A two-step palladium-catalyzed coupling scheme for the synthesis of ferrocene-labeled amino acids

Article abstract of DOI:10.1002/(SICI)1099-0682(200002)2000:2<323::AID-EJIC323>3.0.CO;2-U

This work describes a Pd-catalyzed coupling of ferrocene alkyne derivatives to iodo amino acids. Ferrocene carboxylic acid propargyl amides were easily obtained in high yield. The crystal structures of the propargyl amine derivative 3 and the 1,1-diethylpropargylamine derivative 4 have been determined by X-ray diffraction. Pd-catalyzed coupling to p-iodoanilide amino acids gave the corresponding ferrocene-labeled amino acid derivatives, which were easily purified by diethyl ether extraction in the case of the 1,1- diethyl derivatives 8. The coupling reaction did not require anhydrous solvents and tolerated a variety of functional groups present in peptides such as alcohols (8a, Ser), thioethers (8b, Met), disulfide bonds (cystine, 12) esters (as in the N-labeled Leu derivative 10) and of course amides. A minor by-product of the coupling reaction, namely the homo-dimer bis(ferrocene carboxylic acid propargylamide) 9, was identified in the crude reaction mixtures by mass spectrometry and independently synthesized by oxidative coupling (Glaser and Eglington) of 3. All new compounds were completely characterized spectroscopically, including ¹⁵N- and 2D NMR spectroscopy, Mossbauer spectroscopy and electrochemistry. This work introduces a versatile procedure for a selective functionalization of amino acids with organometallics at the C-terminus which is expected to be of general applicability to peptide chemistry.

Full text of DOI:10.1002/(SICI)1099-0682(200002)2000:2<323::AID-EJIC323>3.0.CO;2-U

FULL PAPER
A Two-Step Palladium-Catalyzed Coupling Scheme for the Synthesis of
Ferrocene-Labeled Amino Acids
[
a]
[a]
[a]
Oliver Brosch, Thomas Weyhermülle,r and Nils Metzler-Nolte*
Keywords: Amino acids / Alkynes / Ferrocene / Palladium / Catalysis / Bioorganometallic chemistry / Biosensors
This work describes a Pd-catalyzed coupling of ferrocene al- derivative 10) and of course amides. A minor by-product of
kyne derivatives to iodo amino acids. Ferrocene carboxylic
the coupling reaction, namely the homo-dimer bis(ferrocene
acid propargyl amides were easily obtained in high yield. carboxylic acid propargylamide) 9, was identified in the
The crystal structures of the propargyl amine derivative 3
and the 1,1-diethylpropargylamine derivative 4 have been
crude reaction mixtures by mass spectrometry and indepen-
dently synthesized by oxidative coupling (Glaser and
determined by X-ray diffraction. Pd-catalyzed coupling to p- Eglington) of 3. All new compounds were completely charac-
iodoanilide amino acids gave the corresponding ferrocene-
labeled amino acid derivatives, which were easily purified
terized spectroscopically, including 15N- and 2D NMR spec-
troscopy, Mössbauer spectroscopy and electrochemistry. This
by diethyl ether extraction in the case of the 1,1-diethyl deri- work introduces a versatile procedure for a selective function-
vatives 8. The coupling reaction did not require anhydrous alization of amino acids with organometallics at the C-termi-
solvents and tolerated a variety of functional groups present nus which is expected to be of general applicability to pep-
in peptides such as alcohols (8a, Ser), thioethers (8b, Met),
disulfide bonds (cystine, 12) esters (as in the N-labeled Leu
tide chemistry.
Introduction
ever, derivatizing a peptide with alkynyl groups is not feas-
able in solid-state synthesis of peptides as the alkyne may
not withstand the concentrated HF frequently used to
cleave the peptide from the support. In an effort to circum-
vent this problem, this work reports the synthesis of alkynyl
ferrocene derivatives and their Pd-catalyzed coupling to
iodobenzene amino acids with different functional groups.
We are exploring new ways of covalently linking organome-
tallic compounds to biomolecules.[
1Ϫ5]
In these conjugates,
the organometallic moiety serves as a sensitive probe for
[6Ϫ8]
the detection of the biomolecule, e. g. electrochemically
or by IR spectroscopy.[
9Ϫ18]
The key issue in any of these
No doubt is to remain about
assays is chemoselectivity:[
12,18]
Iodinated aromatic compounds were previously used as
the number of attached organometallics nor their site of
attachment to the biomolecule Ϫ which may even be, for
[22]
radio-labels for amino acids
and monoclonal anti-
[23]
bodies
and as such were successfully employed in solid
[10,11,13]
example, a large enzyme
or peptide hormone like se-
[24]
support peptide synthesis.
In this study, alternatively-
[
19]
cretin.
Also, the reaction should be mild enough to com-
functionalized amino acids were chosen as model com-
pounds for peptides and ferrocene was selected owing to its
ply with the possibly sensitive organometallic compounds
and the variety of functional groups present in a peptide.
[3,8,25Ϫ31]
potential in electrochemical detection.
[
1]
[20,21]
We and others
have suggested the use of a Pd-cata-
lyzed two-step coupling reaction for this purpose. In the
first step, an anchoring group is incorporated into the pep- Results and Discussion
tide. Secondly, a suitably-functionalized organometallic
Synthesis
compound is reacted with that anchoring group to form the
covalent link to the peptide. The prerequisite of this concept
is that the anchoring group is left untouched under stand-
ard peptide chemistry conditions and vice versa the reaction
that links the organometallic to the peptide may not affect
any functionality present in the peptide other than the
anchoring group. In compliance with this prerequisite, our
group has recently reported the synthesis of alkynyl amino
acids for the coupling with organometallic halides and dem-
onstrated the viability of our approach by selectively labe-
ling the N- and C-protected tripeptide Boc-Phe-Glu-Met-
Ferrocene carboxylic acid chloride 2, which was prepared
in situ by heating ferrocene carboxylic acid 1 at reflux with
oxalic acid chloride, reacts with propargyl amine and 1,1-
diethylpropargyl amine to give the ferrocene amido alkynes
3
and 4 in >90% yield (Scheme 1). Both derivatives are or-
ange, crystalline solids and their solid-state structures were
determined by X-ray diffraction (vide infra).
In these preparations, ferrocene carboxylic acid anhy-
dride was frequently found as a by-product. To avoid the
formation of this anhydride, we explored other means of
activating the organometallic acid. Kraatz et al. prepared
ferrocene amino acids by activation of 1 with hydroxy-
benzotriazole and dicyclohexylcarbodiimide in >70%
yield.[ In our hands, however, yields for this coupling
were usually much lower. Isobutyl chloroformate/N-methyl-
[1]
OMe at the C of Glu with a ferrocene derivative. How-
γ
[
a]
Max-Planck-Institut für Strahlenchemie,
Stiftstrasse 34Ϫ36, D-45470 Mülheim/Ruhr, Germany.
Fax: (internat.) ϩ 49-(0)208/306-3951
32]
E-mail: nils@mpi-muelheim.mpg.de
Eur. J. Inorg. Chem. 2000, 323Ϫ330

WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ1948/00/0202Ϫ323 $ 17.50ϩ.50/0
323

O. Brosch, T. Weyhermüller, N. Metzler-Nolte
FULL PAPER
(
Glaser coupling,[38] 32% yield) or stoichiometric amounts
[38]
of Cu(OAc) under Ar (Eglington coupling,
38% yield,
2
Scheme 4). The bis-ferrocene-diyne 9 is an orange-coloured
solid, which is stable both as a solid and in solution for
prolonged periods of time.
Scheme 1
morpholine in THF is an alternative well-established re-
agent for peptide coupling reactions in solution.[ Accord-
ing to Scheme 2, ferrocene carboxylic acid isobutyl ester 5
could be prepared in 95% yield. However, 14 h of reflux
were necessary to obtain 3 from 5 and propargyl amine.
Unlike amino acids, which react with amines within mi-
nutes under comparable conditions,[ ferrocene carboxylic
acid is not easily activated by the most common reagents.
33]
34]
Scheme 4
Characterization
Scheme 2
Solid-State Structures of 3 and 4
Reaction of organometallic alkynes 3 and 4 with iodo-
arene amino acid derivatives 6 gave the desired ferrocene-
labeled amino acids 7 and 8 in very good yield (Sonogashira
Crystals of suitable quality for an X-ray structure analy-
sis were obtained for the two alkynylϪferrocene derivatives
and 4. Both compounds crystallize in the orthorhombic
3
[
35Ϫ37]
coupling,
Scheme 3). By extracting the crude reaction
space group Pbca with very similar unit cells and packing
in the crystal lattice (see Table 1, Experimental Section).
ORTEP plots of the molecular structures are shown in Fig-
ures 1 and 2, repectively. The amide groups are almost par-
allel to the plane of the neighbouring cyclopentadienyl ring
9° angle between amide and Cp least squares planes for 3
and 15.5° for 4). The tilt of both cyclopentadienyl rings is
.8° (3) and 2.5° (4) away from an eclipsed conformation
mean value of H/CϪCϪCϪH dihedral angles) and the
products with diethyl ether, the diethyl derivatives 8 could
be obtained as analytically pure solids. Owing to their re-
duced solubility, the simpler propargyl amine derivatives 7
were more difficult to separate from impurities. In fact, only
the methionine derivative 7d could be obtained analytically
pure after extensive washing.
(
1
(
rings are almost parallel as shown by the centroidϪ
FeϪcentroid angle (179° and 177.8° for 3 and 4, respec-
tively). All these parameters compare well to related com-
pounds.[
32,39,40]
Unlike ferrocene carboxylic acid, which
forms dimers in the solid state,[
40,41]
both 3 and 4 form hy-
drogen bridges with their nearest neighbours through the
amide bonds in the crystal lattice. By arranging in a “head-
to-tail” fashion, the molecules form one-dimensional zig-
zag chains (Figure 3).
Scheme 3
The inability to obtain pure coupling products 7 Spectroscopy and Discussion
prompted us to carry out a careful product analysis. Elec-
tron spray ionization mass spectrometry (ESI-MS) revealed
The Sonogashira coupling has recently gained some at-
[42,43]
the presence (< 5%) of an iron-containing by-product with tention for the synthesis of organometallic alkynes
and
1
[44,45]
m/z ϭ 532. In addition, the H-NMR spectrum of the crude polymers.
Beck et al. have used p-ethynylphenyl-
reaction mixture contained a number of Cp signals, a signal alanine, which is a potent inhibitor of tryptophan hy-
for one amide proton and a further signal which was not droxylase,[ in Pd-catalyzed alkyne coupling reactions to
assigned. Since we suspected that oxidative homo-coupling obtain a variety of novel phenylalanine derivatives.[
of 3 might have occurred, we set out to synthesize the dimer NMR spectroscopy provides an excellent handle to estab-
46]
47Ϫ49]
9
by air oxidation of 3 with a catalytic amount of CuI lish the constitution of all new compounds. The alkyne pro-
324 Eur. J. Inorg. Chem. 2000, 323Ϫ330

Ferrocene-Labeled Amino Acids
FULL PAPER
Figure 1. ORTEP drawing of 3, indicating the numbering scheme.
˚
Selected bond lengths [A] and angles eg.]: FeϪCCp (av.) 2.038,
FeϪCp(centroid) 1.647 and 1.647 (unsubstituted Cp), C(1)ϪC(6)
1
.476(4), C(6)ϪO(1) 1.233(3), C(6)ϪN(1) 1.338(3), C(8)ϪC(9)
.164(5), O(1)ϪC(6)ϪN(1) 121.2(3), N(1)ϪC(7)ϪC(8) 114.1(3)
1
Figure 3. Part of the solid-state structure of 4, showing the head-
to-tail orientation of neighbouring molecules by means of hydrogen
˚
bridges. Distance N(7b)ϪO(6a) 2.998 A
carbon atom C . There are also characteristic signals in the
α
13
C-NMR spectra of conjugates 7 and 8, in particular for
the two carbon atoms between which the new bond is
formed. The alkyne carbon atom shifts downfield by about
1
3 ppm, whereas the signal of the aryl carbon atom, having
been shielded by the iodine centre in 6 (ca. 87 ppm), is
found at ca. 119 ppm in 7 and 8. The alkyne 13C-NMR
signals for the diyne 9 are observed remarkably upfield (δ ϭ
6
5.5 for the internal carbon atoms and δ ϭ 76.7). These
values are about 6 and 10 ppm higher than in a related phe-
nylacetylene-chromium-tricarbonyl dimer[ or in (ethynyl-
cyclobutadiene)-cyclopentadienyl-cobalt dimer by Bunz
and co-workers.[ Since the NMR signals for all amide
protons are readily detectable in aprotic solvents we used
42]
51]
1
15
2
D indirect detection H- N NMR spectroscopy to detect
15
the N-NMR signals of all nitrogen atoms in the new com-
pounds. There are indeed characteristic ranges for N-
NMR shifts which will facilitate the identification of related
15
Figure 2. ORTEP drawing of 4, indicating the numbering scheme.
˚
Selected bond lengths [A] and angles eg.]: FeϪCCp (av.) 2.050,
FeϪCp(centroid) 1.652 and 1.653 (unsubstituted Cp), C(1)ϪC(6) coupling products in the future, namely δN ϭ Ϫ275 for 7
1
.489(3), C(6)ϪO(6) 1.239(2), C(6)ϪN(7) 1.351(3), C(9)ϪC(10)
.190(3), O(6)ϪC(6)ϪN(7) 122.3(2), N(7)ϪC(8)ϪC(9) 110.3(2)
and δ ϭ Ϫ260 for 8. The N
signal is generally observed
N
Boc
1
at δN ϭ Ϫ290 and the anilide nitrogen atom at δN
ϭ
Ϫ250.[
52,53]
All these chemical shifts are fairly insensitive to
ton in 3 and 4 is readily detected at ca. δ ϭ 2.3 as a singlet solvent changes, which indicates that intermolecular hydro-
4
(
4) or a triplet with J
ϭ 2.6 Hz due to coupling with gen bonds are broken up in solution for 7 and 8. This no-
HH
the methylene protons (3). The success of the Pd-catalyzed tion is further substantiated by IR spectroscopy.
1
coupling can be immediately established by H-NMR spec-
In the IR spectra of 3, 4, 7 and 8, the CϵC stretching
troscopy, especially by the disappearance of this signal of frequency is often too weak to be detected. It is, however,
the terminal alkyne. In an earlier report on ferrocene car- usually the strongest band in the RAMAN spectra. Upon
boxylic acid amides of amino acids,[ two signals were substitution of the terminal proton, its frequency shifts by
32]
Ϫ1
Ϫ1
Ϫ1
observed for the ortho protons of the substituted Cp ring more than 100 cm from 2121 cm (3) and 2105 cm
Ϫ1
owing to the presence of a chiral centre. Even at 500 MHz, (4) to about 2230 cm (see Experimental Section). It is
we were unable to detect more than one signal for these possible to distinguish between propargylamine compounds
ortho protons, probably because of the large distance be- 7 and their 1,1-diethyl derivatives 8 on the basis of their
tween the Cp ring and the chiral centre. From molecular RAMAN spectra alone since there is a difference of about
modelling (Sybyl force field[ ) of the alanine derivative 7e 10 cm in the respective stretching frequencies of the CϵC
50]
Ϫ1
Ϫ1
Ϫ1
(
R ϭ H, RЈ ϭ CH ), it follows that the CϵC triple bond, bond (ca. 2230 cm in 8 and 2240 cm in 7), quite com-
3
an aromatic ring and two amide groups enforce a minimum parable to compounds 3 and 4. Unfortunately, we were un-
˚
distance of >10 A between the iron centre and the chiral able to obtain single crystals of the ferrocene amino acid
Eur. J. Inorg. Chem. 2000, 323Ϫ330
325

O. Brosch, T. Weyhermüller, N. Metzler-Nolte
FULL PAPER
conjugates 7 or 8. However, the IR spectrum of 7d sheds [2.34 mm sϪ1 (4) and 2.32 mm sϪ1 (10)] are very similar to
Ϫ1
Ϫ1 [58]
some light on structural differences between the solid-state the values of ferrocene (0.53 mm s and 2.37 mm s ).
[54,55]
and solutions of 7 and 8.
A broad band well below This similarity indicates that attachment of an amino acid
400 cm for 7d in a KBr pellet is indicative of hydrogen (10) or even functionalization of one Cp ring (4) has no
Ϫ1
3
bonding involving the amide groups. These hydrogen bonds significant influence on the field gradients of the iron nu-
will govern the packing of molecules in the solid state[ as cleus. Significant deviations were observed only in com-
described for 3 and 4. In contrast, there is only one sharp pounds where the two Cp rings were no longer co-
56]
Ϫ1
[59]
amide band observed at 3428 cm in CH Cl solution, planar.
2
2
clearly showing that all hydrogen bonds are broken up even
in aprotic solvents.
Beck and co-workers have prepared a veritable number
of stable Pd complexes of amino acids and peptides, in
[
57]
II
Electrochemical detection Ϫ where applicable Ϫ is a use- which the metal coordinates Ϫ usually in a chelating fa-
ful tool in chromatography (HPLC-ECD) and the use of shion Ϫ to the N, O, or S atoms of the amino acids.[
ferrocene derivatives in peptide chemistry has been explored Other authors reported the hydrolysis of amino acid esters
5,60Ϫ65]
by the group of Eckert.[
6,7]
Their approach of using acti- by ortho-metallated Pd complexes.
[66,67]
In the light of their
vated acids of ferrocene derivatives was hampered by low results, the success of the Pd-catalyzed coupling with amino
yields in the coupling reactions or by precursors which were acids is all the more surprising. A number of ubiquitous
difficult to prepare. Using the methodology outlined in this functional groups in peptide chemistry such as thio-ethers
work, we can easily prepare electrochemically active amino (7d and 8d), alcohols (8a), esters (10), and of course amides
acid derivatives in high yield. To demonstrate the feasibility is tolerated without notable loss of catalytic activity. Since
of ECD, compounds 7 and 8 were investigated electro- disulfide bonds play a pivotal structural role in many en-
chemically. Both groups of compounds show a reversible zymes,[ and insertion reactions into disulfide bonds are
68]
wave in the cyclic voltammogram (CV) at ϩ173 mV (7) and well documented for Pt complexes,[
69,70]
the obvious ques-
between ϩ187 and ϩ197 mV (8) vs. ferrocene/ferrocenium. tion needs to be answered as to whether our coupling would
Similar values have previously been observed for ferrocene work for cystine derivatives. The bis(N-Boc)-bis(p-iodo-ani-
carboxylic acid amides.[ A second, irreversible wave in lined)-cystine 11 was prepared from activated N-protected
32]
the CV of 8d is attributed to oxidation of the sulfur atom.
cystine and two equivalents of p-iodo-aniline. Reaction with
Compounds 7 and 8 demonstrate a general principle for 3 under Pd-catalysis yielded the mono-ferrocene derivative
the functionalization of the C-terminus of amino acids, 12 (Scheme 6).
which has not been achieved before. Naturally, this two-
step procedure can also be applied to the labeling of the N-
terminus of amino acids as shown in Scheme 5.
Scheme 6
Using an excess of 3, the bis-ferrocene derivative 13 could
also be obtained but was impossible to purify. Regardless
of the stoichiometry used, signals were detected for both 12
(
m/z ϭ 1004 for [12 ϩ Na]) and 13 (m/z ϭ 1143 for [13 ϩ
Na]) by ESI-MS in all preparations. We were able to obtain
2 in analytically pure form by liquid chromatography
Scheme 5
1
(
1
HPLC). H-NMR spectroscopy shows characteristic pat-
An excess of p-iodobenzoic acid chloride is reacted with terns for two AAЈXXЈ spin systems. In addition, the pres-
leucine methyl ester and subsequently coupled to 4 under ence of eight 13C NMR signals in the aromatic region is
Pd catalysis. The coupling product 10, which is obtained indicative of two different aromatic rings. A reversible oxi-
ϩ
analytically pure in 89% yield, is easily identified by its dation occurs at a potential of ϩ196 mV vs. Fc/Fc for a
spectral features, namely the disappearance of the signal of solution of 12 in CH Cl . Controlled potential coulometry
2
2
1
the alkyne proton in the H-NMR spectrum, characteristic of this solution requires 89% of the charge calculated for
changes in the 13C-NMR spectrum as described above and one ferrocene unit. All these results taken together allow for
Ϫ1
a strong band at 2227 cm in the RAMAN spectrum. the conclusion that the disulfide bridge in cystine deriva-
Compounds 4 and 10 were also investigated by Fe tives does not interfere with the Pd-catalyzed alkyne coup-
Mössbauer spectroscopy. The isomer shift (0.53 mm s for ling. Furthermore the two iodoarene rings are so far away
5
7
Ϫ1
Ϫ1
4
and 0.52 mm s
for 10) and quadrupolar splitting from each other in 11 that it is impossible to control the
326
Eur. J. Inorg. Chem. 2000, 323Ϫ330

Ferrocene-Labeled Amino Acids
FULL PAPER
ratio of mono- to disubstitution during the Pd-catalyzed ations were carried out on a Nucleosil-7-C18 column (Merck L6000
pump and Shimadzu SPD-2A UV detector operating at 260 nm),
coupling to ferrocene derivative 3.
Ϫ1
4
mL min flow rate with a methanol/water (5:1) mixture. Ϫ Cyc-
lic voltammograms were obtained with a three-electrode cell and
an EG&G Princeton Applied Research model 273A potentiostat.
A Ag/AgNO (0.01 mol L in AgNO ) reference electrode, a glass
3 3
Conclusion
Ϫ1
carbon disk working electrode of 2 mm diameter and a Pt wire
We have demonstrated a general way of attaching amino
acids to ferrocene derivatives by means of a Pd-catalyzed
two-step procedure starting from the amino acid ester and
Ϫ4
Ϫ1
counter electrode were used. CH
2
Cl
as supporting electrolyte. Poten-
tials E Ј were determined by square-wave voltammetry. As an in-
2
solutions (ca. 10 mol L )
Ϫ1
4 6
contained 0.1 mol L Bu NPF
0
ferrocene alkyne derivatives. Using this scheme, a selective ternal standard, ferrocene was added in excess as a reference. Ϫ
labeling of the C-terminus of amino acids is possible.[
A different approach for ferrocene functionalization of
hemin was recently proposed by Ryabov et al. by means of
13,21]
3
NMR spectra were recorded in CDCl at room temp. on a Bruker
1
13
1
ARX 250 ( H at 250.13 MHz and C), DRX 400 ( H at
1
3
1
4
5
00.13 MHz,
C and 2D spectra) and DRX 500 ( H at
00.13 MHz, 13C, N, 2D). H and C spectra were referenced to
15
1
13
activation of the propionic acid groups and reaction with
ferrocene methylamine.[
71]
TMS, using the residual proton signals of the deuterated solvents
The disadvantage of their ap-
1
13
(
(
H) or solvent signals ( C) as internal standards [CDCl
3
ϵ 7.24
3
proach, i.e. unselective reaction of the activated acid with
any primary amine, can only be resolved by employing dif-
ferent, “non-peptide” chemistry. The Pd-catalyzed Sonoga-
shira coupling applied in this work tolerates a wide variety
1
13
1
13
H) and 77.0 ( C), DMSO ϵ 2.49 ( H) and 39.5 ( C), CD OD
1
13
ϵ 3.30 ( H) and 49.0 ( C)]. Positive chemical shift values δ (in
ppm) indicate a downfield shift from the standard, only the abso-
15
lute values of coupling constants are given in Hz. N spectra were
of functional groups often encountered in peptides and referenced to the absolute frequency of 50.6969910 MHz, which
does not require dry solvents. In fact, Schmidtchen and co- was the resonance frequency of neat nitromethane under the same
experimental conditions. All resonances were assigned by 2D NMR
(H,H-COSY and H, C-HMQC for J and long-range couplings).
workers have recently introduced water-soluble cationic
1
13
1
phosphane ligands for Heck-type reactions in water.[
72]
It
1
5
N chemical shifts were taken from the F1 projection of indirect
should be noted that the coupling reactions were usually
carried out for 4 h at 80°C. Very similar yields and product
purity were obtained by stirring for 24 h at room tempera-
ture, making this method suitable for the derivatization of
more sensitive organometallic or biological compounds. In-
vestigations along these lines are currently underway in
our laboratory.
1
15
detection H, N-correlated 2D spectra with 1024/256 data points
in F1/F2, processed after applying a matched cosine function and
zero filling in both dimensions. Ϫ Mössbauer data were recorded
on a spectrometer with alternating constant-accelaration and a
57
Co source in 6 µm Rh matrix. The minimum experimental line
Ϫ1
width was 0.24 mms full width at half maximum. The sample
temperature was maintained constant in an Oxford Instruments
VARIOX cryostat. Isomer shifts are quoted relative to iron metal
at 300 K.
Experimental Section
X-ray Crystallographic Data Collection and Refinement: Trans-
parent yellow-orange single crystals of 0.74 ϫ 0.35 ϫ 0.05 mm (3)
and 0.47 ϫ 0.20 ϫ 0.03 mm (4) were sealed in glass capillaries and
mounted on the diffractometer. Graphite monochromated Mo-Kα
General: All reactions were carried out in ordinary glassware and
solvents without further precautions except where indicated.
Chemicals were purchased from Aldrich-Sigma GmbH and Fluka
AG and used as received, only enantiomerically pure -amino acids
were used. Ferrocene carboxylic acid chloride 1 was prepared by
˚
radiation (λ ϭ 0.71073 A) was used. For 3, cell constants were
obtained from a least square fit of the setting angles of 25 carefully
centred reflections and intensities were collected by the usual ω/2θ
scan technique and corrected for Lorentz and polarization effects.
The Siemens ShelXTL software package (Siemens Analytical X-
ray Instruments, Inc.) was used for solution and refinement of the
structure. Neutral atom scattering factors were taken from the us-
ual source.[ All non-hydrogen atoms were refined anisotropically.
H-atoms were placed at calculated positions and refined as riding
atoms with isotropic displacement parameters. All crystallographic
details are listed in Table 1. Crystallographic data (excluding struc-
ture factors) for the structures reported in this paper have been
deposited with the Cambridge Crystallographic Data Centre and
allocated the deposition numbers CCDC 119109 (3) and CCDC
2 2
refluxing ferrocene carboxylic acid with oxalic chloride in CH Cl
for 1 h, followed by complete removal of all volatiles. The resulting
red oil was handled under argon and used immediately. Iodoarene
amino acids 6 were prepared from the pre-activated N-Boc-pro-
tected amino acids (isobutyl chloroformate and N-
74]
methylmorpholine) and p-iodoaniline in THF and recrystallized
from hot heptane/THF (10:1).[
73]
Ϫ Melting points (uncorrected)
were determined in a Tottoli apparatus (Büchi, Switzerland). Ϫ
Elemental analysis were carried out by H. Kolbe, Analytisches La-
boratorium, Mülheim. Ϫ IR spectra were recorded on a PerkinϪ
Elmer System 2000 instrument as KBr disks, and additionally in
2 2
CH Cl .
solution where indicated. Frequencies ν˜ are given in cm
Ϫ1
1
19110 (4). Copies of the data may be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
Fax: (internat). ϩ44 1223/33 60 33; E-mail: deposit@ccdc.cam.ac.uk].
Ϫ RAMAN spectra were recorded on the same instrument as neat
Ϫ1
substances ( ν˜ in cm ). Ϫ UV/Vis spectra were recorded on a Perki-
[
nϪElmer Lambda 19 spectrometer, only the wavelengths of the
highest-energy ferrocene transition is given in nm,
ε
Preparations: Ferrocene propargylamine derivatives 3 and 4: Ferro-
cene carboxylic acid chloride was dissolved in CH Cl (40 mL).
3
Ϫ1
Ϫ1
(dm mol cm ) in brackets. Ϫ Mass spectra were recorded by the
2
2
mass spectrometry service group, Mülheim, on a MAT 8200 (Finni-
gan GmbH, Bremen) instrument (EI, 70 eV) or on a MAT95 (Fin-
Propargylamine [(0.36 g, 6.5 mmol) for 3, 1,1-diethylpropargylam-
ine (0.72 g, 6.5 mmol) in the case of 4] and triethylamine (0.66 g,
nigan GmbH, Bremen) instrument (ESI, CH
ion detection mode). Only characteristic fragments from EI spectra
are given with relative intensities (%) in brackets. Ϫ HPLC separ- vent was removed in vacuo. The residue was dissolved in chloro-
3
OH solution, positive 6.5 mmol) were added at room temp. and the solution was stirred
for 4 h. After removal of the triethylamineϪhydrochloride the sol-
Eur. J. Inorg. Chem. 2000, 323Ϫ330
327

O. Brosch, T. Weyhermüller, N. Metzler-Nolte
FULL PAPER
form, the organic phase washed three times with water and dried
(CFc ϭ O), 156.1 (CBoc ϭ O), 137.8, 132.4, 119.5, 118.3 (CAr), 85.2
with Na
pure products were obtained which could be recrystallized to yield 68.3, (CCp), 54.3 (C
single crystals. 3 (1.51. g, 87%), recrystallized from warm ethyl acet- [C(CH ], 15.3 (S-CH
): δ ϭ 5.85 (br, 1 (NHBoc), Ϫ274 (NH), Ϫ249 (NHAr). Ϫ IR: ν˜ (cm ) ϭ 3315 (br,
H, NH), 4.66 (pseudo-t, 2 H, HCp), 4.34 (pseudo-t, 2 H, HCp) 4.21 m), 1678 (br, m), 1636 (br, m), 1601 (m). Ϫ IR (CH Cl ): 3428 (m),
s, 5 H, HCp), 2.25 (t, J ϭ 2.6 Hz, 1 H, CϵCH). Ϫ 13C NMR 1701 (s), 1660 (s), 1606 (m). Ϫ Raman: 2240 cm . Ϫ MS (ESI):
CDCl ): δ ϭ 170.2 (CϭO), 80.3 (CϵCH), 71.5 (CϵCH), 75.0, 590 (M ϩ H), 612 (M ϩ Na), 628 (M ϩ K). Ϫ C30 35FeN
0.7, 69.8, 68.2 (CCp), 29.2 (CH ): δ ϭ (589.54): calcd. C 61.1, H 6.0, N 7.1; found C 61.3, H 6.0, N 6.7.
). Ϫ 15N NMR (CDCl
2
SO
4
. After filtration and removal of the solvent, virtually
(CϵC-CH
2
), 82.8 (CϵC-CH
2
), 80.7 [C(CH
), 30.3 (C ), 30.0 (CϵC-CH
). Ϫ N NMR (CDCl ): d ϭ Ϫ291
3
)
3
], 75.1, 70.7, 69.8,
α
), 31.2 (C
β
γ
2
), 28.3
1
5
3
)
3
3
3
Ϫ1
1
ate/methanol, m.p. 167°C. Ϫ H NMR (CDCl
3
2
2
Ϫ1
(
(
3
H
3 4
O S
7
2
3
Ϫ1
1
Ϫ276. Ϫ IR: ν˜ (cm ) ϭ 3281 (m), 3264 (m), 2121 (w), 1634 (s). Ϫ 8a, m.p. 114°C. Ϫ H NMR (CDCl
): δ ϭ 8.89 (s, 1 H, NHAr),
Ϫ Raman: 2121 cm (CϵC). CV: ϩ187 mV. MS (EI, 70 eV): 267 7.46 (app. d, 2 H, HAr), 7.39 (app. d, 2 H, HAr), 5.70 (s, 1 H, NH-
100), 213 (4), 186 (14). Ϫ C14 13FeNO (267.11): calcd. C 63.0, H C(Et) ), 5.65 (br, 1 H, NHBoc), 4.64 (pseudo-t, 2 H, HCp), 4.31
.9, N 5.2; found C 62.9, H 4.9, N 5.2. Ϫ 4 (1.91 g, 91%) recrys- (pseudo-t, 2 H, HCp), 4.25Ϫ4.21 (mult., 7 H, HCp, OH, C H), 3.70
(mult., 1 H, C H), 3.01 (mult., 1 H, C H), 2.42Ϫ2.34 (mult., 2 H,
.61 (br, 1 H, NH), 4.61 (pseudo-t, 2 H, HCp), 4.30 (pseudo-t, 2 H, CH -CH ), 1.96Ϫ1.87 (mult., 2 H, CH
Cp) 4.21 (s, 5 H, HCp), 2.38 (s, 1 H, CϵCH), 2.33Ϫ2.19 and C(CH ), 1.12Ϫ1.06 (overlapping t, 6 H, CH
-CH ), 1.03 (t, J ϭ 7.4 Hz, 6 H, (CDCl
): δ ϭ 169.2 (CϭO), 85.6 (CϵCH), 137.5, 132.6, 119.6, 118.8 (CAr), 90.4 [CϵC-C(Et)
], 30.8 C(Et) ), 81.1 (C(CH ), 76.0, 70.3, 69.7, 68.1 (CCp), 62.3 (C
): δ ϭ Ϫ263. Ϫ IR: ν˜ [CϵC-C(Et)
], 55.9 (C ), 31.1 (CH -CH ), 28.3 [C(CH
cm ) ϭ 3304 (w), 3277 (m), 1631 (s). Ϫ Raman 2105. Ϫ CV: (CH -CH ): δ ϭ Ϫ295 (NHBoc), Ϫ258
). Ϫ 15N NMR (CDCl
3
Ϫ1
(
4
H
2
α
1
tallized from methanol, m.p. 149°C. Ϫ H NMR (CDCl
3
): δ ϭ
β
β
5
H
2
3
2
-CH
3
), 1.46 (s, 9 H,
1
3
3
)
3
2
3
-CH ),. Ϫ C NMR
1.93Ϫ1.79 (mult., 2 H each, CH
2
3
3
): δ ϭ 170.3 (CϭO), 169.1 (CFc ϭ O), 155.1 (CBoc ϭ O),
], 83.6 (CϵC-
), 58.6
], 9.1
CH
2
-CH
3
). Ϫ 13C NMR (CDCl
3
2
76.8 (CCp), 71.6 (CϵCH), 70.3, 69.7, 68.1 (CCp), 57.5 [C(Et)
2
2
3
)
3
β
(
(
CH ), 8.8 (CH
2
Ϫ1
3
). Ϫ 15N NMR (CDCl
3
2
α
2
3
3 3
)
2
3
3
Ϫ1
ϩ182 mV. Ϫ MS (EI, 70 eV): 323 (100), 229 (40), 213 (32), 121 (NH), Ϫ252 (NHAr). Ϫ IR: ν˜ (cm ) ϭ 3235 (br, m), 1686 (m),
Ϫ1
(
19). Ϫ C18
C 67.2, H 6.5, N 4.3. Ϫ 5: Ferrocene carboxylic acid (0.5 g, (400). Ϫ MS (EI, 70 eV): 601 (100), 572 (11), 501 (23), 385 (4), 229
.17 mmol) was dissolved in THF (30 mL) at room temp. and neu- (89), 213 (64), 185 (16). Ϫ C32 39FeN (601.52): calcd. C 63.9,
H 6.5, N 7.0; found C 64.1, H 6.7, N 6.9. Ϫ 8b, m.p. 100°C. Ϫ H
NMR (CDCl ): δ ϭ 7.55 (app. d, 2 H, HAr), 7.45 (s, 1 H, NHAr),
7.38 (app. d, 2 H, HAr), 6.19 (s, 1 H, NH-C(Et) ), 4.85 (br, 1 H,
NHBoc), 4.76 (pseudo-t, 2 H, HCp), 4.41 (s, 2 H, HCp), 4.23 (s, 5 H,
Cp), 4.00 (mult., 1 H, C H), 2.32Ϫ2.26 (mult., 2 H, CH -CH ),
1.84Ϫ1.80 (mult., 2 H, CH -CH ), 1.67Ϫ1.62 (mult., 2 H, C H und
H) 1.46Ϫ1.42 (mult., 1 H, C H), 1.42 [s, 9 H, C(CH ],
): δ ϭ 4.84 (pseudo-t, 2 1.04Ϫ0.97 (overlapping t, 6 H, CH -CH ), 0.94Ϫ0.90 (mult., 6 H,
): δ ϭ 171.3 (CϭO), 168.6 (CFc ϭ O),
), 2.05 (mult., 1 H, CH), 0.98 (d, J ϭ 6.7 Hz, 6 155.7 (CBoc ϭ O), 138.2, 132.7, 119.2, 118.1 (CAr), 90.0 [CϵC-
). Ϫ 13C NMR (CDCl
): δ ϭ 166.5 (Fc-CϭO), 149.9 (Cϭ C(Et) ], 83.5 [CϵC-C(Et) ], 80.1 [C(CH ], 76.0, 71.0, 69.9, 68.3
O), 75.4 (CH ), 72.8, 70.9, 70.2, 67.7 (CCp), 27.7 (CH), 18.8 (CH ). (CCp), 58.6 (CϵC-C(Et) ), 53.0 (C ), 40.9 (C ), 30.3 und 30.9 (CH
Ϫ IR: ν˜ (cm ) ϭ 3450 (br), 1793 (s), 1731 (s). Ϫ MS (EI, 70 eV):
CH ), 28.3 [C(CH ], 24.8 (C ), 22.1 und 22.9 (C ), 8.9 und 9.0
30 (35), 230 (100), 213 (38), 185 (8), 138 (31). Ϫ C16 18FeO (CH ). Ϫ N NMR (CDCl ): δ ϭ Ϫ289 (NHBoc), Ϫ258
330.16): calcd. C 58.2, H 5.5; found C 58.4, H 5.5.
(NH), Ϫ254 (NHAr). Ϫ IR: ν˜ (cm ) ϭ 3421 (m), 3324 (m), 1701
H
21FeNO (323.22): calcd. C 66.9, H 6.6, N 4.3; found
1643 (m). Ϫ Raman: 2227 cm . Ϫ CV: ϩ193 mV. Ϫ UV: 442
2
H
3 5
O
1
tralized with N-methylmorpholine (0.22 g, 2.17 mmol). Upon ad-
dition of isobutyl chloroformate (0.3 g, 2.17 mmol) a white precipi-
tate rapidly formed. After stirring for one hour, the solution was
filtered and the solvent was removed in vacuo. The residue was
dissolved in chloroform, the organic phase washed three times with
3
2
H
α
2
3
water and dried with Na
2
SO
4
. After filtration the solvent was re-
2
3
β
moved to yield 0.57 g (79%) of 5. 5 can be recrystallized from n-
C
γ
β
3 3
)
1
pentane, m.p. 46°C. Ϫ H NMR (CDCl
H, HCp), 4.51 (pseudo-t, 2 H, HCp) 4.28 (s, 5 H, HCp), 4.08 (d, J ϭ
.6 Hz, 2 H, CH
H, CH
3
2
3
1
3
δ 3
C H). Ϫ C NMR (CDCl
6
2
3
3
2
2
3 3
)
2
Ϫ1
3
2
α
β
2
-
3
3
)
3
γ
δ
1
5
3
(
H
4
2
-CH
3
3
Ϫ1
Ϫ1
(
sh), 1654 (br, m). Ϫ Raman: 2228 cm . Ϫ CV: ϩ197 mV. Ϫ UV:
General Procedure for Pd Coupling Reactions: The iodoamino acid
1 mmol), bis(triphenylphosphane)palladium(II) dichloride (35 mg,
.05 mmol), and copper(I) iodide (9.5 mg, 0.05 mmol) were dis-
solved at room temp. in a deoxygenated mixture of THF (40 mL)
and triethylamine (10 mL). The alkyne (1 mmol), dissolved in THF
4
2
6
44 (400). Ϫ MS (EI, 70 eV): 627 (100), 571 (3), 553 (29), 385 (30),
13 (64), 185 (36), 129 (21). Ϫ C35 45FeN (627.60): calcd. C
7.0, H 7.2, N 6.7; found C 66.5, H 6.9, N 6.7. Ϫ 8c. m.p. 194°C.
(
0
H
3 4
O
1
Ϫ H NMR (CDCl
3
): δ ϭ 7.85 (s,br, 1 H, NHAr), 7.39Ϫ7.20 (mult.,
H, HAr and HPhe) 5.70 (s, 1 H, NHDEPA), 5.30 (br, 1 H, NHBoc),
.64 (pseudo-t, 2 H, HCp), 4.31 (s, 2 H, HCp), 4.40 (mult., 1 H,
H), 4.21 (s, 5 H, HCp), 3.13 (d, J ϭ 6.9 Hz, 2 H, C H), 2.43Ϫ2.35
mult., 2 H, CH -CH ), 1.95Ϫ1.87 (mult., 2 H, CH -CH ), 1.40 (s,
), 1.12Ϫ1.06 (overlapping t, 6 H, CH -CH
NMR (CDCl ): δ ϭ 169.6 (CϭO), 169.1 (CFc ϭ O), 155.8 (CBoc
9
4
C
(
9
(3 mL) was added dropwise at room temp. After complete addition,
the reaction mixture was immediately heated at reflux under argon
for 4 hours. After cooling to room temp., the dark suspension was
filtered and the solvents were removed on a rotary evaporator. The
resulting residue was redissolved in chloroform, the organic phase
α
β
2
3
2
3
13
H, CBoc
H
3
2
3
). Ϫ
C
3
ϭ
2 4
was washed three times with water and dried with Na SO . After
O), 137.4, 132.5, 119.5, 118.6 (CAr), 136.5, 129.3, 128.8, 127.8
Phe), 90.6 [CϵC-C(Et) ], 83.3 [CϵC-C(Et) ], 80.7 [C(CH ],
6.0, 70.3, 69.7, 68.1 (CCp), 58.6 [C(Et) ], 56.8 (C ), 38.3 (C ), 30.3
und 31.1 (CH -CH ), 28.2 [C(CH ], 9.24 and 9.11 (CH -CH ). Ϫ
N NMR (CDCl ): δ ϭ Ϫ291 (NHBoc), Ϫ262 (NH), Ϫ249 (NHAr).
Ϫ IR: ν˜ (cm ) ϭ 3432 (br, m), 3310 (br, m), 1665 (br, s), 1601
sh). Ϫ Raman: 2226 cmϪ1. Ϫ MS (EI, 70 eV): 661 (100), 644 (28),
87 (53), 561 (33), 229 (85), 120 (52). Ϫ C38 43FeN (661.62):
calcd. C 69.0, H 6.6, N 6.4; found C 68.7, H 6.5, N 6.3. Ϫ 8d, m.p.
filtration n-pentane was added until a light orange precipitate was
formed. The precipitate was collected and dried in vacuo for several
hours to yield 70Ϫ95% of light orange product. If necessary the
product can be purified by redissolving the precipitate in ether, fil-
(
C
2
2
3 3
)
7
2
α
β
2
3
3
)
3
2
3
15
3
tration and evaporation of the solvent. Ϫ 7d, m.p. 105Ϫ108°C. Ϫ
Ϫ1
1
H NMR (CDCl
3
): δ ϭ 8.78 (s,br, 1 H, NHAr), 7.42 (pseudo-d, 2
), 5.41
d, J ϭ 8 Hz, 1 H, NHBoc), 4.72 (s, 2 H, HCp), 4.37 (mult., 1 H,
H), 4.36 (mult., 2 H, CH -CϵC), 4.33 (s, 2 H, HCp), 4.20 (s, 5
H, HCp), 2.59Ϫ2.55 (mult., 2 H, C H), 2.15Ϫ2.12 (mult., 1 H,
), 1.99Ϫ1.96 (mult., 1 H, C H), 1.41 (s,
). Ϫ 13C NMR (CDCl
): δ ϭ 170.3 (CϭO), 170.2
(
5
H, HAr), 7.29 (pseudo-d, 2 H, HAr), 6.14 (s, 1 H, NH-CH
2
H
3 4
O
(
C
1
α
2
1
07°C. Ϫ H NMR (CDCl
d, 2 H, HAr), 7.38 (app. d, 2 H, HAr), 5.70 (s, 1 H, NH-C(Et)
.25 (d, J ϭ 8 Hz, 1 H, NHBoc), 4.63 (pseudo-t, 2 H, HCp), 4.40
): δ ϭ 8.53 (s,br, 1 H, NHAr), 7.47 (app.
3
γ
),
2
C
9
β
H), 2.07 (s, 3 H, S-CH
H, C(CH
3
β
5
)
3 3
3
(
mult., 1 H, C
α
H), 4.30 (s, 2 H, HCp), 4.21 (s, 5 H, HCp), 2.63Ϫ2.57
328
Eur. J. Inorg. Chem. 2000, 323Ϫ330

Ferrocene-Labeled Amino Acids
FULL PAPER
(
(
C
mult., 2 H, C
mult., 1 H, C
H and CH -CH
ping t, 6 H, CH
γ
H), 2.41Ϫ2.36 (mult., 2 H, CH
H), 2.10 (s, 3 H, S-CH ), 2.01Ϫ1.91 (mult., 3 H,
), 1.43 [s, 9 H, C(CH ], 1.10Ϫ1.06 (overlap-
). Ϫ 13C NMR (CDCl
): δ ϭ 170.3 (CϭO),
2 3
-CH ), 2.20Ϫ2.13 Table 1. Crystallographic details
β
3
β
2
3
3
)
3
3
4
2
-CH
3
3
1
9
6
3
8
69.1 (CFc ϭ O), 155.9 (CBoc ϭ O), 137.8, 132.4, 119.4, 118.4 (CAr), Empirical formula
C H FeNO
C H FeNO
1
4
13
18 21
323.21
0.5 [CϵC-C(Et)
9.6, 68.0 (CCp) 58.5 [C(Et)
2
], 82.4 [CϵC-C(Et)
2
], 80.5 [C(CH
), 31.3 (C
3
], 15.3 (S-CH ), 9.08 and
3
)
3
], 76.0, 70.3, Formula weight
Temperature [K]
β
), 31.34 und
267.10
293 (2)
100 (2)
2
], 54.2 (C
α
Crystal system,
space group
orthorhombic,
Pbca
orthorhombic,
Pbca
1.01(CH
.23 (CH
2
-CH
-CH
3
), 30.3 (C
γ
), 28.3 [C(CH
3
)
3
). Ϫ 15N NMR(CDCl
2
3
3
): δ ϭ Ϫ291 (NHBoc), Ϫ262 Diffractometer used
EnrafϪNonius
CAD4
Siemens SMART
Ϫ1
(
NH), Ϫ249 (NHAr). Ϫ IR: ν˜ (cm ) ϭ 3433 (br, m), 3316 (br, m),
1
(
(
685 (br, s), 1648 (br, s). Ϫ Raman: 2229 cmϪ1. Ϫ MS (ESI): 646
M ϩ H), 668 (M ϩ Na), 684 (M ϩ K). Ϫ C34 43FeN
645.64): calcd. C 63.3, H 6.7, N 6.5; found C 62.9, H 6.7, N 6.2.
Unit cell dimensions,
l. s. on
25 reflections
11.636(2)
9.881(2)
21.053(3)
2420.6(7)
8
8192 reflections
11.844(2)
9.962(1)
25.770(4)
3040.6(8)
8
H
3
O
4
S
˚
a [A]
b [ A˚ ]
1
˚
Ϫ 10, m.p. 132°C. Ϫ H NMR (CDCl
Ar), 7.49 (app. d, 2 H, HAr), 6.49 (d, J ϭ 8 Hz, 1 H, NHLeu), 5.69
s, 1 H, NH-C(Et) ), 4.82 (mult., 1 H, C H), 4.65 (pseudo-t, 2 H,
Cp), 4.32 (s, 2 H, HCp), 4.21 (s, 5 H, HCp), 3.75 (s, 3 H, OCH
3
): δ ϭ 7.72 (app. d, 2 H,
c [A]
˚
3
Volume [A ]
H
(
H
Z
2
α
Absorption coefficient
1.227
0.990
Ϫ1
3
), [mm
]
2.41Ϫ2.32 (mult., 2 H, CH
2
-CH
3
), 2.00Ϫ1.91 (mult., 2 H, CH
and C H), 1.13Ϫ1.07 (overlap-
H). Ϫ
2
-
Absorption correction
None
SADABS
(
G. Sheldrick, 1994)
CH
3
), 1.78Ϫ1.63 (mult., 3 H, C
β
H
2
γ
θ range for data
collection [°]
2.61 to 25.99
2376, 2376
1.58 to 30.00
ping t, 6 H, CH
2
-CH
3
), 0.97Ϫ0.95 (overlapping t, 6 H, C
δ
13
C NMR (CDCl ): δ ϭ 173.6 (CϭO), 169.1 (CFc ϭ O), 166.3 Reflections collected,
3
28110, 4369
(
8
(
C
OMeϭO), 133.2, 131.9, 127.0, 126.4 (CAr), 93.6 [CϵC-C(Et)
2.8 [CϵC-C(Et) ], 76.8, 70.3, 69.7, 68.1 (CCp), 58.2 [C(Et) ], 52.4
), 22.0 and
2
], Independent reflections
R
int
Ϫ
0.0767
4054/0/195
2
2
Data/Restraints/
Parameters
2067/0/160
OCH
3
), 51.2 (C
α
), 41.8 (C
β
), 31.0 (CH
2
-CH
3
), 25.0 (C
γ
). Ϫ 15N NMR (CDCl
): δ ϭ Ϫ267 Goodness-of-fit on F
2
2
2.8 (C
δ
), 9.0 (CH
2
-CH
3
3
1.050
1.039
R ϭ 0.0465,
1
Ϫ1
(
(
(
(
NHLeu), Ϫ263 (NH). Ϫ IR: ν˜ (cm ) ϭ 3313 (m), 1746 (m), 1637 Final R indices
R
1
wR
ϭ 0.0402,
2
[a]
Ϫ1
[I > 2σ(I)]
R indices (all data)[
ϭ 0.1004
ϭ 0.0701,
ϭ 0.1137
0.656, Ϫ0.434
wR
2
ϭ 0.0895
ϭ 0.0809,
ϭ 0.1018
0.557, Ϫ0.561
s), 1608 (w). Ϫ Raman: 2227 cm . Ϫ CV: ϩ197 mV. Ϫ UV: 444
a]
R
1
wR
R
1
400). Ϫ MS (EI, 70 eV): 570 (100), 541 (4), 229 (34), 213 (35), 185
2
wR
2
9). Ϫ C32
H
38FeN
2
O
4
(570.51): calcd. C 67.3, H 6.7, N 4.9; found
Largest diff. peak and
Ϫ3
˚
C 67.5, H 6.8, N 4.8. Ϫ 9: Compound 3 (267 mg, 1 mmol) was hole [eA
]
dissolved in methanol (30 mL). A solution of copper(II) acetate
[
a]
1 o c o 2 o c o
R ϭ (ΣԽF Խ Ϫ ԽF Խ/ΣԽF Խ); wR ϭ [Σw(F Ϫ F ] .
2)2/ΣwF
2
4 1/2
monohydrate (199.6 mg, 1 mmol) in a mixture of methanol (20 mL)
and pyridine (10 mL) was added dropwise and the resulting solu-
tion was stirred at 60°C for one hour. After cooling to room temp.,
the solution was reduced to about one third of the initial volume
(
(
EI, 70 eV): 842 (< 1%), 422 (9), 366 (32), 219 (46), 57 (88), 41
100). Ϫ C28 (842.55): calcd. C 39.9, H 4.3, N 6.7;
and CH
rated, washed three times with water and dried with Na
filtration, the solvent was removed on a rotary evaporator to yield
Cl
2 2
and water were added. The organic phase was sepa-
36 2 4 6 2
H I N O S
2
SO . After
4
1
found C 40.0, H 4.4, N 6.6. Ϫ 12, purified by HPLC: H NMR
(CDCl ): δ ϭ 9.32 (br, 2 H, NHAr), 7.61Ϫ7.54 (mult., 4 H, HAr),
.38Ϫ7.36 (mult., 4 H, HAr), 5.84 (br, 1 H, NH-CH ), 5.61 (br, 2
H, NHBoc), 4.92 (mult., 2 H, C H), 4.68 (pseudo-t, 2 H, HCp),
4.37Ϫ4.34 (mult., 4 H, HCp and CH ), 4.21 (s, 5 H, HCp),
.09Ϫ2.96 (mult., 4 H, C ), 1.45 [s, 18 H, C(CH
(CDCl ): δ ϭ 169.8 (CFc ϭ O), 168.5 (CCysϭO), 156.1 (CBoc ϭ O),
37.8, 137.2, 132.2, 122.6, 119.6, 120.4, 118.7, 85.3 (CAr), 88.2
CϵC-CH ), 82.8 (CϵC-CH ), 80.5 [C(CH ], 75.1, 70.7, 69.8,
8.2 (CCp), 55.6 (C ), 47.4 (C ), 30.0 (CH ), 28.4 [C(CH
NMR (CDCl ): δ ϭ Ϫ292 (NHBoc), Ϫ275 (NH), Ϫ250 (NHAr). Ϫ
IR (CH Cl ): 3420 (w), 3327 (w), 1683 (br, s), 1659 (sh). Ϫ MS
ESI, in CH Cl ): 1004 [M ϩ Na]. Ϫ C42 48FeIN (981.76):
1
1
01 mg (38%) of light-orange product, m.p. 108°C. Ϫ H NMR
CDCl ): δ ϭ 5.76 (br, 2 H, NH), 4.65 (pseudo-t, 4 H, HCp), 4.34
pseudo-t, 4 H, HCp) 4.24Ϫ4.20 (mult., 14 H, HCp and CH ). Ϫ
]DMSO): δ ϭ 169.0 (CϭO), 76.7 (CϵC-CϵC), 75.3,
0.2, 69.3, 68.2 (CCp), 65.5 (CϵC-CϵC), 28.7 (CH
). Ϫ IR: ν˜
cm ) ϭ 3324 (br), 3306 (br), 1637 (s), 1533 (s). Ϫ MS (EI, 70 eV):
32 (100), 467 (19), 401 (14), 211 (15), 121 (19). Ϫ C28
532.20): calcd. C 63.2, H 4.6, N 5.3; found C 62.9, H 4.3, N 5.1. Ϫ
1: Boc-protected cystine (10 mmol, 4.41 g) was dissolved in THF
3
7
2
(
(
3
α
2
1
3
C NMR ([D
6
2
1
3
3
β
H
2
3 3
) ]. Ϫ C NMR
7
(
5
(
2
Ϫ1
3
1
(
6
2 2 2
H24Fe N O
2
2
3 3
)
1
5
α
β
2
3
)
3
]. Ϫ
N
1
(
(
100 mL) at room temp. and neutralized with N-methylmorpholine
2.02 g, 20 mmol). Isobutyl chloroformate (2.74 g, 20 mmol) was
3
2
2
(
2
2
H
5 7 2
O S
added and a white precipitate was rapidly formed. 4-iodoaniline
4.38 g, 20 mmol) was added and the solution was allowed to stir
calcd. C 51.4, H 4.9, N 7.1; found C 51.9, H 5.2, N 7.1. Ϫ 13:
Compound 13 could not be separated completely from 12. Com-
pounds 12 and 13 have virtually identical NMR spectra, except for
the integration ratios. Ϫ MS (ESI, in CH
1
(
for one hour. The N-methylmorpholine hydrochloride was removed
by filtration and the solvent was removed on a rotary evaporator.
The resulting residue was redissolved in ether, the organic phase
2 2
Cl ): 1043 [M ϩ Na],
160 [M ϩ K].
2 4
was washed three times with water and dried with Na SO . After
filtration the solvent was removed to yield 7.1 g (84%) of 11. 11
1
can be recrystallized from hot chloroform, m.p. 218°C. Ϫ H NMR
(
[D
6
]DMSO): δ ϭ 10.14 (s, 2 H, NH), 7.61 and 7.42 (app. d, 4 H
H)
). Ϫ The authors are grateful to Prof. K. Wieghardt for many scientific
]DMSO): δ ϭ 169.3 (CϭO), 155.2 (CBoc ϭ O), discussions and for his generous support of this work. The techni-
Acknowledgments
each, HAr), 7.20 (d, 2 H, NBocH, J ϭ 7.6), 4.32 (mult., 2 H, C
α
3
β 2 3 3
.14 and 2.94 (mult., 2 H each, C H ), 1.36 (s, 18 H, C(CH )
1
3
C NMR ([D
6
1
38.5, 137.3, 121.7, 87.0 (CPhe), 78.4 (C (CH
3
)
3
), 54.5 (C
]. Ϫ 15N NMR ([D
]DMSO): δ ϭ Ϫ290 (NBoc), gratefully appreciated. Our thanks are also extended to Dr. E. Bill
6
α
) 40.1
cal help of H. Schucht (X-ray), K. Sand and J. Bitter (NMR) is
(C
β
), 28.1 [C(CH
3
)
3
Ϫ1
Ϫ249 (NAr). Ϫ IR: ν˜ (cm ) ϭ 3341 (m), 1685 (m), 1670 (s). Ϫ MS
for recording the Mössbauer spectra.
Eur. J. Inorg. Chem. 2000, 323Ϫ330
329

O. Brosch, T. Weyhermüller, N. Metzler-Nolte
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