Synthesis and characterisation of hetero-bimetallic organometallic phenylalanine and PNA monomer derivatives

Article abstract of DOI:10.1039/b819169g

The rational, sequential synthesis of two hetero-bimetallic derivatives of the amino acid phenylalanine and one thymine (T) peptide nucleic acid (PNA) monomer is reported. Ferrocene carboxylic acid and (η-ethene) bis(triphenylphosphine)platinum(0) were su

Full text of DOI:10.1039/b819169g

View Article Online / Journal Homepage / Table of Contents for this issue
This paper is published as part of a Dalton Transactions themed issue on:
Bioorganometallic Chemistry
Guest Editor Charles Riordan
University of Delaware, USA
Published in issue 22, 2009 of Dalton Transactions
Images reproduced with permission of John Peters (left) and Toshikazu Hirao (right)
Papers published in this issue include:
Perspective: Hydrogenase cluster biosynthesis: organometallic chemistry nature's way
Shawn E. McGlynn, David W. Mulder, Eric M. Shepard, Joan B. Broderick and John W. Peters
Dalton Trans., 2009, 4274, DOI: 10.1039/b821432h
Role of aromatic substituents on the antiproliferative effects of diphenyl ferrocenyl butene
compounds
Ouardia Zekri, Elizabeth A. Hillard, Siden Top, Anne Vessières, Pascal Pigeon, Marie-Aude
Plamont, Michel Huché, Sultana Boutamine, Michael J. McGlinchey, Helge Müller-Bunz and
Gérard Jaouen, Dalton Trans., 2009, 4318, DOI: 10.1039/b819812h
Resin-bound models of the [FeFe]-hydrogenase enzyme active site and studies of their reactivity
Kayla N. Green, Jennifer L. Hess, Christine M. Thomas and Marcetta Y. Darensbourg
Dalton Trans., 2009, 4344, DOI: 10.1039/b823152d
Molecular structures of protonated and mercurated derivatives of thimerosal
Wesley Sattler, Kevin Yurkerwich and Gerard Parkin
Dalton Trans., 2009, 4327, DOI: 10.1039/b823467a
Critical aspects of [NiFe]hydrogenase ligand composition
Koji Ichikawa, Takahiro Matsumoto and Seiji Ogo
Dalton Trans., 2009, 4304, DOI: 10.1039/b819395a
Visit the Dalton Transactions website for more cutting-edge inorganic and organometallic research
www.rsc.org/dalton
and for more bioinorganic and biological inorganic chemistry papers in Dalton Transactions:
www.rsc.org/Publishing/Journals/dt/News/BIB.asp

PAPER
www.rsc.org/dalton | Dalton Transactions
Synthesis and characterisation of hetero-bimetallic organometallic
phenylalanine and PNA monomer derivatives†
Gilles Gasser,a Oliver Brosch,b Alexandra Ewers,b Thomas Weyhermu¨llerb and Nils Metzler-Nolte*a
Received 29th October 2008, Accepted 24th December 2008
First published as an Advance Article on the web 9th February 2009
DOI: 10.1039/b819169g
The rational, sequential synthesis of two hetero-bimetallic derivatives of the amino acid phenylalanine
and one thymine (T) peptide nucleic acid (PNA) monomer is reported. Ferrocene carboxylic acid and
(h-ethene)bis(triphenylphosphine)platinum(0) were successfully reacted with propargylamide amino
acid (1a and 1b) or a T PNA monomer derivative (6) to give the expected three bimetallic compounds
4a, 4b and 9 in good yield. An enzymatic route using cross-linked enzyme crystals (CLEC) of
subtilopeptidase A in organic solvents gave the ferrocene carboxylate phenylalanine propargylamide
precursor (Fc-CO-Phe-NH-CH2-CCH, 3a) in comparable yield and purity to the traditional
deprotection-peptide coupling sequence. 31P NMR spectra of these bioorganometallics showed two
doublets with 195Pt satellites corresponding to two chemically different 31P atoms. Interestingly, in the
case of the T PNA monomer derivative 9, these signals were also doubled in a 60 : 40 ratio as a
consequence of the existence of two slowly interconverting isomers in solution. Furthermore, the
single-crystal X-ray structures of 3a and the hetero-bimetallic phenylalanine derivative 4b were
˚
determined, showing the presence of the two organometallics moieties separated by ca. 8.5 A in 4b as
well as illustrating the stability of such compounds.
group synthesised DNA oligomers with covalently attached
Introduction
rhodium and ruthenium complexes for the study of electron
transfer through DNA.18 For similar endeavours, Ogawa et al.
studied the electron transfer along artificial b-strands between
cobalt and ruthenium complexes.19
For a long time, organometallics have been neglected for the
labelling of biomolecules, mainly because they were thought to
be too unstable in an aqueous, aerobic environment. Recently,
however, numerous examples of the labelling of DNA, peptide
nucleic acids (PNAs), peptides, hormones, drugs and proteins to
organometallic compounds have been reported for different appli-
cations including biosensing, cytotoxicity, cellular localisation or
increase of cellular uptake.1–8 Thus, low-valent, organometallic
fragments are obviously well-suited for a selective labelling of
biomolecules. In the great majority of cases, the conjugates contain
one organometallic complex per biomolecule, in most cases
ferrocene.9,10 An unspecific labelling with an ill-defined number
of metal complexes was observed for reactions with proteins, such
as glucose oxidase (GOD).11–15
There are, however, to the best of our knowledge, no
reports on the rational, well-designed synthesis of hetero-
multiorganometallic-containing biomolecules, such as peptides,
DNA or PNA.16 This is regrettable as it would be very interesting
to combine the properties of several different organometallics
into the same biomolecule. There are, however, a few reports
on biomolecules containing different coordination complexes. For
example, heterobimetallic amino acid derivatives were synthesised
by Beck and co-workers8,17 for peptidomimetic purposes. Barton’s
However, all the bimetallic biomolecules described above
contain at least one classical coordination complex with an
(N,O) ligand bound to a metal ion. Interestingly, Lang and
co-workers recently reported the synthesis, characterisation and
electrochemical studies of up to heteropenta-organometallics.20
However, the bridging units between the metal complexes were
not biomolecules. The reason for this lack of bioorganometallic
compounds with several different metals is possibly the difficulty
to identify suitable chemistry. Any metal-containing compound
that could be considered as a promising candidate must itself be
stable in aerobic, aqueous solutions. Moreover, the chemistry of
attaching the metal complex to the biomolecule must be “bio-
compatible” with the variety of functional groups present in the
biomolecule, and yet specific for a given site of attachment.
In this contribution, we report our initial results on the rational,
sequential formation of hetero-bimetallic derivatives of the amino
acid phenylalanine and their crystallographic characterisation.
Using the same chemistry, the synthesis of a hetero-bimetallic
thymine (T) PNA monomer is also described, using ferrocene and
bis(phosphine)platinum–alkyne complexes.
aLehrstuhl fu¨r Anorganische Chemie I–Bioanorganische Chemie, Fakulta¨t
fu¨r Chemie und Biochemie, Ruhr-Universita¨t Bochum, Universita¨tsstrasse
150, D-44801, Bochum, Germany. E-mail: nils.metzler-nolte@rub.de;
Fax: +49 (0) 234 321 4378; Tel: +49 (0) 234 322 8152
Results and discussion
The synthetic strategy chosen to achieve our primary aim, namely
the synthesis of hetero-bimetallic amino acid or PNA monomer
derivatives, was to attach a carboxylic acid metal derivative to
their N-termini and an alkyne group to their C-termini. The
bMax-Planck-Institut fu¨r Bioanorganische Chemie, Stiftstraße 34–36,
D-45470, Mu¨lheim, Ruhr, Germany
† CCDC reference numbers 702132 (3a) and 702132 (4b). For crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/b819169g
4310 | Dalton Trans., 2009, 4310–4317
This journal is
The Royal Society of Chemistry 2009
©

latter would then serve as a ligand for another organometallic
compound. Because of its favourable electrochemical properties
and chemical robustness, ferrocene carboxylic acid was chosen as
the first organometallic moiety.9,21 Also, importantly for the scope
of this research, propargylamine derivatives of amino acids were
already used in Sonogashira coupling to suitably functionalised
organometallics by our group.22,23 In these reactions, the alkyne
group was found to be unreactive under conditions typically
employed in peptide chemistry such as deprotection and coupling
to activated amino acids. A further significant example of the
suitability of the alkyne group in biomolecules is the success of
the so-called “click chemistry”.24–28 Alkynes and azido derivatives
proved to be very stable and unreactive in biomolecules unless
heated or in the presence of a Cu(I) catalyst,29 or if activated
alkynes30–33 or oxanobornadiene derivatives34,35 are used.
To achieve the preparation of both amino acid and PNA
monomer heterobimetallics, propargylamine was first reacted with
the C-terminus of the amino acid or the PNA monomer using stan-
dard peptide coupling. A ferrocene moiety was then introduced
to the N-terminus. Finally, a Pt(0) organometallics, namely
(h-ethene)bis(triphenylphosphine)platinum(0) [(C2H4)Pt(Ph3P)2],36
was reacted stoichiometrically with the alkyne containing amino
acid or PNA monomer (Scheme 1 and 2), as it readily reacts
with alkynes to form stable metal complexes, with the release of
ethene.37–39
In the case of the heterobimetallic amino acid derivatives, the
synthesis of a suitable ferrocene derivative was accomplished
by two different routes. First, N-Boc-protected propargylamine
22,40
derivatives of phenylalanine (1)
were Boc-deprotected by
TFA (Scheme 1, a: R = H for propargylamine; b: R = Et for
1,1-diethylpropargylamine). Without isolation, the intermediate
phenylalaninylpropargylamides 2 were reacted with ferrocene
carboxylic acid chloride41 to yield 3 in >80% yield. 3a could
also be obtained by an enzymatic route starting from ferrocene
phenylalanine methyl ester 5.42,43 Although the methyl ester is most
difficult to remove chemically, it proved to be the best choice for the
direct enzymatic transformation with propargylamine to 3a. This
reaction was catalyzed by CLEC-immobilized subtilopeptidase A
at 37 ◦C in acetonitrile. The reaction was monitored by HPLC and
stopped after 80 h when maximum transformation was achieved
(80% of 3a). A number of enzymatic transformations have been
performed on organometallic compounds but they generally
demand aqueous solvents.44,45 CLEC,46–49 on the contrary, are
designed to work in organic solvents and are therefore much better
suited for applications in organometallic chemistry. For work-up,
the catalyst is simply removed by filtration and the product is
purified by preparative HPLC. The overall yield of 3a is similar
for both preparations. In addition, the CLEC catalyst can be re-
used without notable loss of activity.
Compounds 3 were reacted with (h-ethene)bis(triphenyl-
phosphine)platinum(0) to yield the heterobimetallic compounds
4. The reaction is quantitative with elimination of ethene and 4a
(R = H) and 4b (R = Et) are obtained practically pure after
removal of all volatiles from the reaction mixture. The formation
of 4 from 3 is indicated by a number of characteristic spectroscopic
changes. In CDCl3, the alkyne proton of 3b is observed as a singlet
at 2.31 ppm in the 1H NMR spectrum. On the contrary, in 3a, a
4
triplet with JHH = 2.3 Hz is observed at 2.17 ppm due to good
coupling transmission through the triple bond. After coordination
of the Pt(0) fragment to the alkyne, this signal shifts to 6.46 ppm
and now appears as a doublet of doublets due to coupling to
the two chemically inequivalent 31P nuclei (4a: 3JPH = 20 Hz and
3JP¢H = 11 Hz). In addition, Pt-satellites of this signal indicate
coupling to 195Pt (2JPtH = 55 Hz in 4a). The 31P NMR spectrum
of 4 (see Fig. 3 for 4a) clearly shows two doublets with different
Scheme 1 Synthesis of 4.
Scheme 2 Synthesis of 9.
This journal is
The Royal Society of Chemistry 2009
Dalton Trans., 2009, 4310–4317 | 4311
©

1JPtP coupling of about 3550 Hz for two inequivalent phosphorus
atoms as expected for a square planar coordination around the Pt
centre. All these NMR parameters correlate well with what was
found for other organoplatinum compounds.50–52 Finally, a strong
band is observed at 2123 and 2110 cm-1 in the Raman spectrum
for 3a and 3b, respectively, assigned to the terminal alkyne, which
disappeared in 4. Importantly, the bimetallic compounds 4 are
air-stable in the solid state and in solution and can be handled
without special precautions.
Single crystals of 3a and 4b were grown from CHCl3 and diethyl
ether–pentane, respectively. Fig. 1 shows an ORTEP plot for
compound 3a, together with selected bond lengths and angles.
The unit cell of 4b contains two independent molecules, the
geometries of which are very similar. An ORTEP plot of molecule
A is shown in Fig. 2 together with selected bond lengths and
angles, and in the following only pertinent structural features of
molecule A are discussed. All amide bonds are trans-configured
Fig. 2 ORTEP plot (50% probability) of 4b (molecule A) with numbering
scheme. Pertinent parameters for molecule B differ only marginally
from those given here. Hydrogen atoms are omitted for clarity. Se-
˚
lected bond lengths and angles: Pt(1)–C(112) 2.053(10) A, Pt(1)–C(113)
and◦practically planar. The ferrocene groups are almost eclipsed
˚
˚
˚
2.034(10) A, Pt(1)–P(1) 2.270(2) A, Pt(1)–P(2) 2.292(3) A, C(112)–C(113)
◦
∫
(3.6 dihedral twist angle for 3a, 11.0 for 4b). The C C triple bond
˚
˚
1.279(13) A, Fe–CCp (av.) 2.050 and 2.048 A (unsubstituted Cp),
˚
is elongated by 0.10 A upon Pt coordination and the alkyne group
is no longer linear as indicated by a C–C C angle of 141.8 in 4b.
˚
Fe–Cp(centroid) 1.652 and 1.649 A◦(unsubstituted Cp), C(119)–C(120)
◦
◦
∫
˚
1.473(15) A; P(1)–Pt(1)–P(2) 107.3(1) , C(111)–C(112)–C(113) 141.9(10) ,
Cp(centroid)–Fe–Cp(centroid) 177.1◦, C(120)–C(119)–N(118) 117.4(9)◦,
angle between planes C(120)–C(124) and O(119)–C(119)–N(118) 1.6◦;
angle between Cp planes 3.3◦.
The Pt atom in 4b is square-planar coordinated by two phosphorus
atoms and the alkyne carbon atoms. The structural parameters of
the Pt-alkyne group resemble those of the (PPh3)2Pt(tolane)37 or
(PPh3)2Pt(C2(CF3)2)53 complexes. The bonding situation in alkyne-
Pt(0) complexes has been the subject of theoretical studies.54 In 4b,
appears to be mainly governed by the need to accommodate the
bulky triphenylphosphine groups.
˚
the distance between the two metal centres is 8.7 A. Inter-residue
hydrogen bonds are crucial for the formation and stability of
secondary and tertiary structures in peptides. They also govern the
packing of 3a and 4b in the solid state. In 3a, the chiral information
of each single molecule is transformed in the chiral space group
P3121 in a fascinating way: each molecule of 3a has two amide
bonds that can be used for intermolecular hydrogen bonds. Two
neighbouring molecules form a couple with two hydrogen bonds
by using one of their two amide groups. The second amide bond
forms hydrogen bridges to the neighbouring couple, thus leading
to a one-dimensional supramolecular “sheet” perpendicular to
the crystallographic c-axis. 4b also forms extended networks via
hydrogen bridges in the solid state, but the packing in the unit cell
For the synthesis of the hetero-bimetallic PNA monomer,
N-Boc-protected thymine PNA monomer (Boc-T-PNA-OH) was
turned into the propargylamide 6 in 90% yield. The N-terminus
of 6 was Boc-deprotected with TFA in CH2Cl2 to give 7, which
was then reacted with ferrocene carboxylic acid in the presence
of the coupling reagent HBTU to yield the ferrocene derivative 8.
The ferrocene-T-PNA-propargylamide 8 was isolated and fully
characterised. The spectroscopic data of 8 resemble those of
the ferrocene T-PNA methyl ester Fc-T-PNA-OMe.55 In NMR
spectroscopy, because of cis–trans isomerism about the central
amide bond, all signals are doubled in a 60 : 40 ratio which
are in slow exchange on the NMR time scale (400 MHz at
room temperature). The solvent dependence of the ratio of
the two species, denoted major (ma) and minor (mi), is well
established and the barrier of rotation about the central amide
bond has been determined to be about 60 kJ mol-1.56–58 In 8,
additional characteristic signals for the alkyne group are observed
at 2.45 ppm (ma) and 2.47 (mi) in the 1H NMR spectrum
4
with characteristic JHH coupling as observed for 3a. 8 reacts
smoothly with (h-ethene)bis(triphenylphosphine)platinum(0) to
yield the bimetallic PNA derivatives 9 in almost quantitative yield.
Similar to compounds 4, Pt coordination to the alkyne group is
immediately established from the 1H NMR spectrum of 9 by the
disappearance of the alkyne signal at 2.45 ppm and the appearance
of a new signal at 6.5 ppm with 31P coupling and 195Pt satellites.
The 31P NMR spectrum of 9 is most instructive (Fig. 3). As for
4b, there are two doublets with 195Pt satellites for two chemically
different 31P atoms. However, these signals are also doubled as a
consequence of the existence of two slowly interconverting isomers
in solution. The major/minor ratio of 60 : 40 in the 31P NMR
spectrum fits perfectly with the value of 62 : 38 determined in
Fig. 1 ORTEP plot (40% probability) of 3a with numbering scheme.
Selected bond lengths and angles: Fe–CCp (av.) 2.047 and 2.039 A
˚
˚
(unsubstituted Cp), Fe–Cp(centroid) 1.656 and 1.643 A (unsubsti-
◦
˚
tuted Cp), C(1)–C(6) 1.514(10) A; Cp(centroid)–Fe–Cp(centroid) 177.5 ,
C(1)–C(6)–N(7) 117.3(6)◦, angle between planes C(2)–C(1)–C(5) and
O(6)–C(6)–N(7) 10.8◦; angle between Cp planes 2.4◦.
the H NMR spectrum of 9, given the limited accuracy of the
1
4312 | Dalton Trans., 2009, 4310–4317
This journal is
The Royal Society of Chemistry 2009
©

PNA monomer were used to exemplify a general principle for
the chemoselective introduction of two different organometallic
groups into biomolecules by using chemically selective reactions
at two different sites of a biomolecule. Transfer of this chemistry
to larger biomolecules including peptides and PNA oligomers is
currently in progress in our laboratory.
Experimental
Materials
All reactions were carried out in ordinary glassware and solvents
were used without further precautions except where indicated.
Chemicals were purchased from commercials suppliers and used
as received. Only enantiomerically pure L-phenylalanine was used.
PeptiCLECTM catalyst was purchased from Altus Biologics Inc.
Cambridge, Massachusetts, USA. The N-Boc-protected T-PNA
monomer was purchased from PE Applied Biosystems GmbH,
Weiterstadt, Germany (now available from Link Technologies,
Lanarkshire, Scotland or ASM Research Chemicals, Hannover,
Germany).
Fig. 3 31P NMR spectra of 4a (top) and 9 (bottom). Due to the existence
of two isomers in solution, denoted major (ma) and minor (mi), all signals
are doubled in a 60 : 40 ratio in the bottom spectrum (see text).
Instrumentation and methods
Elemental analyses were carried out by H. Kolbe, Analytisches
Laboratorium, Mu¨lheim on an Analytic Jena multi EA 3100.
IR spectra were recorded on a Perkin Elmer System 2000
instrument as KBr disks, additionally in CH2Cl2 solution if
indicated. Wavenumbers n are given in cm-1. UV/Vis spectra were
recorded on a Perkin Elmer Lambda 19 spectrometer, only the
wavelength of the lowest-energy ferrocene transition is given in nm,
e (dm3 mol-1 cm-1) in parentheses. Melting points (uncorrected)
were determined on a Tottoli apparatus (Bu¨chi, Switzerland).
Mass spectra were recorded by the mass spectrometry service
group, Mu¨lheim, on a MAT 8200 (Finnigan GmbH, Bremen)
instrument (EI, 70 eV) or on a MAT95 (Finnigan GmbH, Bremen)
instrument (ESI, CH3OH solution, positive ion detection mode).
Only characteristic fragments are given with intensities (%) and
possible composition in parentheses. Analytical RP-HPLC was
carried out on a Nucleosil-N-7-C18 column (Nr. 312014, Size
250 ¥ 20 mm) with a Merck C 6200 pump and a Shimadzu
SPD-6-A V-detector at 260 and 420 nm. The eluents were a
mixture of methanol–water in different ratio. The flow rate was
1 mL min-1 (analytical) or 4 mL min-1 (preparative). NMR spectra
were recorded at room temperature using a Bruker ARX 250 (1H
at 250.13 MHz and 13C) or a DRX 400 (1H at 400.13 MHz,
13C and 2D spectra) or DRX 500 (1H at 500.13 MHz, 13C,
15N, 2D) spectrometer. 1H and 13C spectra were referenced to
TMS, using the 13C signals or the residual proton signals of
the deuterated solvents as internal standards. Positive chemical
shift values d (in ppm) indicate a downfield shift from the
standard, only the absolute values of coupling constants are given
in Hz. 15N spectra were referenced to the absolute frequency
of 50.6969910 MHz, which was the resonance frequency of
neat nitromethane under the same experimental conditions. All
resonances were assigned by 2D NMR (H–H-COSY and 1H–13C-
1
integration (overlapping signals in the H NMR spectrum and
poor S/N ration of the 31P NMR spectrum). We were unable
to grow crystals of 9 of suitable quality for an X-ray structure
determination. Indeed, no crystal structure of any PNA monomer
has been reported to date to the best of our knowledge and this
may possibly be a consequence of the cis–trans flexibility of PNA
monomers. However, the spectroscopic data and in particular a
comparison of the 31P NMR spectra presented in Fig. 3 support
the suggested constitution of 9 unambiguously.
Conclusions
In this work, to the best of our knowledge, the first hetero-
organobimetallic amino acid (4a and 4b) and PNA (9) deriva-
tives are reported. They contain a ferrocene group attached to
their N-termini and a bis(triphenylphosphine)platinum(0) moiety
complexed to an alkyne bond at their C-termini. The ferrocenoyl
phenylalanine propargylamide 3a could be obtained by a classical
deprotection-peptide coupling reaction or an enzymatic reaction
using a CLEC peptidase in organic solvents. While both reactions
yield 3a in similar yield and purity, the CLEC reaction is easier
to perform experimentally but required HPLC purification of the
product. All compounds were fully characterised spectroscopi-
cally. Hence, the complexation of the alkyne derivatives 3a, 3b
and 8 with bis(triphenylphosphine)platinum(0) was confirmed by
Raman spectroscopy with the disappearance of the alkyne band
at about 2100 cm-1. Furthermore, 31P NMR spectra of 4a and
4b contain two doublets with 195Pt satellites corresponding to two
chemically different 31P atoms. For 9, these signals are doubled
as a consequence of the existence of two slowly interconverting
isomers in solution. For compounds 3a and 4b, the solid-state
structures could be determined by single-crystal X-ray crystal-
lography. In conclusion, amino acid derivatives and a thymine
1
HMQC for J and long-range couplings). Where unambiguous
or proven spectroscopically, the following conventions are used:
d/d¢ denotes pairs of signals originating from cis/trans isomers.
This journal is
The Royal Society of Chemistry 2009
Dalton Trans., 2009, 4310–4317 | 4313
©

15N chemical shifts and coupling constants were taken from
the F1 projection of indirect detection 1H–15N correlated 2D
spectra with 1024/256 data points in F1/F2, processed after
applying a matched cosine function and zero filling in both
dimensions.
Characterisation data for 3b. Found: C, 68.8; H, 6.6; N, 5.8.
Calc. for C27H3¢N2O2Fe: C, 68.9; H, 6.4; N, 6.0%. Major IR bands:
3422 (w), 3304 (br, m), 1665 (m), 1626 (s). Raman: 2110. Mp 184–
187 ◦C. 1H NMR (CDCl3): 7.32–7.22 (5H, m, HPhe), 6.34 (1H, d,
NHPhe), 6.17 (1H, s, NDEPAH), 4.72 (1H, m, CaH), 4.64 (1H, s, HCp),
4.56 (1H, s, HCp), 4.30 (2H, s, HCp), 4.04 (5H, s, HCp), 3.13 (2H, m,
∫
CbH2), 2.31 (1H, s, C CH), 2.01–1.92 (2H, m, CH2CH3), 1.85–
Synthesis and characterisation
1.72 (2H, m, CH2CH3), 0.90–0.83 (6H, m, CH2CH3). 13C NMR
(CDCl3): 170.7 (CO), 170.0 (Fc–CO), 136.9, 129.3 128.8, 127.1
N-Boc-protected propargylamine derivative of phenylalanine
(1a). 1a was prepared following the procedure published by
Curran et al. The spectroscopic data of the products matched
that reported previously.40
∫
∫
(CPhe), 84.6 (C CH), 75.0 (CCp), 71.6 (C CH), 70.6, 69.8, 68.5,
67.9 (CHCp), 56.6 (C(Et)2), 54.8 (Ca), 38.1 (Cb), 30.4 (CH2CH3),
8.39 and 8.43 (CH2CH3). 15N NMR (CDCl3): -255 (NHDEPA),
-266 (NHPhe). MS: m/z 470 (100), 331 (14), 213 (60), 185 (24), 129
(22%).
N-Boc-protected propargylamine derivative of phenylalanine
(1b). 1b was prepared following the procedure published by
Metzler-Nolte et al.22 The spectroscopic data of the products
matched that reported previously.22
General procedure for the synthesis of ferrocene–Pt(0)–
propargylamine derivatives of phenylalanine (4a and 5a). A so-
lution of (C2H4)Pt(PPh3)2 (0.37 g, 0.50 mmol) in degassed THF
(30 mL) was added dropwise, under Ar, to a solution of the alkyne
3a or 3b (0.50 mmol) in degassed THF (40 mL). After evolution
of gas had ceased, stirring was continued for an additional hour at
room temperature and all volatiles were removed from the reaction
mixture in vacuo. Dry and degassed diethyl ether (20 mL) was then
added to the residue, which was filtered through a cannula. The
solution was evaporated to dryness to give the pure compound 4a
or 4b, respectively (550 mg, 97% for 4a and 530 mg, 89% for 4b).
General procedure for the synthesis of ferrocene-propargylamine
derivatives of phenylanine (3a and 3b). 1a or 1b, respectively
(5 mmol) were stirred in a mixture of TFA–CH2Cl2 (10 mL–
20 mL) for 30 min at 0 ◦C. The volatiles were then evaporated
to dryness to give a residual oil. To this residue was then added
diethyl ether (40 mL) and a white solid precipitated after stirring
for 5 min. The precipitate was filtered off and air-dried to give
2a or 2b respectively, which were used for the next synthetic step
without further purification.
2a or 2b (5 mmol), were dissolved in dry THF and then
neutralised with NEt3 (0.51 g, 5 mmol). To this solution were added
ferrocene carboxylic acid chloride41 (1.15 g, 5 mmol) dissolved in
dry THF and NEt3 (0.51 g, 5 mmol). The reaction mixture was
stirred for 4 h at room temperature before being filtered. The filtrate
was evaporated to dryness. To the residue was then added a mixture
of chloroform/water and the phases separated. The organic phase
was then washed with H2O (3¥), dried over Na2SO4, filtered and
then evaporated to dryness to give 3a and 3b, respectively (1.82 g,
88% for 3a; 2.02 g, 86% for 3b). 3a can be recrystallised from ethyl
acetate–heptane or from chloroform.
Characterisation data for 4a. Found: C, 62.3; H, 4.6; N, 2.4.
Calc. for C59H52N2O2FePtP2: C, 62.5; H, 4.6; N, 2.5%. Major IR
bands: 3423 (br, m), 3293 (s), 1655 (s), 1648 (s), 1625 (s). Mp
118 C (decomp.). H NMR (CDCl3): 7.31–7.09 (35H, m, HPhe
and HPPh3 ), 6.47–6.36 (1H, dd, CH), 6.25 (1H, d, J = 8.0 Hz,
NHPhe), 5.72 (1H, br, NHProp), 4.61 (1H, m, HCp), 4.51 (1H, s,
◦
1
H
Cp), 4.41 (1H, m, CaH), 4.28 (2H, s, HCp), 4.10 (2H, m, CH2),
4.05 (5H, s, HCp), 2.90 (2H, m, CbH2). 13C NMR (CDCl3): 169.9
and 169.87 (CO), 136.7, 129.3 128.7, 126.6 (CPhe), 136.9–136.8 (6C,
C
ipso), 134.0–133.7 (12C, Cortho), 129.3–129.1 (6C, Cpara), 128.0–
∫
∫
127.9 (12C, Cmeta), 125.2 (HC C(Pt)), 108.5 (HC C(Pt)), 75.6,
70.4, 69.8, 68.6, 67.7 (CCp), 53.9 (Ca), 38.6 (Cb), 37.7 and 37.6
(CH2). 31P NMR (CDCl3): 2 doublets at 29.1 and 27.7 ppm
(2JP1–P2 = 31 Hz, 1JPt–P1 = 3545 Hz, 1JPt–P2 = 3550 Hz). 15N NMR
(CDCl3): -267 (NHPhe), -257 (NHProp). ESI-MS (positive, CH2Cl2):
m/z 1134 [M + H]+, 1134 [M + Na]+.
Alternative method for the synthesis of 3a through an enzymatic
pathway with PeptiCLECTM
. 5 (200 mg, 0.51 mmol) was dis-
solved in acetonitrile. To this solution was added propargylamine
(120 mg, 2.04 mmol) and then PeptiCLECLTM (30 mg). This
◦
solution was then shaken at 37 C and the reaction followed by
analytical HPLC. After 118 h, the reaction was completed. The
product was filtered and then purified by preparative HPLC to
give 3a (170 mg, 80%).
Characterisation data for 4b. Found: C, 63.7; H, 5.1; N, 2.4.
Calc. for C63H60N2O2FePtP2: C, 63.6; H, 5.1; N, 2.4%. Major
IR bands: 3437 (br, m), 3289 (br, m), 1655 (m), 1644 (m), 1630
◦
1
Characterisation data for 3a. Found: C, 66.6; H, 5.4; N, 6.8.
Calc. for C23H22N2O2Fe: C, 66.7; H, 5.4; N, 6.8%. Major IR bands:
3440 (w), 3304 (m), 1665 (m), 1626 (s). Raman: 2123. Mp 184 ◦C.
1H NMR (CDCl3): 7.31 (1H, m, HPhe), 6.50 (1H, s br, NHprop), 6.20
(1H, d, J = 7.5 Hz, CaH), 4.64 (1H, s, HCp), 4.54 (1H, s, HCp), 4.32
(m). Mp 112 C (decomp.). H NMR (CDCl3): 7.40–7.00 (35H,
m, HPhe and HPPh ), 6.26 (1H, d, NHPhe, J = 5 Hz), 6.15–5.95
3
(1H, dd, CH), 5.78 (1H, s, br, NDEPAH), 4.56 (1H, m, HCp), 4.51
(1H, m, HCp), 4.23 (2H, s, HCp), 4.00 (5H, s, HCp), 3.89 (1H, m,
CaH), 2.58–2.44 (2H, m, CbH2), 2.15–1.95 (2H, m, CH2CH3),
1.45–1.30 (2H, m, CH2CH3), 0.92 (3H, t, J = 7 Hz, CH2CH3),
0.63 (3H, t, J = 7 Hz, CH2CH3). 13C NMR (CDCl3): 169.6 and
169.2 (CO) and (Fc–CO), 136.4, 129.3 128.9, 126.8 (CPhe), 137.7–
135.9 (6C, Cipso), 134.2–133.7 (12C, Cortho), 129.5–129.0 (6C, Cpara),
∫
(2H, s, HCp), 4.04 (5H, s, HCp), 3.98 (2H, m, C C–CH2), 3.16 (2H,
m, CbH2), 2.17 (1H, t, J = 2.4 Hz, C CH). 13C NMR (CDCl3):
∫
171.3 (CO), 171.0 (Fc–CO), 136.9, 129.2 128.7, 127.1 (CPhe), 79.2
∫
∫
∫
(C CH), 74.8 (CCp), 71.6 (C CH), 70.7, 69.8, 68.7, 67.8 (CHCp),
54.2 (Ca), 37.8 (Cb), 29.0 (C CH–CH2). 15N NMR (CDCl3): -269
128.2–127.7 (12C, Cmeta), 135.8 (HC C(Pt)), 110.6 (HC C(Pt)),
76.1, 70.2, 69.8, 68.4, 67.8 (CCp), 53.3 (Ca), 38.7 (Cb), 30.8 and
30.3 (CH2CH3), 9.2 and 9.1 (CH2CH3). 15N NMR (CDCl3): -268
∫
∫
(NHProp), -267 (NHPhe). MS: m/z 414 (100), 331 (18), 213 (56), 129
(21%).
4314 | Dalton Trans., 2009, 4310–4317
This journal is
The Royal Society of Chemistry 2009
©

=
=
(NHPhe), -245 (NHDEPA). ESI-MS (positive, CH2Cl2): m/z 1190
(COT), 165.0 (COT), 152 (HC C), 142.5 (HC C), 79.2/79.1
(Calkyne), 72.4/72.3 (HCalkyne), 72.0/71.4/71.08/70.6/69.2/69.0
(CCp), 51.3/51.0 (CH2), 49.3/49.2 (CH2CH2NH), 49.0/48.6
(CH2), 38.1/38.0 (CH2CH2NH), 29.6/29.2 (CH2–Calkyne), 12.3
(CH3,T). 15N NMR (CD3CN): -226 (NHT), -272 (NH), -275(NH).
IR: 3449 (m), 1676 (s), 1535 (m), 1407 (w), 1222 (w). Raman: 2113.
UV (CH3CN): 255 (450 nm), 14700 (264 nm). MS: m/z 533 (86),
376 (100), 213 (28), 95 (27), 65 (31%).
([M + H]+).
Ferrocene phenylalanine methyl ester (5). 5 was prepared
following the procedure published by Herrick, Jarret and Curran
et al.42 The spectroscopic data of the product matched that
reported previously.42,43
Synthesis of N-Boc-protected propargylamide T-PNA monomer
(6). HBTU (0.12 g, 0.32 mmol) was added to a solution of
Boc-T-PNA-OH (0.1 g, 0.32 mmol), propargylamine (0.02 g,
0.32 mmol) and NEt3 (0.07 g, 0.64 mmol) in acetonitrile. After
15 min of stirring at room temperature, brine (10 mL) was added,
the organic phase was separated, the aqueous layer was extracted
with EtOAc and the combined organic phases were washed with
2 M HCl(aq), water, sat. NaHCO3(aq) and water. After drying over
Na2SO4 and filtration, all solvents were removed in vacuo and 6
was obtained as a white solid (0.13 g, 95%). 1H NMR (CD3CN):
9.5 (1H, s, NHT), 7.21/7.03 (1H, s, br, NHCO), 7.09/7.08 (1H, s,
Ferrocene–Pt(0)–propargylamide T-PNA monomer 9. A solu-
tion of (C2H4)Pt(PPh3)2 (0.14 g, 0.19 mmol) in degassed THF
(20 mL) was added dropwise under Ar to a solution of alkyne 8
(0.10 g, 0.19 mmol) in degassed THF (20 mL). After evolution of
gas had ceased, stirring was continued for an additional hour and
all volatiles were removed from the reaction mixture in vacuo.
The product appeared rather pure by 1H NMR spectroscopy,
but analytically pure samples were obtained by HPLC, yielding
9 (80 mg, 33%). 1H NMR (d6-DMSO): 11.25 (1H, br, NHT),
8.55/8.25 (1H, br, NH), 8.05/7.75 (1H, br, NH), 7.31–7.18 (31H,
=
C CH), 5.9/5.45 (1H, s, br, NHBOC), 4.56/4.42 (2H, s, CH2),
=
m, HPPh and C CH), 6.58–6.44 (1H, dd, CHAlkyne), 4.75/4.71 (2H,
pseudo-t, HCp), 4.72/4.47 (s, 2H, CH2), 4.29/4.28 (pseudo-t, 2H,
Cp), 4.16/4.10 (s, 5H, HCp), 4.11/3.93 (s, 2H, HCp), 3.82/3.78 (m,
3
4.03/3.92 (2H, s, CH2), 4.04/3.91 (2H, s, CH2,alkyne), 3.41/3.37
(2H, m, CH2CH2NH), 3.25/3.12 (2H, m, CH2CH2NH), 2.48/2.44
(1H, t, CHalkyne), 1.81 (s, 3H, CH3,T), 1.39 (s, 9H, CH3 BOC). 13C
NMR (CD3CN): 171.7 (CO), 169.3/168.7 (CO), 165.3 (COT),
H
2H, CH2,alkyne), 3.44/3.30 (m, 4H, CH2CH2NH and CH2CH2NH),
1.73/1.70 (s, 3H, CH3,T). 13C NMR (d6-DMSO) : 141.8 (HC C),
=
=
=
157 (COBOC), 152.4 (HC C), 142.7 (HC C), 80.9 (Calkyne), 79.9
(CBOC(CH3)3), 72.1/72.4 (HCalkyne), 51.5/50.9 (CH2), 49.4/49.3
(CH2), 49.2/48.9 (CH2CH2NH), 39.3/38.8 (CH2CH2NH), 29.9
(CH3,BOC), 14.5 (CH3,T). 15N NMR (d6-DMSO): -224 (NTH), -272
(NH). IR: 3435 (m), 1686 (s), 560 (w). Raman: 2123. ESI-MS
(positive, CH3OH): m/z 422 [M + H]+, 439 ([M + NH4]+, 860
[2M + NH4]+.
133.1/129.1/127.7 (CPPh ), 69.2/67.7 (CCp), 49.9/48.9 (CH2), 47.7
3
(CH2), 39.6 (CH2CH2NH), 36.9 (CH2,Alkyne), 11.6 (CH3). 31P NMR
2
1
(d6-DMSO): 29.6/26.8 (ma, JP1–P2 = 31.5 Hz, JPt–P = 3504 and
2
1
3558 Hz), 29.8/26.2 (mi, JP1–P2 = 31.6 Hz, JPt–P = 3502 and
3557 Hz). ESI-MS (positive, CH3CN–THF): m/z 1252 [M]+. IR:
1685 (s), 1535 (w), 695 (m).
X-Ray crystallographic data collection and refinement
of the structures
Synthesis of propargylamide T-PNA monomer (7). 6 (0.50 g,
1.22 mmol) was stirred in a mixture of TFA–CH2Cl2 (9 : 1 v/v)
(20 mL) for 15 min at room temperature before all the volatiles
were evaporated to dryness. The residual oil was then again stirred
in a mixture of TFA–CH2Cl2 (9 : 1 v/v) (20 mL) for 15 min at
room temperature. After evaporation of the volatiles, dry diethyl
ether (20 mL) was added to the residual oil and the mixture stirred
for 5 min at room temperature. The reaction mixture was again
evaporated to dryness. 7 was isolated as a white, hygroscopic solid
and was used without further purification to the next synthetic
step.
Yellow–orange single crystals of 3a and 4b were coated with
perfluoropolyether, picked up with nylon loops and were mounted
in the nitrogen cold stream of a Nonius KappaCCD and a Siemens
SMART diffractometer, respectively. Graphite-monochromated
˚
Mo-Ka radiation (l = 0.71073 A) was used throughout. Final cell
constants were obtained from least squares fits of several thousand
strong reflections. Intensity data were corrected for absorption
using intensities of redundant reflections. The structures were
readily solved by Patterson methods and subsequent difference
Fourier techniques. The Siemens ShelXTL59 software package was
used for solution and artwork of the structures, ShelXL97 was used
for the refinement. All non-hydrogen atoms were anisotropically
refined and hydrogen atoms were placed at calculated positions
and refined as riding atoms with isotropic displacement pa-
rameters. Crystallographic data of the compounds are listed in
Table 1.
Synthesis of ferrocene-propargylamide T-PNA monomer 8. To
a solution of 7 (73.8 mg, 0.24 mmol) and ferrocene carboxylic
acid (0.05 g, 0.24 mmol) in CH3CN, NEt3 (0.05 g, 0.48 mmol)
and HBTU (0.09 g, 0.24 mmol) were added to the reaction
mixture. Brine (10 mL) was added after 15 min of stirring at room
temperature and after another 20 min of stirring, the organic phase
was separated and the aqueous layer extracted with CHCl3. The
organic phase was washed with 2 M HCl, H2O, saturated NaHCO3
and H2O. After drying over MgSO4 and filtration, all volatiles were
Diffraction data quality of 3a was found to be low due to the
crystal quality indicated by weak diffraction and a high mosaicity
of 1.2◦. Data were collected to a 2q angle of 55◦ but a data cut-off
was applied at 45◦ (Rint = 0.21) since the data quality at higher
angles was out of limits. Structure solution and refinement of
compound 3a was performed in enantiomorphic space groups
P3121 (no. 152) and P3221 (no. 154). Though the diffraction data
quality is not superb, space group assignment was unambiguously
possible. The Flack parameter60 for a refinement in P3121 gave a
value close to 0 (-0.03(4)) whilst the parameter refined to a value
1
removed in vacuo, yielding 8 (0.11 g, 89%). H NMR (CD3CN):
9.16/9.12 (1H, br, NH), 7.28/7.26/7.03/6.90 (all NH), 7.05/6.87
=
(1H, s, C CH), 4.71/4.62 (2H, pseudo-t, HCp), 4.57/4.44
(2H, s, CH2), 4.36/4.32 (2H, pseudo-t, HCp), 4.19/4.17 (5H, s,
H
Cp), 4.09/3.97 (2H, s, CH2), 4.00/3.97 (2H, m, CH2–Calkyne),
3.52/3.38 (2H, m, CH2CH2NH), 3.52/3.26 (2H, m, CH2CH2NH),
2.45/2.48 (1H, s, HCalkyne) 1.75/1.74 (3H, s, CH3,T). 13C NMR
=
=
=
(CD3CN): 171.3 (C OPROP), 170.8 (Cp–C O), 168.5 (C O), 165.1
This journal is The Royal Society of Chemistry 2009
Dalton Trans., 2009, 4310–4317 | 4315
©

Table 1 Crystallographic data for 3a and 4b
Acknowledgements
3a
4b
This work was supported by the Fond der Chemischen Indus-
trie and the Alexander von Humboldt Foundation (fellowship
to G. G.). Additional information is available on the DFG-
funded Research Unit “Biological Function of Organometallic
Compounds” (FOR 630, www.rub.de/for630). The authors are
grateful to Heike Schucht and Dr Klaus Merz for technical help
with the X-ray structure determination and to Manuela Trinoga
for expert HPLC service.
Formula
Mr
C23H22FeN2O2
414.28
C63H60FeN2O2P2Pt
1190.01
Crystal size/mm
Crystal system
Space group
0.32 ¥ 0.14 ¥ 0.14
Trigonal
P3121 (no. 152)
9.6860(10)
9.6860(10)
36.733(5)
90
2984.5(6)
6
100(2)
0.44 ¥ 0.14 ¥ 0.14
Monoclinic
P21 (no. 4)
16.116(2)
18.556(2)
19.210(3)
111.24(2)
5354.5(12)
4
100(2)
1.476
52151 (60.00)
24746 (18101)
0.0470
˚
a/A
˚
b/A
˚
c/A
b/◦
3
˚
V/A
Z
References
T/K
1 G. Jaouen, Bioorganometallics, Wiley-VCH, Weinheim, 2005.
2 N. Metzler-Nolte, in Comprehensive Organometallic Chemistry III, ed.
G. Parkin, Elsevier, Amsterdam, 2006, vol. 1, pp. 883–920.
3 U. Schatzschneider and N. Metzler-Nolte, Angew. Chem., Int. Ed., 2006,
45, 1504–1507, and references therein.
4 R. W. Fish and G. Jaouen, Organometallics, 2003, 22, 2166–2177.
5 N. Metzler-Nolte and K. Severin, in Concepts and Models in Bioinor-
ganic Chemistry, eds. H.-B. Kraatz and N. Metzler-Nolte, Wiley-VCH
Verlag GmbH &, Co, Weinheim, Germany, 2006, pp. 113–136.
6 N. Metzler-Nolte, Angew. Chem., Int. Ed., 2001, 40, 1040–1043.
7 A. D. Ryabov, Angew. Chem., Int. Ed. Engl., 1991, 30, 931–941.
8 K. Severin, R. Bergs and W. Beck, Angew. Chem., Int. Ed., 1998, 37,
1634–1654, and references therein.
Dc/g cm-3
1.383
Refl. collected (2Hmax/◦)
Unique refl. (with I > 2s(I))
Rint
6782 (45.00)
2560 (1845)
0.2138
253/0
0.71073
7.79
0.0694/1.063
0.1166
No. params/restr.
1283/1
0.71073
29.86
0.0452/0.935
0.0975
˚
l(Mo-Ka)/A
m(Mo-Ka)/cm-1
R1a/goodness of fitb
wR2c (I > 2s(I))
-3
˚
Dr(max./min.)/e A
+0.48/-0.43
+1.54/-2.21
ꢀ
ꢀ
a Observation criterion: I > 2s(I). R1 = ꢀFo| - |Fcꢀ/ |Fo|. b GOF =
ꢀ
ꢀ
ꢀ
2
2
[
[w(Fo - Fc2)2]/(n - p)]1/2
.
c wR2 = [ [w(Fo - Fc2)2]/ [w(Fo2)2]]1/2
9 D. R. van Staveren and N. Metzler-Nolte, Chem. Rev., 2004, 104, 5931–
5985, and references therein.
10 N. Metzler-Nolte, and M. Salmain, in Ferrocenes: Ligands, Materials
and Biomolecules, ed. P. Stepnicka, John Wiley & Sons Ltd., Chichester,
2008, pp. 499–639.
where w = 1/s (Fo2) + (aP)2 + bP, P = (Fo + 2Fc2)/3.
2
2
of about 1.0 upon space group change to P3221. The R-factors
were also slightly better for the first choice. Atomic displacement
parameters of the Cp-ring carbon atoms containing C(21) to C(25)
were restrained using the SIMU instruction of ShelXL97.
11 P. N. Bartlett, R. G. Whitaker, M. J. Green and J. Frew, J. Chem. Soc.,
Chem. Commun., 1987, 1603–1604.
12 P. N. Bartlett, V. Q. Bradford and R. G. Whitaker, Talanta, 1991, 38,
57–63.
13 Y. Degani and A. Heller, J. Am. Chem. Soc., 1988, 110, 2615–2620.
14 A. Badia, R. Carlini, A. Fernandez, F. Battaglini, S. R. Mikkelsen and
A. M. English, J. Am. Chem. Soc., 1993, 115, 7053–7060.
15 R. Nagata, K. Yokoyama, S. A. Clark and I. Karube, Biosens.
Bioelectron., 1995, 10, 261–267.
16 P. E. Nielsen, M. Egholm, R. H. Berg and O. Buchardt, Science, 1991,
254, 1497–1500.
17 D. Freiesleben, K. Polborn, C. Robl, K. Suenkel and W. Beck,
Can. J. Chem., 1995, 73, 1164–1174.
18 R. E. Molmlin, P. J. Dandliker and J. K. Barton, Angew. Chem., Int.
Ed., 1998, 36, 2715–2730.
Compound 4b crystallizes in chiral space group P21 (no. 4)
with two crystallographically independent molecules per asym-
metric unit. Due to a pseudo-centrosymmetric packing of these
molecules, the space group appeared first to be P21/c (no. 14).
Reflections fulfilling the extinction requirements for a c-glide
plane were found to be weak, but a considerable number of
them were observed using the standard 3s criterion. Nevertheless,
a refinement in P21/c was initially performed and seemed to
work well, but resulted in a disorder of the chiral C-atom
in the phenylalanine unit of the molecule. Refinement in P21
yielded two independent molecules with the expected L-amino-
acid configuration and a Flack parameter of -0.029(7). Atomic
displacement parameters of the phenyl-ring carbon atoms C(151)
to C(156) and carbon atoms C(212) and C(213) were restrained
using the DELU instruction of ShelXL97.
19 S. R. L. Fernando, G. V. Kozlov and M. Y. Ogawa, Inorg. Chem., 1998,
37, 1900–1905.
20 R. Packheiser, P. Ecorchard, T. Ru¨ffer, B. Walfort and H. Lang,
Eur. J. Inorg. Chem., 2008, 4152–4165.
21 J. H. R. Tucker and S. R. Collinson, Chem. Soc. Rev., 2002, 31, 147–156,
and references therein.
22 O. Brosch, T. Weyhermu¨ller and N. Metzler-Nolte, Inorg. Chem., 1999,
38, 5308–5313.
23 O. Brosch, T. Weyhermu¨ller and N. Metzler-Nolte, Eur. J. Inorg. Chem.,
2000, 2, 323–330.
24 R. Huisgen, Angew. Chem., Int. Ed. Engl., 1963, 2, 565–598.
25 H. C. Kolb, M. G. Finn and K. B. Sharpless, Angew. Chem., Int. Ed.,
2001, 40, 2004–2021.
Abbreviations
26 C. W. Tornoe, C. Christensen and L. Meldal, J. Org. Chem., 2002, 67,
CLEC
ESI-MS
Fc
cross-linked enzyme crystals
electrospray ionisation mass spectrometry
Ferrocenyl ((h-C5H4)Fe(h-C5H5))
O-(1H-Benzotriazol-1-yl)-N,N,N¢,N¢-tetramethyl-
uronium hexafluorophosphate
major
3057–3064.
27 G. Gasser, N. Hu¨sken, S. D. Ko¨ster and N. Metzler-Nolte, Chem.
Commun., 2008, 3675–3677.
28 S. D. Ko¨ster, J. Dittrich, G. Gasser, N. Hu¨sken, I. Hernandez, J. L. Jios
and N. Metzler-Nolte, Organometallics, 2008, 27, 6326–6332.
29 J. E. Moses and A. D. Moorhouse, Chem. Soc. Rev., 2007, 36, 1249–
1262.
HBTU
ma
30 J. M. Baskin, J. A. Prescher, S. T. Laughlin, N. J. Agard, P. V. Chang,
I. A. Miller, A. Lo, J. A. Codelli and C. R. Bertozzi, Proc. Natl. Acad.
Sci. U. S. A., 2007, 104, 16793–16797.
31 S. T. Laughlin, J. M. Baskin, S. L. Amacher and C. R. Bertozzi, Science,
2008, 320, 664–667.
mi
minor
phenylalanine
peptide nucleic acid
trifluoroacetic acid
Phe
PNA
TFA
4316 | Dalton Trans., 2009, 4310–4317
This journal is
The Royal Society of Chemistry 2009
©

32 J. A. Codelli, J. M. Baskin, N. J. Agard and C. R. Bertozzi, J. Am.
Chem. Soc., 2008, 130, 11486–11493.
33 J. M. Baskin and C. R. Bertozzi, QSAR Com. Sci., 2007, 11–12, 1211–
1219.
34 S. S. Van Berkel, A. T. J. Dirks, M. F. Debets, F. L. van Delft, J. J. L. M.
Cornelissen, R. J. M. Nolte and F. P. J. T. Rutjes, ChemBioChem, 2007,
8, 1504–1508.
35 S. S. Van Berkel, A. T. J. Dirks, S. A. Meeuwissen, D. L. L. Pingen,
O. C. Boerman, P. Laverman, F. L. Van Delft, J. J. L. M. Cornelissen
and F. P. J. T. Rutjes, ChemBioChem, 2008, 9, 1805–1815.
36 U. Nagel, Chem. Ber., 1982, 115, 1998–1999.
37 J. O. Glanville, J. M. Stewart and S. O. Grim, J. Organomet. Chem.,
1967, 7, P9–P10.
38 B. Kayser, J. Altman, H. Noeth, J. Knizek and W. Beck, Eur. J. Inorg.
Chem., 1998, 11, 1791–1798.
39 W. Weigand and C. Robl, Chem. Ber., 1993, 126, 1807–1809.
40 T. P. Curran, A. L. Grant, R. A. Lucht, J. C. Carter and J. Affonso,
Org. Lett., 2002, 4, 2917–2920.
41 H. H. Lau and H. Hart, J. Org. Chem., 1959, 24, 280–281.
42 R. S. Herrick, R. M. Jarret, T. P. Curran, D. R. Dragoli, M. B. Flaherty,
S. E. Lindyberg, R. A. Slate and L. C. Thornton, Tetrahedron Lett.,
1996, 37, 5289–5292.
46 A. L. Margolin, N. Khalaf, C. Govardhan, J. J. Lalonde, R. A.
Persichetti and Y.-F. Wang, J. Am. Chem. Soc., 1996, 118, 5494–5495.
47 A. L. Margolin, R. A. Persichetti, N. L. St,. Clair, J. P. Griffith and
M. A. Navia, J. Am. Chem. Soc., 1995, 117, 2732–2337.
48 M. A. Navia and N. L. St,. Clair, J. Am. Chem. Soc., 1992, 114, 7314–
7316.
49 A. L. Margolin, K. Visuri, J. J. Lalonde, C. Govardhan, N. Khalaf and
A. G. Martinez, J. Am. Chem. Soc., 1995, 117, 2732–2737.
50 J. D. Kennedy, W. McFarlane, R. J. Puddephatt and P. J. Thompson,
J. Chem. Soc., Dalton Trans., 1976, 874–879.
51 M. Green, D. M. Grove, J. A. K. Howard, J. L. Spencer and F. G. A.
Stone, J. Chem. Soc., Chem. Commun., 1976, 759–760.
52 N. M. Boag, M. Green, D. M. Grove, J. A. K. Howard, J. L. Spencer
and F. G. A. Stone, J. Chem. Soc., Dalton Trans., 1980, 2170–2181.
53 B. W. Davies, R. J. Puddephatt and N. C. Payne, Can. J. Chem., 1972,
50, 2276–2284.
54 T. Ziegler, Inorg. Chem., 1985, 24, 1547–1552.
55 A. Hess and N. Metzler-Nolte, Chem. Commun., 1999, 885–886.
56 K. L. Dueholm, M. Egholm, C. Behrens, L. Christensen, H. F. Hansen,
T. Vulpius, E. F. Pettersen, R. H. Berg, P. E. Nielsen and O. Buchardt,
J. Org. Chem., 1994, 59, 5767–5773.
57 S.-M. Chen, V. Mohan, J. S. Kiely, M. C. Griffith and R. H. Griffey,
Tetrahedron Lett., 1994, 35, 5105–5108.
58 M. Eriksson and P. E. Nielsen, Q. Rev. Biophys., 1996, 29, 369–394.
59 ShelXTL 6.14, Bruker AXS Inc., Madison, WI, USA, 2003.
60 H. D. Flack, Acta Crystallogr., Sect. A: Found. Crystallogr., 1983, 39,
876–881.
43 S. I. Kirin, D. Wissenbach and N. Metzler-Nolte, New J. Chem., 2005,
29, 1168–1173.
44 A. D. Ryabov, Angew. Chem., 1991, 103, 945–955.
45 S. Top, G. Jaouen, J. Gillois, C. Baldoli and S. Maiorana, J. Chem. Soc.,
Chem. Commun., 1988, 1284–1285.
This journal is
The Royal Society of Chemistry 2009
Dalton Trans., 2009, 4310–4317 | 4317
©