abdou, A. A. Mohamed, J. P. Fackler Jr, A. Burini, R. Galassi,
J. M. Lꢃpez-de-Luzuriaga, M. E. Olmos, Coord. Chem. Rev. 2009,
253, 1661–1669.
8.69 (d, 3J
NHLeu), 8.42 (m, 4H; NHPhe, NHLys, NHPrg), 7.63 (brs, 1H; Ar2-DPPBA),
7.52–7.32 (m, 12H; Ar), 7.29–7.13 (m, 10H; ArPhe), 6.86 (dd, 3J
(H,H)=
10.4, 8.1 Hz, 1H; Ar2-DPPBA), 6.28 (dd, 3J
(H,H)=7.0, 3.4 Hz, 1H;
NHwLys), 5.22 (m, 4H; HaPhe, HaLeu), 4.97 (m, 4H; HaPrg, HaLys, 2HgAcp),
ACHTUNGTRENNUNG ACHTUNTGREN(NUGN H,H)=9.3 Hz, 1H;
(H,H)=9.4 Hz, 1H; NHLeu), 8.61 (d, 3J
[8] a) K. Ogata, D. Sasano, T. Yokoi, K. Isozaki, H. Seike, N. Yasuda, T.
Ogawa, H. Kurata, H. Takaya, M. Nakamura, Chem. Lett. 2012, 41,
194–196; b) T. Moriuchi, T. Hirao, Acc. Chem. Res. 2010, 43, 1040–
1051; c) F. Fujimura, S. Kimura, Org. Lett. 2007, 9, 793–796; d) T.
Moriuchi, A. Nomoto, K. Yoshida, A. Ogawa, T. Hirao, J. Am.
Chem. Soc. 2001, 123, 68–75; e) Bioorganometallics: Biomolecules,
Labeling, Medicine, (Ed.: G. Jaouen), Wiley-VCH, Weinheim, 2006.
[9] a) M. R. Ghadiri, J. R. Granja, R. A. Milligan, D. E. McRee, N. Kha-
zanovich, Nature 1993, 366, 324–327; b) J. D. Hartgerink, T. D.
Clark, M. R. Ghadiri, Chem. Eur. J. 1998, 4, 1367–1372; c) D. T.
Bong, T. D. Clark, J. R. Granja, M. R. Ghadiri, Angew. Chem. 2001,
113, 1016–1041; Angew. Chem. Int. Ed. 2001, 40, 988–1011; d) R. J.
Brea, C. Reiriz, J. R. Granja, Chem. Soc. Rev. 2010, 39, 1448–1456.
[10] a) R. Garcꢁa-FandiÇo, J. R. Granja, M. DꢀAbramo, M. Orozco, J.
Am. Chem. Soc. 2009, 131, 15678–15686; b) C. Reiriz, R. J. Brea, R.
Arranz, J. L. Carrascosa, A. Garibotti, B. Manning, J. M. Valpuesta,
R. Eritja, L. Castedo, J. R. Granja, J. Am. Chem. Soc. 2009, 131,
11335–11337.
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
3
4.81 (pentet, J
1H; HwLys), 3.09 (s, 9H; Me-N), 2.97 (s, 3H; Me-N), 2.76–2.60 (m, 3H;
HaAch), 2.58 (s, 3H; Me-N), 2.52 (s, 3H; Me-N), 0.96 (d, 3J
(H,H)=
5.4 Hz, 6H; MeLeu), 0.90 (d, 3J
(H,H)=6.2 Hz, 3H; MeLeu), 0.89 ppm (d,
3J(H,H)=6.1 Hz, 3H; MeLeu); 31P NMR (121 MHz, CDCl3, 258C): d=
ACHTUNGTRENNUNG(H,H)=8.6 Hz, 1H; HgAcp), 4.36 (m, 3H; HgAch), 3.70 (m,
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
40.1 ppm; FTIR (293 K, CHCl3): n˜ =3300 (amide A), 2999, 2956, 2931,
2870, 1664 (amide III), 1624 (amide I), 1531 cmÀ1 (amide II); MS-
MALDI-TOF: m/z (%): 2129 (100) [M+Ag]+.
Acknowledgements
This work was supported by the Spanish Ministry of Economy and Com-
petivity (MEC) and the ERDF ((CTQ2010–15725) and Consolider In-
genio 2010 (CSD2007–00006)), by the Xunta de Galicia (GRC2010/132),
and European project Magnifyco (NMP4-SL-2009–228622). M.A. thanks
the Spanish MEC for his Ramꢃn y Cajal contract and M.P. thanks the
Spanish Ministry of Foreign Affairs and Cooperation for her MAEC-
AECID fellowship grand.
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Received: September 10, 2012
Revised: December 14, 2012
Published online: February 19, 2013
4834
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ꢄ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 4826 – 4834