Covalently bonded platinum(II) complexes of α-amino acids and peptides as a potential tool for protein labeling

Article abstract of DOI:10.1002/1521-3765(20021202)8:23<5368::AID-CHEM5368>3.0.CO;2-D

Arylplatinum(II) complexes have been covalently bonded to the N and C termini and to the α-carbon of various amino acid derivatives. These organometallic-functionalized amino acid compounds can be converted into the corresponding free amino acids under bo

Full text of DOI:10.1002/1521-3765(20021202)8:23<5368::AID-CHEM5368>3.0.CO;2-D

FULL PAPER
Covalently Bonded Platinum(ii) Complexes of a-Amino Acids and Peptides as
a Potential Tool for Protein Labeling
Gabriela Guillena, Gema RodrÌguez, Martin Albrecht, and Gerard van Koten*[a]
Abstract: Arylplatinumꢀii) complexes
have been covalently bonded to the N
and C termini and to the a-carbon of
various amino acid derivatives. These
properties of these biomolecules. Due to
markers. Furthermore, the ability of the
arylplatinum functional group to bind
SO2 gas, selectively and reversibly as
indicated by changes in the spectroscop-
ic properties ( H, C, Pt NMRand
UV spectra) of these compounds, allows
for the potential use of these complexes
as in vitro biosensors.
1
95
the NMRactivity displayed by the
Pt
nucleus (natural abundance 33.8%, I ˆ
1
³2) these compounds are functional bio-
1
13
195
organometallic-functionalized
amino
acid compounds can be converted into
the corresponding free amino acids
under both basic and acidic conditions;
this demonstrates the excellent stability
Keywords: amino acids ¥ biomarkers ¥
biosensors ¥ NMRspectroscopy
¥
platinum
Introduction
stable under physiological conditions, and they should not
interfere with the labeled system. Moreover, the organo-
metallic group must be left untouched under standard peptide
chemistry conditions and, vice versa, the reaction that links
the biomarker to the peptide may not affect the labeled
biomolecule. Another essential requirement of the organo-
metallic moiety is its chemoselectivity, that is, no doubt should
remain either about the number of attached organometallic
centers, or about their site of attachment to the biomolecule.
Recently, we have reported the potential application of
organoplatinumꢀii) complexes of the type [PtX(NCN-R)]
(NCN-Ris the abbreviation for the terdentate coordinat-
ing monoanionic 2,6-bis(dimethylaminomethyl)-4-R-phenyl
™pincer∫ ligand containing a functional group R: see Figure 1)
for the labeling of biomolecules.[ The use of these plati-
numꢀii) species as biomarkers is based on the NMR
Labeling of peptides and/or proteins has furnished valuable
insights into the structure and function of biomolecules. In
addition to fundamental aspects, these insights also have an
impact on medicinal research and applications.[1] Radioactive
isotopes (RIs) have been widely used as biomarkers, because
of their high detection sensitivity.[ However, because of their
hazardous nature and short shelf life, the development of an
alternative detection system that is convenient and practical
without relying on RIs is eagerly hoped for. In the last decade,
improvements in fluorescence-based techniques have made
2]
[
3]
fluorescence labels competitive with RI techniques. Some
biological molecules, such as proteins with high tryptophan
residue contents, display an intrinsic fluorescence emission.
To overcome their interference, new dyes with absorption in
the near-infrared region have been developed. These new
types of fluorescence labels, however, are normally large
aromatic molecules that might modify the native structure of
the labeled biomolecule.[ Therefore, the use of organo-
metallic compounds as an alternative method for the labeling
of amino acids or peptides has recently been at the center of
6]
substituent R:
4]
diverse flexibility
R
[5]
the attention of the scientific community. Appropriate
organometallic biomarkers must emit a characteristic signal
remote from the signals of the biomolecule, they must be
Me2N
Pt
X
NMe2
pincer ligand:
high stability
[
a] Prof. Dr. G. van Koten, Dr. G. Guillena,
Dr. G. RodrÌguez, Dr. M. Albrecht
Debye Institute, Department of Metal-Mediated Synthesis
Utrecht University, Padualaan 8
platinum(II) center:
active site
3
584 CH Utrecht (The Netherlands)
Figure 1. A diagnostic NCN ™pincer∫ platinumꢀii) entity for a-amino acids.
Various functional groups may be introduced into the aryl moiety of the
ligand system.
Fax : (‡31)30-2523615
E-mail: g.vankoten@chem.uu.nl
5368
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Chem. Eur. J. 2002, 8, No. 23

5
368±5376
activity displayed by the 195Pt nucleus (natural abundance
OH
I
CHO
1
[7]
3
3.8%, I ˆ ³
2
). Chemical shift values and coupling constants
a
b
are direct consequences of the steric and electronic environ-
ment around the observed nuclei, and different values are
therefore usually obtained, depending on the Rgroup
attached to the organometallic site. Thus, peptide functional-
ization with these complexes provides a biomarker not only
for biochemical purposes, but also for medical applications,
Me2N
Br
NMe2
2
Me N
Br
NMe2
Me2N
Br
NMe2
1
2
3
Scheme 1. Reagents and conditions: a) tBuLi (2 equiv), THF, À1008C,
0 min; then DMF, RT, 12 h; b) NaBH (2 equiv), MeOH, RT, 1 h.
1
95
since the potential use of the Pt nucleus in MRI techniques
has been demonstrated.[
1
4
8]
A further important property of the NCN platinumꢀii) com-
procedure. The key molecule used to achieve this goal was the
plexes is their ability to bind SO selectively and reversibly;
2
bifunctional ligand precursor [NC(Br)N-I-4] (1),[ containing
11]
this is readily indicated by a change in their spectroscopic
properties, detectable by UV-visible spectroscopy even at
very low concentrations (mm).[ This provides functional
biomarkers, which can be simultaneously used as biosensors.
Here we report on an extension of the application of NCN
platinumꢀii) complexes as biomarkers and biosensors. We
demonstrate the successful labeling of the N and C termini
and the a-carbons of several amino acids and peptides with
these organometallic sites, as well as the identification of the
two carbon ± halogen bonds (CarylÀI and C ÀBr) with differ-
aryl
ent reactivities. The selective lithiation of the para position
was accomplished by iodine/lithium exchange at À1008C,
with tBuLi as base. The aryllithium intermediate formed was
trapped with DMF; this afforded, after aqueous workup,
aldehyde [NC(Br)N-CHO-4] (2) in 87% yield. Reduction of 2
with sodium borohydride in methanol at room temperature
yielded alcohol 3 (86%).
9]
Condensation of aldehyde 2 with several a-amino esters in
their hydrochloride forms[ was performed in the presence of
triethylamine and magnesium sulfate, yielding the corre-
sponding Schiff bases.[ In situ reduction of the imine
intermediate with sodium cyanoborohydride afforded the
N-substituted a-amino esters 4, containing the required pincer
ligand precursor for the direct introduction of the metallic site
attachment by exploitation of the SO recognition ability and
NMRactivity of the Pt center.
2
12]
II
13]
Results and Discussion
Synthesis of a-amino acids labeled at the N and C termini: To
preserve the enantiomeric purity of the starting a-amino acid
derivatives, standard peptide chemistry was applied to attach
the ™pincer∫ ligand [X(NCN-R)] to either the N or C termini.
Furthermore, any synthetic method chosen had to be com-
patible with the organometallic functional group of the
desired molecule.[
[14]
(
Scheme 2, route A, Table 1). [{Pt(4-tol) (SEt )} ] was used
2
2
2
CHO
route A
route B
10]
Me2N
Br
NMe2
Aldehydes are valuable synthons, commonly used to
functionalize or synthesize a-amino acids, and therefore we
have used them to label the N termini of several amino acids
2
a
b
(
Scheme 1). Reduction of the carbonyl moiety to the corre-
CHO
Pt
sponding alcohol could be achieved under mild conditions.
This alcohol was used to introduce the ligand at the C
terminus of an a-amino acid by a simple esterification
R
MeO2C
N
H
NMe2
Br
NMe2
Me2N
NMe2
Abstract in Dutch: Platina-gemarkeerde a-aminozuren wer-
den gesynthetiseerd door NCN-platina complexen via de para-
positie covalent te koppelen met de N,C termini en de a-
koolstofterminus van verschillende a-aminozuren. Deze orga-
nometaal gefunctionaliseerde a-aminozuren kunnen eenvou-
dig omgezet worden in het vrije aminozuur door gebruik te
maken van zure en basische reagentia,hetgeen de uitstekende
stabiliteit van de NCN-platina groep in deze biomoleculen
aantoont. Dankzij de NMR activiteit van de
(
geschikt als biomarkers. Verder blijkt de NCN-platina groep
ook in deze verbindingen selectief en reversibel met SO gas te
Br
4
5
b
a
R
1
95
Pt kern
MeO2C
N
NMe2
Br
natuurlijk voorkomen 33.8%,I ˆ 1/2) zijn deze verbindingen
H
Pt
2
NMe2
reageren,hetgeen tot uiting komt in een ogenblikkelijke
6
1
verandering van hun spectroscopische eigenschappen ( H,
Scheme 2. Synthesis of a-amino acids labeled at their N termini. Reagents
and conditions: a) MeO CCH(R)NH Cl , MgSO , Et N, CH Cl , R T,
2 3 4 3 2 2
13
195
‡
À
C, Pt en UV). Deze complexen kunnen tevens worden
gebruikt als potentiele in vitro biosensoren.
12 h; then NaBH
SEt )] , C , 508C, 3 h.
3 2
CN, HOAc, MeOH, 108C to RT, 2 h; b) [Pt(4-tol) -
(
2
2
6 6
H
Chem. Eur. J. 2002, 8, No. 23
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5369

G. van Koten et al.
FULL PAPER
Table 1. Synthesis of a-amino acids labeled at their N termini.
Table 2. Synthesis of a-amino acids labeled at their C termini.
[
a]
[a]
Entry a-Amin oo ue ts et er RR
Product
Entry N -o Bu ot ec RR
a-amino
Product
No. Yield (%)[b] No. Yield (%)[b]
No. Yield (%)[b] No. Yield (%)[b]
acids
1
2
3
4
5
l-ValOMe
l-ValOMe
l-PheOMe
GlyOEt
(CH
(CH
PhCH
H
3
3
)
)
2
CH
CH
A
B
A
A
A
4a 87
76
4b 85
4c
4d 61
6a 51
6a 49
6b 52
2
5
1
2
3
4
5
l-Val
l-Val
l-Phe
Gly
(CH
(CH
PhCH
H
3
3
)
)
2
CH
CH
A
B
A
7a 37
9a 15
9a 71
9b 47
9c 44
9d 61
2
2
8
59
±
±
6c
±
2
7b
7c
7d
l-Asp(OMe)
2
CH
2
CO
2
Me
6d 32
A
±
l-Asp[ CH
c]
CO
±
2
2
Me B
[
a] See Scheme 2. [b] Overall yield of the isolated pure product after column
chromatography.
[a] See Scheme 3. [b] Overall yield of the isolated pure product after
column chromatography. [c] The carboxylic moiety at the 4-position was
protected as a benzyl ester.
as a metalation reagent, affording the organoplatinum-
OH
labeled a-amino ester derivatives 6 (Scheme 2, Table 1).
Similar yields were obtained when valine and phenylalanine
methyl esters were used as starting materials (entries 1 and 3,
Table 1). When glycine ethyl ester was used, condensation
with 2 took place in a good yield, but only decomposition
products were obtained in the subsequent reduction step
route A
route B
Me2N
Br
NMe2
3
(
entry 4, Table 1). For the aspartic acid derivative, with both
a
b
carboxylate functions protected, the yield for the formation of
OH
4
4
d was lower than for the corresponding compounds 4a and
b (cf. entry 5 with 1 and 2 in Table 1), while the metalation
O
step proceeded equally well in all three cases.
BocHN
O
NMe2
Alternatively, a modular approach can be used for the
direct attachment of the organometallic pincer derivative at
the N termini of a-amino acids (route B, Scheme 2). Thus,
platination of 2 by the same procedure as that used for the
pincer-bound a-amino acids (vide supra) led to the metalated
aldehyde 5 in 76% yield. Subsequently, 5 was treated with the
respective a-amino esters in the presence of triethylamine and
magnesium sulfate. Further reduction of the formed imines
with sodium cyanoborohydride led to the labeled a-amino
acids without affecting the organometallic site (Scheme 2). In
the case of valine, 6a was obtained by this method (entry 2,
Table 1), the yield being similar to that obtained by route A.
However, route B required more precise control both of
reaction temperature (below 108C) and time (not longer than
R
Br
Me2N
Pt
Br
NMe2
NMe2
7
8
a
b
O
BocHN
O
NMe2
Br
R
Pt
NMe2
9
2
hours). Despite these restrictions, this modular approach
Scheme 3. Synthesis of a-amino acids labeled at their C termini. Reagents
demonstrates the excellent stability properties of the organo-
platinum unit.
and conditions: a) HO CCH(R)NHBoc, DCC, 4-DMAP, CH Cl , R T, 12 h;
2
2
2
b) [Pt(4-tol)
2
(SEt
2
)]
2
6 6
, C H , 508C, 3 h.
a-Amino acids labeled at their C termini can also be
obtained by both approaches: namely by chemical condensa-
tion between the pincer ligand alcohol derivative [NC(Br)N-
examples of C-termini-labeled a-amino acids directly bound
to the organometallic unit (Scheme 4).
CH OH] (3) by use of dicyclohexylcarbodiimide (DCC)
Thus, direct introduction of the platinated alcohol deriva-
tive 10, again by means of DCC coupling, allowed the
synthesis of the desired phenolic ester derivatives 11. In this
way, valine and phenylalanine C-terminus-platinated phenolic
derivatives were obtained in 57 and 55% yields, respectively
(Scheme 4).
2
and 4-dimethylaminopyridine (4-DMAP) and subsequent
platination, or vice versa (Scheme 3, routes A and B, respec-
tively).
Attempts to purify the intermediate ligand 7 that contains
Boc-protected ester derivatives by column chromatography
led to lower overall yields in the case of valine (entry 1,
Table 2). Hence, the platination step was carried out with
crude 7, and the obtained organoplatinum a-amino acids
derivatives 9 were then isolated by column chromatography.
Despite this, the isolated yields for 9 were always superior
when route B was followed (entry 5, Table 2).
Synthesis of labeled free a-amino acids: Conversion of the N-
and C-labeled a-amino esters into the corresponding free a-
amino acids would widen the applicability of the [PtX(NCN)]
unit as a biomarker, since this would offer the possibility to
include these labeled a-amino acids in peptide chemistry.
Interestingly, 6a and 6b were easily hydrolyzed by treatment
The organometallic unit in an a-amino acid labeled at the C
terminus is bound through a methylene linker. To study the
of solutions of 6a and 6b in THF/H O with lithium hydroxide,
2
without affecting the platinumꢀii) center (Scheme 5).[ The
15]
possible electronic and chemical influence of this CH unit
2
(
vide infra) in the arylplatinum moiety, we prepared two
deprotected derivatives were first obtained as lithium salts
5370
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Chem. Eur. J. 2002, 8, No. 23

Pt Amino Acid Complexes
5368±5376
OH
When the same deprotection methods were applied to 9a,
the benzylic bond between the amino acid and the NCN-Pt
entity was cleaved, affording the free a-amino acid and the
starting platinated alcohol 8. However, this result is also
potentially useful for those studies in which the recovery of
the nonplatinated amino acid or peptide is required.
Br
Me2N
Pt
Br
NMe2
OH
Labeling of peptides: We studied the introduction of the
biomarker into peptides by the methodology developed in this
work for the attachment of the [PtX(NCN)]-unit to a-amino
acids.
10
a
To show the feasibility of this approach, the dipeptide l-
Phe-l-Val was attached to the pincer ligand. Treatment of a
R
methanol solution of l-Phe-l-Val with SOCl afforded the
2
O
[16]
methyl ester-protected dipeptide 15. This was followed by
BocNH
NMe2
Br
the introduction of the ligand and the metal center (vide
supra, Scheme 2, route A). The obtained product was purified
by column chromatography to give 16 in 31% overall yield
O
Pt
NMe2
(
Scheme 6).
11
Scheme 4. Synthesis of a-amino acids labeled at their C termini. Reagents
Synthesis of a-labeled a-amino acids: Even more challenging
would be the introduction of the organometallic site at the a-
position of an amino acid. This
and conditions: a) HO
2
CCH(R)NHBoc, DCC, 4-DMAP, CH
2
Cl
2
, RT, 12 h.
R
R
new labeled a-amino acid
MeO2C
N
H
NMe2
Br
a
HO2C
N
NMe2
Br
would allow the insertion of
the biomarker at any position
in a peptide chain. To this end
we followed a recently reported
procedure for the preparation
of enantiomerically pure a-ami-
no acids bearing an aryl moiety
in the side chain.[ Eventually,
protected racemic allyl glycine
ester[ was used as a substrate
for the hydroboration/Suzuki
coupling reaction with the bi-
functional precursor [NC(Br)
N-I-4] (1). The reaction was
H
Pt
Pt
NMe2
NMe2
6
6
a R = CHMe2
b R = CH2Ph
12a R = CHMe2
2b R = CH2Ph
1
17]
18]
O
O
O
BocNH
NMe2
Br
Br H3N
NMe2
b
O
Pt
Pt
NMe2
Br
NMe2
accomplished
with
[PdCl2
1
1a
Scheme 5. Deprotection of a-amino acids bound to platinum ™pincer∫ markers. Reagents and conditions:
a) LiOH, MeOH, RT, 12 h; b) HBr/AcOH or HBr/Et O, RT, 1 h.
13
(dppf)] as a catalyst, affording
18 after 12 h at reflux. The
metalation of the obtained
product was carried out with
2
and then transformed into the acids by ion-exchange chro-
matography, affording 12a and 12b each in 70% yield.
Deprotection of Boc-protected a-amino acids is normally
accomplished by treatment with trifluoroacetic acid (TFA).
When this method was applied to the C-terminus-labeled a-
amino acids 9 or 11, only decomposition products were
obtained, probably due to initial displacement of the bromine
atom attached to the platinum center by trifluoroacetate,
leading to reactive platinum derivatives. Consequently, an
alternative deprotection method had to be used. Thus, 11a
was treated with a solution of HBr/HOAc at room temper-
ature, yielding 13 as its ammonium salt. Although the
platinum ± carbon bond remained intact, about 10% of the
bromine was replaced by acetate. However, pure 13 was
[{Pt(4-tol) (SEt )} ],
yielding
2
2
2
Ph
Ph
O
O
H
H
N
b, c
N
HN
OMe
Cl H N
3
OR
O
O
Me2N
Br
Pt
1
4 R = H
a
Me2N
1
5 R = Me
16
Scheme 6. Synthesis of a dipeptide labeled at the N terminus. Reagents
and conditions: a) SOCl , MeOH, D, 1 h; b) 2, MgSO , Et N, CH Cl , R T,
2
4
3
2
2
obtained by treatment of 11a with a solution of HBr/Et O
12 h, then NaBH CN, HOAc, MeOH, 108C to RT, 2 h; c) [Pt(4-tol) -
2
3
2
(
Scheme 5).
(SEt
2
)]
2
, C
6
H
6
, 508C, 3 h.
Chem. Eur. J. 2002, 8, No. 23
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5371

G. van Koten et al.
FULL PAPER
the expected a-labeled amino acid 19 in 45% overall yield
after purification (Scheme 7).
were found in a somewhat narrower range of d ˆ À1963 to
À1967 ppm. The absence of the methylene linker in 11 does
not have any influence on the platinum chemical shifts of
these complexes. Furthermore, spectra of 6b recorded at
various concentrations in the range of 0.01 ± 0.1m showed an
Even the metalated compound [PtBr(NCN-I-4)] 17 could
be used as starting material in the hydroboration/Suzuki
coupling reaction, which took place at room temperature (i.e.,
under very mild conditions) in only 3 h. In this way, 19 was
obtained in 29% overall yield (Scheme 7).
1
95
195
almost constant Pt chemical shift value. However, the Pt
NMRshifts are dependent on the nature of the solvent, as has
been shown for 6a (entry 5, Table 3). These results suggest
The hydrolysis of the product to give the free a-metalated
amino acid was accomplished in two steps (Scheme 7).
II
that it is possible to distinguish between NCN-Pt N- and/or
Treatment of 19 with LiOH in a THF/H O mixture gave acid
C-labeled a-amino acids and acid derivatives. The a-function-
2
1
95
2
0 (77%), and subsequent treatment with HBr/Et O yielded
alized compounds have Pt NMRshifts at d ˆ À1997 to
À1980 ppm.
2
the free a-labeled amino acid 21 (75%).
Large 195Pt NMRchemical shifts were observed upon
195Pt NMRmeasurements on the pincer-Pt II
labeled a-amino
coordination of SO , which also produced an instantaneous
2
change of the color of the solution from colorless to orange.[
20]
acids: To study whether functionalization of NCN-pincer
platinumꢀii) complexes with a-amino acids would provide
diagnostic organometallic biomarkers for biochemical appli-
The downfield shift points to a strong deshielding of the
platinum nucleus upon SO binding and is in accordance with
2
cations,[
19]
195
Pt NMRspectra of the various NCN-pincer
a platinum-to-ligand charge transfer. As expected, the ob-
served chemical shifts were also dependent on the concen-
platinumꢀii)-labeled a-amino acid derivatives were recorded
in CDCl3 (0.1m) (Table 3). The chemical shifts for the
N-terminus derivatives amounted to d ˆ À1973 to
À1980 ppm, while for the C-terminus complexes these values
tration of SO in solution.
2
Conclusion
I
A new methodology, involving covalent linking of an NCN
™
pincer∫ platinumꢀii)-entity, has been developed for the
route A
route B
labeling of a-amino acids, and possibly also peptides, at either
their N or their C termini, or at the a-carbon. The excellent
chemical stability of the [PtX(NCN)]-entity under physiolog-
ical conditions provides a route to peptide labeling with a
broad application potential. The ability of the [PtX(NCN)]
Me2N
Br
NMe2
1
a
b
entity to bind SO , changing the spectroscopic properties and
2
the color of the labeled systems, both in solution and in solid
phase,[ allows their application in combinatorial and solid-
phase in vitro biochemistry studies.
21]
CO2Me
NMe2
Pt Br
NMe2
BocHN
I
NMe2
Br
Experimental Section
18
17
NMe2
General: Syntheses involving organolithium compounds were carried out
under nitrogen atmosphere by using standard Schlenk techniques. THF,
benzene, and Et
use. CH Cl was distilled from CaH
from CaH and stored over molecular sieves. The platinum salt [{Pt(4-
tol) (SEt )}
pounds 2, 4a,[6] 5, 6a, and 17
procedures. All other reagents were obtained commercially and used
2
O were dried from Na/benzophenone and distilled prior to
. DMF and NEt were flash distilled
3
b
2
2
2
a
2
[
14a]
[11]
2
2
2
6]
],
the ligand precursor [NC(Br)N-I-4] (1),
and com-
[
[6]
[6]
[11]
R
CO2R'
were prepared by published
1
13
without further purification. The H and C NMRspectra were recorded at
NMe2
Br
2
58C at 300 and 75 MHz, respectively, and were referenced to external
1
95
SiMe
4
(d ˆ 0.00 ppm, J in Hz).
Pt NMRspectra (64.5 MHz) were
Pt
[
11b]
referenced to external Na
2
PtCl
6
(d ˆ 0 ppm).
Elemental analyses were
19
N
performed by Kolbe, Mikroanalytisches Laboratorium (M¸lheim, Germa-
ny). ES-MS were obtained from the Biomolecular Mass Spectrometry
Department of Utrecht University. MALDI-TOF-MS spectra were ac-
quired with a Voyager-DE BioSpectrometry Workstation (PerSeptive
Biosystems, Framingham, MA) mass spectrometer equipped with a nitro-
gen laser emitting at 337 nm. The instrument was operated in the linear
mode at an accelerating voltage in the range of 22000 V. External
calibration was performed with C60/C70, and detection was performed with
a linear detector and digitizing oscilloscope operating at 500 MHz. Sample
Me2
1
2
2
9 R = BocHN, R' = Me
0 R = BocHN, R' = H
1 R = BrH3N, R' = H
c
d
Scheme 7. Synthesis of an a-amino acid labeled at the a-carbon. Reagents
and conditions: a) Boc-allylOMe, 9-BBN, THF, 2 h RT, then K PO , DMF,
(dppf)], 17, R T,
, 508C, 3 h; c) LiOH, MeOH, RT, 12 h;
3
4
À1
1
3
0% [PdCl
h; b) [Pt(4-tol)
O, RT, 1 h.
2
(dppf)], 1, D, 12 h or K
3
PO
4
, DMF, 10% [PdCl
2
solutions of ꢀ10 mgmL in THF were used, and the matrix was either 3,5-
À1
2
(SEt )] , C
2
2
6
H
6
dihydroxybenzoic acid or 5-chlorosalycilic acid in THF (10 mgmL ). A
d) HBr/Et
2
solution of silver(i) trifluoroacetate in THF was in some cases added to the
5372
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/02/0823-5372 $ 20.00+.50/0
Chem. Eur. J. 2002, 8, No. 23

Pt Amino Acid Complexes
5368±5376
Table 3. 195Pt NMRdata for platinum complexes. [a]
508C for 3 h. Volatile components
were removed at reduced pressure,
and the resulting oil was washed with
pentane (2 Â 30 mL). The formed pre-
cipitate was removed by centrifuga-
tion and decanting of the clear super-
natant. The solid residue was concen-
trated and purified by gradient column
R
SO2
R
Me2N
Pt
Br
NMe2
Me2N
Pt
Br
NMe2
SO2
SO2
2 2 2
chromatography (SiO , CH Cl /ace-
tone). The platinum-containing frac-
tions were collected and evaporated to
dryness, yielding 6 as a solid.
Entry
Compound
RSolvent
d
Pt
d
Pt/SO adduct
Dd
2
1
2
3
[PtBr(NCN)]
17
5
H
I
CHO
CDCl
CDCl
CDCl
3
3
3
À 1982
À 1942
À 1960
À 743
À 901
1239
1041
804
Route B: A mixture of 5 (110 mg,
À 1156
0
.23 mmol), l-valine methyl ester hy-
N termini
drochloride (75 mg, 0.45 mmol), tri-
ethylamine (0.06 mL, 0.45 mmol), and
MgSO (1.0 g) was stirred in CH Cl
4 2 2
(10 mL) at room temperature for 24 h.
All solids were filtered off, volatile
components were removed under re-
duced pressure, and the residue was
dissolved in MeOH (10 mL) and
HOAc (0.02 mL, 0.23 mmol). This sol-
ution was kept below 108C while
4
5
6
7
8
9
6a
6b
CH
2
2
-l-Val-OMe
-l-Phe-OMe
CDCl
3
À 1982
À 1944
À 1973
À 1980
À 1983
À 1972
À 1973
À 1983
À 751
À 830
À 732
±
1231
1114
1241
±
1029
802
C
6
D
6
CH
CDCl
CDCl
CDCl
3
3
3
[
b]
6d
12a
12b
16
CH
CH
CH
CH
2
2
2
2
-l-Asp-OMe[c]
-l-Val-OH
-l-Phe-OH
À 954
À 1170
À 1170
À 954
CD
CD
3
OD
OD
1
1
0
1
3
803
1029
-l-Phe-l-Val-OMe
CDCl
3
C termini
portions of NaBH
3
CN (27.9 mg,
1
1
1
1
1
1
1
2
3
4
5
6
7
8
9a
9b
9c
CH
CH
CH
CH
2
2
2
2
-l-Val-Boc
-l-Phe-Boc
-Gly-Boc
-l-Asp-Boc[
CDCl
CDCl
CDCl
CDCl
CDCl
CDCl
3
3
3
3
3
3
À 1964
À 1963
À 1964
À 1964
À 1967
À 1967
À 1982
À 870
À 1219
À 776
À 1152
À 790
À 883
±
1094
744
1188
812
1177
1084
±
0
.44 mmol) were added. The reaction
mixture was then warmed to room
temperature and stirred for 2 h. All
volatile components were removed in
vacuo, and the residue was extracted
c]
9d
11a
11b
13
l-Val-Boc
l-Phe-Boc
l-Val-NH
with NaOH (2m, 20 mL) and CH
3 Â 20 mL). The combined organic
layers were washed with brine
20 mL) and dried over MgSO . The
MgSO was filtered off, and the vola-
2 2
Cl
3
Br
3
CD OD
(
a-labeled
19
20
21
19
20
21
BocHN{CH(CH
BocHN{CH(CH
2
2
)
)
3
}CO
}CO
2
2
Me
H
CDCl
CDCl
DMSO
3
3
À 1997
À 1982
À 1980
À 1078
À 998
±
919
984
±
(
4
3
4
BrH
3
N{CH(CH
2
)}CO
2
H
tile components from the filtrate were
removed in vacuo. The resulting oil
was purified as described in route A.
Yield of 6a: 85 mg (49%).
[
a] 0.01m solutions; d (ppm). [b] 0.1m solutions. [c] The carboxylic acid moiety at the 4-position was protected as a
methyl ester in 6d and as a benzyl ester in 9d.
[
H
NC(Br)N-(CH
2
-l-Val-OMe)-4] (4a):
1
NMR(CDCl
3
): d ˆ 0.91 (d,
3
3
sample in order to improve the peak resolution. The sample solution
J(H,H) ˆ 5.6 Hz, 3H; CH(CH
CH(CH ), 1.88 (m, 1H; CH(CH
NCH
3
)
2
), 0.94 (d, J(H,H) ˆ 5.2 Hz, 3H;
(
0.2 mL) and the matrix solution (0.2 mL) were combined and placed on a
gold MALDI target and analyzed after evaporation of the solvents.
NC(Br)N-CH OH-4] (3): NaBH (0.23 g, 6.2 mmol) was added to a
3
)
2
3 2
) ), 2.24 (s, 1H; NH), 2.31 (s, 12H;
3
3
), 2.96 (d, J(H,H) ˆ 6.2 Hz, 1H; NH-CH-CO), 3.52 (downfield part
3
of AB signal, J(H,H) ˆ 6.2 Hz, 1H; Ar-CH
2
-NH), 3.53 (s, 4H; CH
2
NMe
2
),
[
2
4
3
3
.71 (s, 3H; OCH
Ar-CH -NH), 7.29 (s, 2H; ArH); C NMR(CDCl
9.3 (CH(CH ), 31.7 (CH(CH ), 45.6 (NCH ), 51.3 (OCH
-NH), 64.0 (CH NMe ), 66.4 (NH-CH-CO), 125.3 (C), 129.3, 138.5 (C),
3
), 3.81 (upfield part of AB signal, J(H,H) ˆ 6.2 Hz, 1H;
solution of 2 (0.93 g, 3.1 mmol) in MeOH (40 mL). The solution was stirred
for 1 h at room temperature. The solvent was removed in vacuo, and the
1
3
2
3
): d ˆ 18.6 (CH(CH
3 2
) ),
1
CH
3
)
2
3
)
2
3
3
), 51.7 (Ar-
resulting residue was dissolved in CH
2
Cl
2
(25 mL) and washed with H
2
O
and brine. The organic layer was dried over MgSO
4
, and solvent was
2
2
2
1
38.6 (C), 175.6 (COOMe); elemental analysis calcd (%) for C19
H
32BrN
3
O
2
removed under reduced pressure to afford 3 as a yellowish oil (0.80 g,
1
(414.39): C 55.07, H 7.78, N 10.14; found: C 55.21, H 7.85, N 9.96.
8
3
6%). H NMR(CDCl
3
): d ˆ 2.29 (s, 12H; NCH
), 4.62 (s, 2H; CH
OH), 7.35 (s, 2H; ArH); 13C NMR
): d ˆ 45.5 (NCH ), 63.7 (CH NMe ), 64.3 (CH OH), 97.2, 125.6,
27.9 (ArH), 138.4; elemental analysis calcd (%) for C13 O (301.23):
3 2
), 3.40 (brs, 1H; CH OH)
25
.55 (s, 4H; CH
2
NMe
2
2
[NC(Br)N-(CH
2
-l-Phe-OMe)-4] (4b): [a]
D
ˆ À3.08 (c ˆ 1.7 in CHCl
3
);
1
3
(
CDCl
3
3
2
2
2
H NMR(CDCl
3
): d ˆ 2.29 (s, 12H; NCH
3
), 2.93 (d, J(H,H) ˆ 6.5 Hz, 2H;
1
H21BrN
2
CH
2
Ph), 3.47 ± 3.64 (m, 5H; CH
2
NMe
2
, NH-CH-CO), 3.58 (downfield part
3
C 51.83, H 7.03, N 9.30; found: C 51.91, H 6.97, N 9.19.
of AB signal, J(H,H) ˆ 13.4 Hz, 1H; Ar-CH
2
-NH), 3,64 (s, 3H; OCH
3
),
3
3
.80 (upfield part of AB signal, J(H,H) ˆ 13.4 Hz, 1H; Ar-CH
2
-NH), 7.20
General procedure for the synthesis of a-amino acids 6, labeled at their N
termini–Route A: A mixture of a-amino acid hydrochloride, protected as
an ester (12 mmol), triethylamine (1.63 mL, 12 mmol), and an excess of
MgSO (8 g) were stirred in CH Cl (25 mL) at room temperature for 16 h.
4 2 2
All solids were filtered off, and the volatile components were removed
under reduced pressure to yield a yellow oil, which was dissolved in MeOH
1
3
(
(
(
(
m, 7H; ArH); C NMR(CDCl ), 51.1
3
): d ˆ 39.7 (CH
2
Ph), 45.2 (NCH
3
OCH ), 51.6 (Ar-CH -NH), 61.9 (NH-CH-CO), 63.8 (CH NMe ), 125.4
3
2
2
2
C), 126.6, 128.3, 129.1, 129.3, 129.7 (C), 137.1 (C), 138.2 (C), 174.8
COOMe); MS (MALDI-TOF): m/z calcd: 461.2 [M ]; found: 461.1;
H32BrN O (462.42): C 59.74, H 6.98, N
3 2
.09; found: C 59.59, H 7.01, N 8.94.
‡
elemental analysis calcd (%) for C23
9
(
1
20 mL) and HOAc (0.33 mL, 5.85 mmol). This solution was cooled below
08C, and NaBH CN (0.73 g, 12 mmol) was added in portions. The reaction
{NC(Br)N-[CH
2
-l-Asp-(OMe)
2
]-4} (4d): [a]2
D
5
ˆ À0.68 (c ˆ 0.5 in CHCl
3
);
3
1
mixture was allowed to warm to room temperature and stirred for an
additional 2 h. All volatile components were removed in vacuo, and the
resulting residue was diluted with NaOH (2m, 50 mL) and extracted with
EtOAc (3 Â 30 mL). The combined organic layers were washed with brine
H NMR(CDCl
CO
3.66 (s, 3H; OCH
3
): d ˆ 2.24 (s, 1H; NH), 2.33 (s, 12H; NCH
3
), 2.67 ± 2.71
(m, 2H; CH
2
2
Me), 3.55 (m, 1H; NH-CH-CO), 3.60 (s, 4H; CH
2
NMe
2
),
3
3
), 3.67 (downfield part of AB signal, J(H,H) ˆ 13.4 Hz,
1H; Ar-CH
2
-NH), 3.71 (s, 3H; OCH
3
), 3.85 (upfield part of AB signal,
3
13
(
30 mL) and dried over MgSO
4
. Volatile components were removed, and
, EtOAc/
OH, 80:8:2) to yield 4. A mixture of 4 (0.43 mmol) and [{Pt(4-
2
] (200 mg, 0.22 mmol) in dry benzene (30 mL) was heated at
J(H,H) ˆ 13.4 Hz, 1H; Ar-CH
): d ˆ 37.8 (CH CO Me), 45.3 (NCH
52.0 (Ar-CH -NH), 56.9 (NH-CH-CO), 63.6 (CH
137.9 (C), 138.5 (C), 171.2 (COOMe), 173.8 (COOMe); MS (MALDI-
2
-NH), 7.31 (s, 2H; ArH); C NMR
the resulting oil was purified by column chromatography (SiO
MeOH/NH
tol) (SEt )}
2
(CDCl
3
2
2
3
), 51.1 (OCH
3 3
), 51.7 (OCH ),
4
2
2
NMe ), 125.1 (C), 129.7,
2
2
2
Chem. Eur. J. 2002, 8, No. 23
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/02/0823-5373 $ 20.00+.50/0
5373

G. van Koten et al.
FULL PAPER
‡
3
TOF): m/z calcd: 443.4 [M ]; found: 445.3; elemental analysis calcd (%) for
J(H,H) ˆ 7.0 Hz, 3H; CH(CH
3
)
2
), 1.41 (s, 9H; OC(CH
), 3.55 (s, 4H; CH
3
)
3
), 2.10 ± 2.14 (m,
C
19
H
30BrN
3
O
4
(444.38): C 51.35, H 6.81, N 9.46; found: C 51.49, H 6.90, N
1H; CH(CH ), 2.29 (s, 12H; NCH
3
)
2
3
2
NMe ), 4.22 ± 4.26
2
9
.49.
(m, 1H; NH-CH-CO), 5.03 ± 5.10 (brs, 1H; NH), 5.07 (downfield part of
3
2
5
AB signal, J(H,H) ˆ 12.2 Hz, 1H; Ar-CH
2
-O), 5.16 (upfield part of AB
-O), 7.35 (s, 2H; ArH); C NMR
[
PtBr(NCN-{CH
2
-l-Val-OMe}-4)] (6a): [a]
D
ˆ À7.78 (c ˆ 1 in CHCl
), 0.92 (d,
), 2.28 (s, 1H;
3
);
3
13
1
3
signal, J(H,H) ˆ 12.2 Hz, 1H; Ar-CH
2
H NMR(CDCl
3
): d ˆ 0.88 (d, J(H,H) ˆ 3.4 Hz, 3H; CH(CH
3 2
)
3
(CDCl
31.3 (CH(CH
(NH-CH-CO), 79.7 (OCMe
3
): d ˆ 17.5 (CH(CH
3
)
2
), 18.9 (CH(CH
), 58.5 (Ar-CH
), 126.8 (C), 129.4, 134.1 (C), 138.8 (C), 155.6
3
)
2
), 28.2 (O(CH
3
)
3
, C(CH
3 3
) ),
J(H,H) ˆ 3.8 Hz, 3H; CH(CH
3
)
2
), 1.90 (m, 1H; CH(CH
3
)
2
3
3
3
)
2
), 45.5 (NCH
3
2
-NH), 63.6 (CH
2
NMe ), 66.2
2
NH), 3.07 (s, J(Pt,H) ˆ 37.8 Hz, 12H; NCH
3
), 3.05 (d, J(H,H) ˆ 17.2 Hz,
3
3
1
1
H; NH-CH-CO), 3.39 (downfield part of AB signal, J(H,H) ˆ 13.4 Hz,
‡
3
(NHCOO), 172.1 (COOMe); MS (MALDI-TOF): m/z calcd: 442.1 [M À
H; Ar-CH
2
-NH), 3.61 (upfield part of AB signal, J(H,H) ˆ 13.4 Hz, 1H;
‡
3
tBu], 398.1 [M À CO
2
tBu]; found: 441.6, 398.0; elemental analysis calcd
(500.48): C 55.20, H 7.65, N 8.40; found: C 55.28, H
Ar-CH
CH NMe
9.1 (CH(CH
2
-NH), 3.69 (s, 3H; OCH
3
), 3.97 (s, J(Pt,H) ˆ 46.0 Hz, 4H;
1
3
(%) for C23
H
38BrN
3
O
4
2
2
), 6.77 (s, 2H; ArH); C NMR(CDCl
3
): d ˆ 18.7 (CH(CH
), 53.3 (Ar-CH -NH), 55.0
NMe ), 119.6,
3 2
) ),
7.60, N 8.32.
1
3
)
2
), 31.6 (CH(CH
3
)
2
), 51.4 (OCH
), 66.6 (NH-CH-CO), 77.4 ( J(Pt,C) ˆ 53.6 Hz, CH
3
2
3
25
(
NCH
3
2
2
[PtBr(NCN-{CH -l-Val-Boc}-4)] (9a): [a] ˆ À15.08 (c ˆ 1.5, CHCl );
2
D
3
2
1
3
1
35.0 (C), 143.3 ( J(Pt,C) ˆ 78.4 Hz, (C)), 145.0 (C), 175.4 (COOMe); ES-
H NMR(CDCl ): d ˆ 0.83 (d, J(H,H) ˆ 6.7 Hz, 3H; CH(CH ) ), 0.92
3
3 2
‡
3
MS: m/z calcd: 610.5 [M ‡H]; found: 610.4; elemental analysis calcd (%)
(d, J(H,H) ˆ 6.7 Hz, 3H; CH(CH ) ), 1.42 (s, 9H; OC(CH ) ), 2.10 ± 2.14
3
2
3 3
3
for C19
5
H
32BrN
3
O
2
Pt (609.48): C 37.44, H 5.29, N 6.89; found: C 37.30, H
(m, 1H; CH(CH ) ), 3.10 (s, J(Pt,H) ˆ 38.5 Hz, 12H; NCH ), 4.00 (s,
3
2
3
3
.22, N 6.78.
J(Pt,H) ˆ 44.3 Hz, 4H; CH NMe ), 4.20 ± 4.25 (m, 1H; NH-CH-CO), 4.94
2
2
3
-l-Phe-OMe}-4)] (6b): [a]2
5
(downfield part of AB signal, J(H,H) ˆ 11.9 Hz, 1H; Ar-CH
2
-O), 5.02
[
PtBr(NCN-{CH
2
D
ˆ À3.68 (c ˆ 1 in C
6
H
6
);
3
1
3
(upfield part of AB signal, J(H,H) ˆ 11.9 Hz, 1H; Ar-CH
2
-O), 6.80 (s, 2H;
), 28.2
), 58.4 (NH-CH-CO), 67.7 (Ar-
), 120.1, 130.4 (C), 143.5 (C), 147.1
2
); MS (MALDI-TOF): m/z calcd: 694.2
H NMR(CDCl
3
): d ˆ 2.70 ± 2.75 (m, 2H; CH
2
Ph), 3.07 (s, J(Pt,H) ˆ
1
3
3
ArH); C NMR(CDCl
(C(CH ), 31.3 (CH(CH
CH -O), 77.2 (CH NMe ), 79.6 (C(CH
(C), 155.6 (NHCO ), 172.3 (CO
3
): d ˆ 17.3 (CH(CH
3 2 3 2
) ), 19.0 (CH(CH )
3
7.8 Hz, 12H; NCH
3
), 3.45 (downfield part of AB signal, J(H,H) ˆ
3
3
)
3
3
)
2
), 55.0 (NCH
3
7
3
3
.0 Hz, 1H; Ar-CH
2
-NH), 3.54 (t, J(H,H) ˆ 7.0 Hz, 1H; NH-CH-CO),
3
2
2
2
3 3
)
.61 (upfield part of AB signal, J(H,H) ˆ 7.0 Hz, 1H; Ar-CH
2
-NH), 3.63 (s,
3
2
H; OCH
3
), 3.93 (s, J(Pt,H) ˆ 45.8 Hz, 4H; CH
2
NMe
2
), 6.64 (s, 2H; ArH),
Ph), 51.9
), 61.7 (NH-CH-CO), 77.4
), 119.9, 126.9, 128.5, 129.3 (C), 136.7 (C), 143.5 (C), 145.2 (C),
‡
‡
1
3
[M ], 615.3 [M À Br]; found: 695.0, 616.3; elemental analysis calcd (%) for
7
(
(
1
5
4
.14 ± 7.26 (m, 5H; ArH); C NMR(CDCl
OCH ), 52.4 (Ar-CH -NH), 55.0 (NCH
CH NMe
74.5 (COOMe); MS (MALDI-TOF): m/z calcd: 577.2 [M À Br]; found:
77.7; elemental analysis calcd (%) for C23 Pt (656.13): C 42.01, H
.91, N 6.39; found: C 42.13, H 4.85, N 6.31.
3
): d ˆ 39.0 (CH
2
C
23
H
38BrN
3
O
4
Pt ¥ 0.5C
3
H
6
O (723.10): C 40.70, H 5.51, N 5.81; found: C
3
2
3
4
0.50, H 5.74, N 6.04.
2
2
‡
25
[PtBr(NCN-{CH -l-Phe-Boc}-4)] (9b): [a] ˆ À7.38 (c ˆ 1 in CHCl );
2
D
3
H
32BrN
3
O
2
1
H NMR(CDCl ): d ˆ 1.40 (s, 9H; C(CH ) ), 3.06 (AB signal overlapped,
3
3 3
3
3
2H; CH Ph), 3.11 (s,
2
J(Pt,H) ˆ 33.0 Hz, 12H; NCH ), 4.00 (s,
3
J(Pt,H) ˆ
}-4)] (6d): [a]2
5
2 2
45.4 Hz, 4H; CH NMe ), 4.57 ± 4.64 (m, 1H; NH-CH-CO), 4.94 (s, 2H; Ar-
[
PtBr(NCN-{CH
2
-l-Asp-(OMe)
2
D
ˆ À0.58 (c ˆ 3 in CHCl
3
);
1
3
1
3
CH -O), 6.80 (s, 2H; ArH), 7.02 ± 7.21 (m, 5H; Ph); C NMR(CDCl ): d ˆ
H NMR(CDCl
3
): d ˆ 2.34 (br, 1H; NH), 2.73 (t, J(H,H) ˆ 7.0 Hz, 2H;
2
3
3
3 3 2 3
28.2 (C(CH ) ), 40.5 (CH Ph), 54.3 (NH-CH-CO), 55.0 (NCH ), 67.9 (Ar-
CH
2
CO
2
Me), 3.09 (s, J(Pt,H) ˆ 36.6 Hz, 12H; NCH
3
), 3.54 (downfield part
3
2 2 2 3 3
CH -O), 77.2 (CH NMe ), 80.2 (C(CH ) ), 120.3, 126.8 (C), 128.4, 128.6 (C),
of AB signal, J(H,H) ˆ 12.5 Hz, 1H; Ar-CH
2
-NH), 3.56 ± 3.66 (m, 1H;
1
29.3, 130.2 (C), 135.9, 143.5 (C), 155.0 (NHCO
2
), 171.7 (CO
2
); MS
NH-CH-CO), 3.66 (s, 3H; OCH
3
), 3.72 (upfield part of AB signal,
‡
3
(MALDI-TOF): m/z calcd: 662.2 [M À Br]; found: 664.8; elemental
J(H,H) ˆ 12.5 Hz, 1H; Ar-CH
J(Pt,H) ˆ 44.8 Hz, 4H; CH NMe
CO Me), 51.8 (OCH
), 56.8 (NH-CH-CO), 77.3 (CH
45.2 (C), 171.2 (COOMe), 173.8 (COOMe); MS (MALDI-TOF): m/z
2
-NH), 3.73 (s, 3H; OCH
3
), 3.98 (s,
):
-NH), 55.0
), 119.6, 134.3 (C), 143.3 (C),
3
13
analysis calcd (%) for C H BrN O ¥ 0.3C H (768.18): C 45.26, H 5.24, N
27 38
3
4
6
6
2
2
), 6.77 (s, 2H; ArH); C NMR(CDCl
3
5
.46; found: C 45.59, H 5.97, N 5.58.
d ˆ 37.6 (CH
NCH
2
2
3
), 52.1 (OCH
NMe
3 2
), 52.6 (Ar-CH
(
1
3
2
2
-Gly-Boc}-4)] (9c): 1H NMR(CDCl
[
PtBr(NCN-{CH
2
3
): d ˆ 1.40 (s, 9H;
3
3
C(CH
2
CH
3
)
3
), 3.08 (s, J(Pt,H) ˆ 41.5 Hz, 12H; NCH
3
), 3.89 (d, J(H,H) ˆ 5.5,
‡
‡
calcd: 559.2, [M À Br], 364.2 [M À PtBr]; found: 557.3, 362.3; elemental
analysis calcd (%) for C19 Pt (639.47): C 35.69, H 4.73, N 6.57;
found: C 35.87, H 4.70, N 6.38.
3
H; NH-CH
2
-CO), 3.98 (s, J(Pt,H) ˆ 49.7, 4H; CH
-O), 5.03 (s, 1H; NH-CH -CO), 6.80 (s, 2H; ArH); C NMR(CDCl
), 42.4 (NH-CH -CO), 55.0 (NCH ), 67.9 (Ar-CH -O),
), 79.9 (C(CH ), 120.2, 130.2 (C), 143.6 (C), 147.3 (C),
), 170.2 (CO
); MS (MALDI-TOF): m/z calcd: 572.2 [M À
2 2
NMe ), 4.99 (s, 2H; Ar-
H30BrN
3
O
4
13
2
2
3
):
d ˆ 28.2 (C(CH
3
)
3
2
3
2
General procedure for the synthesis of a-amino acids 9, labeled at their C
termini–Route A: A solution of Boc-protected a-amino acid (0.5 mmol)
77.2 (CH NMe
2
2
3 3
)
155.6 (NHCO
2
2
‡
in CH
DCC (0.156 g, 0.75 mmol), 4-DMAP (0.012 g, 0.01 mmol), and the alcohol
(0.180 g, 0.6 mmol) in CH Cl (20 mL). The mixture was stirred at this
temperature for 16 h. All solids were filtered off, and the organic layer was
washed with a saturated solution of NH Cl, water, and brine, and dried over
MgSO . Volatile components were removed, and the resulting oil was
purified by column chromatography (SiO EtOAc/MeOH/NH OH,
0:29:1) to afford compound 7a. Compounds 7b and 7c were used without
further purification. A mixture of 7 (0.40 mmol) and [{Pt(4-tol) (SEt )}
188 mg, 0.20 mmol) in dry benzene (30 mL) was heated at 508C for 3 h. All
2
Cl
2
(5 mL) was slowly added at room temperature to a solution of
Br] ; found: 573.6; elemental analysis calcd (%) for C27
H
38BrN
3
O
4
(652.12): C 37.67, H 5.42, N 6.28, Br 11.93; found: C 37.76, H 5.37, N 6.27,
Br 11.79.
3
2
2
25
[
PtBr(NCN-{CH
2
-l-Asp-Boc 4-benzyl ester}-4)] (9d): [a]
D
ˆ ‡8.08 (c ˆ 1
4
in CHCl
); H NMR(CDCl
1
): d ˆ 1.41 (s, 9H; C(CH
3 3
) ), 2.84 (downfield
3
3
4
part of ABX signal, J(H,H) ˆ 4.6, 16.7 Hz, 1H; NH-CH-CH
3
2
), 3.09
2
,
4
(
upfield part of ABX signal overlapped with a s, J(Pt,H) ˆ 36.6 Hz, 13H;
3
7
3
NCH
(
1
1
2
2
3
and NH-CH-CH
2
), 3.98 (s, J(Pt,H) ˆ 44.6 Hz, 4H; CH
2
NMe
2
), 4.58
2
2
2
]
m, 1H; NH-CH-CO); 4.92 (downfield part of AB signal, J(H,H) ˆ
3
(
3
1.9 Hz, 1H; CH
H; CH Ph), 5.07 (s, 2H; Ar-CH
H; ArH), 7.34 (m, 5H; Ph); C NMR(CDCl
8.5 (C(CH ), 50.3 (NH-CH-CO), 55.3 (NCH
-O), 77.5 (CH NMe ), 80.4 (C(CH ), 120.4, 128.4, 128.6 (C),
2
Ph), 5.00 (upfield part of AB signal, J(H,H) ˆ 11.9 Hz,
-O), 5.46 (brd, 1H; NH-CH -CO), 6.75 (s,
): d ˆ 24.9 (NH-CH-CH ),
), 66.9 (Ar-CH -O), 68.7
volatile components were removed at reduced pressure and the resulting
oil was washed with pentane (2 Â 30 mL). The formed precipitate was
removed by centrifugation and decanting of the clear supernatant. The
solid residue was concentrated and purified by gradient chromatography
2
2
2
13
3
2
3
)
3
3
2
(
Ph-CH
2
2
2
3 3
)
(
2 2 2
SiO , CH Cl /acetone). The platinum-containing fractions were collected
1
1
28.9, 130.4 (C), 135.6, 143.8 (C), 147.5 (C), 155.6 (NHCO
2
), 170.9 (CO
2
),
and evaporated to dryness, yielding compounds 9 as solids.
‡
71.2 (CO
2
); MS (MALDI-TOF): m/z calcd: 720.2 [M À Br]; found: 721.9;
Route B: A solution of Boc-protected a-amino acid (0.33 mmol) in CH
2
Cl
2
3 4 2 6
elemental analysis calcd (%) for C27H38BrN O ¥ C H O (874.25): C 45.26,
(
(
(
5 mL) was slowly added at room temperature to a solution of DCC
0.103 g, 0.5 mmol), 4-DMAP (0.005 g, 0.03 mmol), and the alcohols 8 or 10
0.4 mmol) in CH Cl (20 mL). The mixture was stirred at room temper-
H 5.75, N 4.80; found: C 45.03, H 5.39, N 4.97.
25
[
PtBr(NCN-{L-Val-Boc})-4] (11a): [a]
D
ˆ À11.68 (c ˆ 1 in CHCl
), 1.04 (d,
), 2.24 ± 2.30 (m,
), 3.98 (s,
3
);
2
2
1
3
H NMR(CDCl
3
): d ˆ 0.98 (d, J(H,H) ˆ 7.2 Hz, 3H; CH(CH
3 2
)
ature for 16 h. All solids were filtered off, and the organic layer was washed
with a saturated solution of NH Cl, water, and brine, and dried over
MgSO . Volatile components were then removed and the resulting oil was
purified by column chromatography as described in route A.
3
J(H,H) ˆ 7.2 Hz, 3H; CH(CH
3 2 3 3
) ), 1.44 (s, 9H; OC(CH )
4
3
1
H; CH(CH
3
)
2
), 3.09 (s, J(Pt,H) ˆ 36.3 Hz, 12H; NCH
3
4
3
J(Pt,H) ˆ 44.1 Hz, 4H; CH
2
NMe
2
), 4.39 (m, 1H; NH-CH-CO), 5.03 (d,
3
13
J(H,H) ˆ 8.9 Hz, 1H; NH-CH-CO), 6.53 (s, 2H; ArH); C NMR(CDCl
3
):
),
2
5
[
NC(Br)N-(CH
2
-l-Val-Boc)-4] (7a): [a]
D
ˆ À2.18 (c ˆ 2.3 in CHCl
3
);
d ˆ 17.7 (CH(CH
3
)
2
), 19.0 (CH(CH
3
)
2
), 28.3 (C(CH
3 3 3
) ), 31.3 (CH(CH )
2
1
3
H NMR(CDCl
3
): d ˆ 0.82 (d, J(H,H) ˆ 7.0 Hz, 3H; CH(CH
3
)
2
), 0.90 (d,
55.0 (NCH ), 58.6 (NH-CH-CO), 77.2 (CH
3
2
NMe ), 79.9 (C(CH
2
3
)
3
), 112.7,
5374
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/02/0823-5374 $ 20.00+.50/0
Chem. Eur. J. 2002, 8, No. 23

Pt Amino Acid Complexes
5368±5376
1
43.6 (C), 143.9 (C), 147.1 (C), 155.6 (NHCO
2
‡
), 171.4 (CO
2
); MS (MALDI-
TOF): m/z calcd: 681.15 [M ], 601.4 [M À Br]; found: 681.3, 600.6;
elemental analysis calcd (%) for C22 Pt (681.52): C 38.77, H 5.32,
N 6.08; found: C 38.63, H 5.28, N 6.08.
(CH(CH
CH -NH), 55.0 (NCH
(CH NMe ), 119.8, 127.0, 128.6 (C), 128.7, 129.2, 134.2 (C), 136.1 (C), 143.7
3
)
2
), 31.0 (CH(CH
3 2 2 3
) ), 38.8 (CH Ph), 52.1 (OCH ), 52.6 (Ar-
‡
2
3
), 56.9 (NH-CH-CO), 62.7 (NH-CH-CO), 77.2
H
36BrN
3
O
4
2
2
(C), 153.0 (NHCO), 172.2 (CO); MS (MALDI-TOF): m/z calcd: 676.3
‡
PtBr(NCN-{L-Phe-Boc}-4)] (11b): [a]2
5
[M À Br]; found: 673.7; elemental analysis calcd (%) for C28
4 3
H41BrN O
[
D
ˆ À10.68 (c ˆ 1, CHCl
3
);
1
3
(756.6): C 44.45, H 5.46, N 7.40; found: C 44.36, H 5.57, N 7.35.
H NMR(CDCl
2H; NCH ), 3.16 ± 3.21 (m, 2H; CH
CH NMe
3
): d ˆ 1.43 (s, 9H; C(CH
3
)
3
), 3.10 (s, J(Pt,H) ˆ 43.8 Hz,
3
1
3
2
Ph), 3.98 (s, J(Pt,H) ˆ 43.2 Hz, 4H;
Synthesis of a-labeled a-amino acid 19–Route A: 9-Borabicyclo[3.3.1]-
nonane (9-BBN; 0.5m in THF, 6.0 mL, 3.00 mmol) was added at 08C to a
solution of Boc-allylglycine methyl ester (0.343 g, 1.5 mmol) in degassed
THF (7 mL), and the reaction mixture was warmed to RT and stirred for
2 h. Degassed DMF (4 mL) was added, followed by careful addition (H2
evolution) of aq. K PO (3m, 1.0 mL, 3.1 mmol), followed by a quick
3
2
2
), 4.76 ± 4.78 (m, 1H; NH-CH-CO), 5.03 (d, J(H,H) ˆ 7.9 Hz,
1
3
1
(
(
H; NH-CH-CO), 6.44 (s, 2H; ArH), 7.22 ± 7.36 (m, 5H; Ph); C NMR
CDCl ), 38.3 (CH Ph), 54.6 (NH-CH-CO), 55.1
): d ˆ 28.2 (C(CH
NCH ), 77.2 (CH NMe ), 80.2 (C(CH ), 112.6, 127.2 (C), 128.6 (C),
3
3
)
3
2
3
2
2
3 3
)
1
29.4, 135.8, 143.6, 143.9 (C), 147.1 (C), 155.1 (NHCO
2
), 170.9 (CO
2
); MS
3
4
‡
(
MALDI-TOF): m/z calcd: 649.2 [M À Br]; found: 647.7; elemental
addition of 1 (0.510 g, 1.3 mmol) and, finally, [PdCl (dppf)] (0.109 g,
2
analysis calcd (%) for C26
H36BrN
3
O
4
Pt (729.59): C 42.80, H 4.97, N 5.76;
0.15 mmol). The reaction mixture was heated under reflux overnight and
found: C 42.95, H 5.08, N 5.68.
the solvent was removed in vacuo. The residue was taken up in diethyl ether
(
20 mL) and washed with sat. NaHCO
extracted twice with diethyl ether (20 mL), and the combined organic
layers were dried over MgSO . The volatile components were removed,
and the resulting oil was percolated by column chromatography (SiO
Et O and Et O/MeOH 1:1) to yield compound 18 (0.530 g, 72% yield),
which was used in the next step without further purification. A mixture of
8 (0.377 g, 0.76 mmol) and [{Pt(tol-4) (SEt )} ] (355 mg, 0.76 mmol) in dry
3
(15 mL). The aqueous layer was re-
General procedure for the deprotection of a-amino acids 6, labeled at their
N termini: A solution of 6 (0.05 mmol) and LiOH ¥ H O (8 mg, 0.35 mmol,
6%) in THF/H O (2:1, 3 mL) was stirred at room temperature overnight.
2
5
2
4
,
After this time an aqueous solution of HBr was carefully added until pH ˆ
2
. Dowex¾ resin was added to this solution, and the mixture was stirred
overnight at room temperature. Dowex resin was filtrated off. The filtrate
2
2
6
¾
1
2
2
2
was concentrated to afford 12 (0.035 mmol, 70%).
benzene (30 mL) was heated at 508C for 3 h. All volatile components were
removed at reduced pressure and the resulting oil was washed with pentane
[
PtBr(NCN-{CH
2
-l-Val-OH}-4)] (12a): 1H NMR(CD
3
OD): d ˆ 1.02 (d,
3
3
J(H,H) ˆ 6.8 Hz, 3H; CH(CH
), 2.31 ± 2.38 (m, 1H; CH(CH
H; NH-CH-CO), 4.10 (m, 6H; CH NMe
OD): d ˆ 17.9 (CH(CH
), 51.4 (NH-CH-CO), 55.0 (NCH
), 122.7, 126.7 (C), 145.9 (C), 149.7 (C), 170.4 (CO
3
)
2
), 1.14 (d, J(H,H) ˆ 6.8 Hz, 3H;
(
2 Â 30 mL). The formed precipitate was removed by centrifugation and
decanting of the clear supernatant. The solid residue was concentrated and
purified by gradient chromatography (SiO , CH Cl /acetone). The plati-
CH(CH
1
3
)
2
3
)
2
), 3.00 (s, 12H; NCH
and Ar-CH -NH), 6.96 (s, 2H;
), 19.6 (CH(CH ), 30.6
), 55.2 (Ar-CH -NH), 77.9
); MS
MALDI-TOF): m/z calcd: 515.2 [M À Br], 320.2 [M À PtBr]; found:
14.4, 320.4.
3
), 3.83 (d,
2
2
2
2
2
2
1
3
ArH); C NMR(CD
3
3
)
2
3 2
)
num-containing fractions were collected and evaporated to dryness,
yielding 19 as white solid (0.470 g, 45%).
(
(
(
CH(CH
3
)
2
3
2
CH NMe
2
2
2
‡
‡
Route B: The procedure was similar to that used above, but instead of 1, 17
was used as alkyl iodide. After addition of all reagents, the reaction mixture
was stirred for 3 h at RTand the solvent was removed in vacuo. The residue
5
2
5
[
PtBr(NCN-{CH
2
-l-Phe-OH}-4)] (12b): [a]
D
ˆ À3.08 (c ˆ 1 in CH
3
OH);
), 3.22 (dd,
was taken up in diethyl ether (20 mL) and washed with sat. NaHCO
3
1
3
H NMR(CD
3
OD): d ˆ 3.05 (s, J(Pt,H) ˆ 37.8 Hz, 12H; NCH
3
(
(
15 mL). The aqueous layer was re-extracted twice with diethyl ether
20 mL), and the combined organic layers were dried over MgSO . The
3
J(H,H) ˆ 6.0, 15.3 Hz, 2H; CH
2
Ph), 3.66 ± 3.71 (m, 1H; NH-CH-CO), 3.86
3
4
(
downfield part of AB signal, J(H,H) ˆ 12.6 Hz, 1H; Ar-CH
2
-NH), 3.95
volatile components were removed, and the resulting oil was purified by
gradient chromatography (SiO , Et O and then CH Cl /acetone). The
platinum-containing fractions were collected and evaporated to dryness,
3
(
upfield part of AB signal, J(H,H) ˆ 12.6 Hz, 1H; Ar-CH
2
-NH), 4.05 (s,
3
2
2
2
2
J(Pt,H) ˆ 43.2 Hz, 4H; CH
OD): d ˆ 37.0 (CH
CH-CO), 55.0 (NCH ), 77.9 (CH NMe
2
NMe
2
), 6.79 (s, 2H; ArH), 7.25 ± 7.33 (m, 5H;
Ph), 52.4 (Ar-CH -NH), 54.5 (NH-
), 122.4, 126.7 (C), 128.8, 130.0,
Ph); 13C NMR(CD
3
2
2
yielding 19 as a white solid (yield 29%).
3
2
2
1
1
30.5, 135.7 (C), 146.0 (C), 149.5 (C), 171.5 (COOH); MS (MALDI-TOF):
[PtBr(NCN-{BocHN[CH(CH
1.43 (s, 9H; OC(CH ) ), 1.48 ± 1.85 (m, 4H; CH CH ), 2.44 ± 2.51 (m, 2H;
3 3 2 2
CH
2
)
3
]CO
2
Me}-4)] (19): H NMR(CDCl
3
): d ˆ
‡
m/z calcd: 562.2 [M À Br]; found: 561.3; elemental analysis calcd (%) for
3
C
22
H
29BrN
3
O
2
Pt ¥ 2H
2
O (678.52): C 38.94, H 4.90, N 6.16; found: C 38.81, H
2
3
CH), 3.10 (s, J(Pt,H) ˆ 36.9 Hz, 12H; NCH
3 3
), 3.71 (s, 3H; OCH ), 3.98
4
.93, N 6.09.
PtBr(NCN-{l-Val-NH
.14 mmol, 10%) was added to a solution of 11a (100 mg, 0.014 mmol) in
glacial HOAc (0.8 mL). The mixture was stirred at room temperature for
h. After this time, a yellow solid had precipitated from the reaction
mixture. The solid was triturated twice with 5 mL of Et O, and the solvent
(s, J(Pt,H) ˆ 44.4 Hz, 4H; CH
2
NMe
2
), 4.29 ± 4.31 (m, 1H; NH-CH-CO),
3
13
4
.98 (d, J(H,H) ˆ 8.0 Hz, 1H; NH), 6.60 (s, 2H; ArH); C NMR(CDCl
3
):
CH), 52.2
NMe ), 79.9
), 119.3, 136.9 (C), 143.3 (C), 145.0 (C), 155.3 (NHCO), 173.3
[
3
Br}-4)] (13): A solution of HBr/HOAc (0.8 mL,
d ˆ 27.3 (CH
2
CH
), 53.2 (NH-CH-CO), 53.6 (NCH
OC(CH
CO
); MS (MALDI-TOF): m/z calcd: 615.7 [M À Br]; found: 614.7;
Pt (694.17): C 39.72, H 5.51,
2
), 28.3 (OC(CH
3
)
3
), 32.3 (CH
2 2 2
CH ), 35.7 (CH
0
(
(
(
OCH
3
3
), 77.4 (CH
2
2
3
)
3
1
‡
2
2
elemental analysis calcd (%) for C23
3 4
H38BrN O
1
was removed by decantation to afford 13 (76 mg, 76%). H NMR(CDCl
3
):
N 6.04; found: C 39.85, H 5.62, N 6.08.
3
3
d ˆ 0.97 (d, J(H,H) ˆ 6.8 Hz, 3H; CH(CH
3
)
2
), 1.03 (d, J(H,H) ˆ 6.8 Hz,
3
3
H; CH(CH
3
)
2
), 2.12 ± 2.16 (m, 1H; CH(CH
3
)
2
), 3.07 (s, J(Pt,H) ˆ 33.0 Hz,
Hydrolysis of compound 19: A solution of 19 (85 mg, 0.14 mmol) and
LiOH ¥ H O (29 mg, 0.7 mmol, 56%) in THF/H O (4:1, 5 mL) was stirred at
room temperature overnight. After this time the reaction mixture was
3
1
2H; NCH
3
), 3.47 (m, J(H,H) ˆ 4.9 Hz, 1H; NH-CH-CO), 3.97 (s,
2
2
3
J(Pt,H) ˆ 35.4 Hz, 4H; CH
2
NMe
2
), 4.05 (downfield part of AB signal,
3
3
J(H,H) ˆ 7.3 Hz, 1 H ; Ar-CH
J(H,H) ˆ 7.3 Hz, 1 H ; Ar-CH
), 19.1 (CH(CH
2
-O), 4.09 (upfield part of AB signal,
treated with 1m HCl (aq.) The aqueous phase was extracted with EtOAc
13
2
-O), 6.52 (s, 2H; ArH); C NMR(CDCl
3
):
(3 Â 20 mL) and the collective organic layer were washed with brine and
1
d ˆ 17.1 (CH(CH
3
)
2
3
)
2
), 32.2 (CH(CH
3
)
2
), 54.9 (NCH
), 112.6, 143.4 (C), 143.8 (C), 147.2 (C), 174.3
3
), 59.8
dried over MgSO
4
to afford 20 (62 mg, 77%). H NMR(CD
3
OD): d ˆ 1.43
(
(
NH-CH-CO), 77.1 (CH
CO
2
NMe
2
(s, 9H; OC(CH
CH
39.1 Hz, 4H; CH
3
)
3
), 1.67 ± 1.85 (m, 4H; CH
2
CH
2
), 2.44 ± 2.51 (m, 2H;
‡
3
3
CH), 3.10 (s, J(Pt,H) ˆ 23.8 Hz, 12H; NCH
3
), 3.98 (s, J(Pt,H) ˆ
2
); ES-MS: m/z calcd: 582.4 [M À Br]; found: 582.1; elemental
2
analysis calcd (%) for C17
H
29Br
2
N
3
O
2
Pt (662.35): C 30.83, H 4.41, N 6.35;
2
NMe
2
), 4.29 ± 4.31 (m, 1H; NH-CH-CO), 4.98 (d,
3
13
found: C 30.75, H 4.36, N 6.28.
J(H,H) ˆ 8.0 Hz, 1H; NH), 6.62 (s, 2H; ArH); C NMR(CDCl
3
): d ˆ
CH), 53.2 (NH-
), 119.4, 136.8 (C),
); MS (MALDI-TOF): m/z
-l-Phe-l-Val-OMe}-4)] (16): [a]2
5
27.3 (CH
2
CH
2
), 28.3 (OC(CH
3
)
3
), 31.9 (CH
2 2 2
CH ), 35.7 (CH
NMe ), 80.2 (OC(CH )
[
PtBr(NCN-{CH
2
D
ˆ À168 (c ˆ 1 in
1
3
CH-CO), 53.6 (NCH
143.3 (C), 145.3 (C), 155.3 (NHCO), 177.3 (CO
calcd: 600.25 [M À Br]; found: 600.4.
Synthesis of compound 21: A solution of HBr/HOAc (0.5 mL, 0.10 mmol,
10%) was added to a solution of 20 (60 mg, 0.10 mmol) in glacial HOAc
(0.5 mL). The mixture was stirred at room temperature for 1 h. After this
time, a brown solid had precipitated from the reaction mixture. The solid
was triturated twice with Et
decantation to afford 21 (50 mg, 75% yield). H NMR(DMSO): d ˆ 1.75 ±
3
), 77.4 (CH
2
2
3 3
CHCl
3
); H NMR(CDCl
3
): d ˆ 0.94 (d, J(H,H) ˆ 6.7 Hz, 3H; CH(CH
3
)
)
2
),
),
3
2
0
2
3
.91 (d, J(H,H) ˆ 6.7 Hz, 3H; CH(CH
3
)
2
), 2.16 ± 2.23 (m, 1H; CH(CH
3
2
‡
.65 (dd, 2H; 3J(H,H) ˆ 10.0, 13.7 Hz, 2H; CH
3
2
Ph), 3.01 (s, J(Pt,H) ˆ
7.8 Hz, 12H; NCH
3
), 3.24 ± 3.60 (m, 1H; NH-CH-CO), 3.67 (downfield
3
part of AB signal, J(H,H) ˆ 7.6 Hz, 1H; Ar-CH
2
-NH), 3.62 (upfield part of
3
AB signal, J(H,H) ˆ 7.6 Hz, 1H; Ar-CH
2
-NH), 3.75 (s, 3H; OCH
), 4.57 (dd, J(H,H) ˆ 4.9, 9.5 Hz, 1H;
3
), 3.93 (s,
3
3
J(Pt,H) ˆ 43.9 Hz, 4H; CH
2
NMe
2
3
NH-CH-CO), 6.52 (s, 2H; ArH), 7.15 ± 7.31 (m, 5H; Ph), 7.89 (d, J(H,H) ˆ
2
O (5 mL), and the solvent was removed by
1
3
1
9
.5 Hz, 1H; NH);
C
NMR(CDCl
3
): d ˆ 17.8 (CH(CH
3
)
2
), 19.1
Chem. Eur. J. 2002, 8, No. 23
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G. van Koten et al.
FULL PAPER
1
3
.89 (m, 4H; CH
.87 ± 3.92 (m, 1H; NH-CH-CO), 4.00 (s, 4H; CH
2
CH
2
), 2.48 ± 2.50 (m, 2H; CH
2
CH), 2.93 (s, 12H; NCH
NMe ), 6.60 (s, 2H;
): d ˆ 27.5 (CH CH ), 30.7
CH), 53.0 (NH-CH-CO), 55.4 (NCH ), 77.4
), 120.1, 137.1 (C), 143.3 (C), 144.6 (C), 172.1 (CO ); ES-MS:
3
),
[8] K. M. Bri e¡ re, R. Goel, F. H. Shirazi, D. J. Stewart, I. C. P. Smith,
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2
2
1
3
ArH), 8.2 (brs, 3H; NH
3
); C NMR(CDCl
3
2
2
(
(
CH
CH
2
CH
2
), 36.3 (CH
2
3
2
NMe
2
2
‡
m/z calcd: 582.44 [M À Br]; found: 582.1.
[
[
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results.
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competitive formation of the N,O-chelate complexes during the
metalation step. See, for instance, ref. [5a].
Acknowledgement
Dr. G. Guillena Townley and Dr. G. RodrÌguez Longarela are Marie Curie
Fellows and thank the European Commission for Marie Curie TRM Grants
(
0
Contract No. HPMF-CT-2000 ± 00472 and Contract No. HPMF-CT-1999 ±
0236, respectively). This work was also supported in part by the Council
for Chemical Sciences from the Dutch Organization for Scientific Research
CW-NWO).
[
[
[
(
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[
[
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[
[
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[
[
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[11b]
studied in our group.
It has been shown that a linear correlation
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[
[
2
Received: May 30, 2002 [F4137]
5376
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0947-6539/02/0823-5376 $ 20.00+.50/0
Chem. Eur. J. 2002, 8, No. 23