An entry to novel platinum complexes: Carboxylation of dihydroxoplatinum(IV) complexes with succinic anhydride and subsequent derivatization

Article abstract of DOI:10.1002/ejic.200600108

An improved carboxylation method of (OC-6-33)-dichloro-(ethane-1,2-diamine) dihydroxyplatinum(IV) based on succinic anhydride is reported. Reaction of the uncoordinated carboxylic acid with simple amines and alcohols leads to the corresponding amides and esters in the presence of 1,1′- carbonyldiimidazole. The resulting new complexes are characterized by IR, ¹H, ¹³C, ¹⁵N, and ¹⁹⁵Pt NMR spectroscopy, mass spectrometry, and elemental analysis. This reaction provides an entry to a new class of kinetically inert platinum(IV) complexes. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejic.200600108

FULL PAPER
DOI: 10.1002/ejic.200600108
An Entry to Novel Platinum Complexes: Carboxylation of
Dihydroxoplatinum(IV) Complexes with Succinic Anhydride and Subsequent
Derivatization
Michael Reithofer,[a] Markus Galanski,*[a] Alexander Roller,[a] and Bernhard K. Keppler[a]
Keywords: Antitumor agents / Bioinorganic chemistry / Carboxylate ligands / Drug design / Platinum
An improved carboxylation method of (OC-6-33)-dichloro-
(ethane-1,2-diamine)dihydroxyplatinum(IV) based on suc-
cinic anhydride is reported. Reaction of the uncoordinated
carboxylic acid with simple amines and alcohols leads to the
terized by IR, 1H, 13C, 15N, and 195Pt NMR spectroscopy, mass
spectrometry, and elemental analysis. This reaction provides
an entry to a new class of kinetically inert platinum(IV) com-
plexes.
corresponding amides and esters in the presence of 1,1Ј-car- (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
bonyldiimidazole. The resulting new complexes are charac-
Germany, 2006)
Introduction
Cisplatin,
cis-diamminedichloroplatinum(II)
(Fig-
ure 1),[1,2] is a highly effective platinum-based anticancer
agent that is used in nearly 50% of all tumor therapies all
over the world. Cisplatin alone, or in combination with
other antineoplastic drugs, is used against a series of solid
tumors, including ovarian cancer, non-small cell lung can-
cer, and head and neck cancer. Cure rates above 90% have
been reported in the case of testicular germ-cell cancer, de-
pending on the point of diagnosis; it is thus one of the few
anticancer drugs with real curative potential. Nevertheless,
severe adverse effects such as a dose-limiting nephrotoxicity,
peripheral neuropathy, tinnitus, and hearing loss in the high
frequency range are known.[3] Additionally, acquired or in-
trinsic resistance of tumors to cisplatin therapy narrows the
use of this drug.[4] After evaluation of thousands of plati-
num compounds in preclinical settings during the last 40
Figure 1. Chemical structures of the anticancer drug cisplatin and
of tumor inhibiting platinum(IV) complexes in clinical evaluation.
Tetraplatin and iproplatin were abandoned.
years, the second- and third-generation platinum complexes by the patient. From the chemical point of view, octahe-
carboplatin [cis-diammine(1,1-cyclobutanedicarboxylato)- drally coordinated platinum(IV) complexes exhibit a higher
platinum(II)] and oxaliplatin [(trans-R,R-cyclohexane-1,2- coordination number than their square-planar platinum(II)
diamine)platinum(II)] were successfully introduced into counterparts, and therefore variation in the ligand sphere is
clinical practice.[5,6]
more easily accessible. This is of great significance in order
Besides platinum(II) complexes, which have to be admin- to fine-tune important properties such as lipophilicity, sta-
istered intravenously due to their instability in the gastroin- bility, reduction behavior, and biological activity.[7] Plati-
testinal tract, platinum(IV) complexes have also been inves- num(IV) complexes are kinetically inert and therefore show
tigated, thereby opening up the possibility of an oral ab- a significantly decreased reactivity. It is generally accepted
sorption. In this context it has to be mentioned that, in that platinum(IV) complexes act as prodrugs by extra- or
principle, an orally administrable drug offers some advan- intracellular reduction to the more reactive platinum(II)
tages in the clinical routine, such as a reduction of the hos- complexes upon release of the axial ligands (activation by
pitalization costs and a better acceptance of chemotherapy reduction).[8,9] The first platinum(IV) complexes, tetraplatin
and iproplatin (Figure 1), which were investigated in phase-
[a] Institute of Inorganic Chemistry, University of Vienna,
I clinical trials both showed an unfavorable pharmaco-
Waehringer Strasse 42, 1090 Vienna, Austria
kinetic behavior in vivo. Tetraplatin (two axial chloro ligands;
Fax: +43-1-4277-52680
E-mail: markus.galanski@univie.ac.at
2612
reduction potential: –90 mV)[10] displays a high systemic
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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An Entry to Novel Platinum Complexes
FULL PAPER
toxicity due to a very fast reduction of the platinum(IV) dinated carboxylic acid with simple amines and alcohols,
complex in the blood stream, whereas iproplatin (two axial leading to the corresponding amides and esters in the pres-
hydroxy ligands; reduction potential: –730 mV) was found ence of 1,1Ј-carbonyldiimidazole, is described. The plati-
to be inactive because it is not reduced fast enough to the num(IV) complexes have been synthesized for the first time
more (re)active platinum(II) species in the body. A break- and were characterized in detail by multinuclear NMR
through was reached with the synthesis of satraplatin (Fig- spectroscopy.
ure 1), which contains two carboxylate ligands in the axial
positions. Satraplatin is currently being investigated in
phase-III clinical trials in hormone refractory prostate can-
Results and Discussion
cer.[11] The reduction potential (which is most influenced by
the axial ligands) of satraplatin adopts an average value
Derivatization of kinetically inert platinum(IV) com-
with –250 mV, but the lipophilicity of this complex also plexes is an attractive entry to novel platinum compounds.
seems to be in an appropriate range. Very recently, a close Besides the well-established carboxylation of hydroxide co-
analogue to satraplatin, namely LA-12, a platinum(IV) ordinated to the PtIV center, derivatization of peripheral hy-
complex with a bulky and hydrophobic 1-adamantylamine droxo groups in diaminetetrachloroplatinum(IV) complexes
ligand instead of cyclohexylamine, entered clinical phase I has also been reported.[25] With the use of cyclic anhydrides,
trials.[12,13] LA-12 shows high cytotoxic potential in leuke- a further functional group is now accessible in the axial
mia, melanoma, and colorectal cancer cells and has been position. In order to set up a general reaction procedure,
found to overcome acquired resistance to cisplatin in hu- synthesis of the bis(carboxylato)platinum(IV) complex 2
man ovarian A2780cisR cells.[14]
The success of satraplatin is a direct consequence of pro- dinated carboxylic acid group was evaluated (Figure 2).
gress in the synthesis and derivatization of platinum(IV) The starting (OC-6-33)-dichloro(ethane-1,2-diamine)di-
was improved and subsequent derivatization of the uncoor-
complexes. Some years ago, the design of platinum(IV) co- hydroxoplatinum(IV) complex 1 was prepared by reaction
ordination compounds was limited to oxidation of the cor- of K2PtCl4 with ethane-1,2-diamine; the dichloroplati-
responding platinum(II) species with hydrogen peroxide or num(II) compound was then oxidized with hydrogen perox-
chlorine gas:[15,16] selective ligand substitution was difficult ide. The carboxylation reaction with succinic anhydride was
to perform since platinum(IV) complexes are kinetically in- performed in DMF at 70 °C, affording 2 in a good yield of
ert (substitution of chloride for hydroxide, for example 85%. This is in clear contrast to the synthetic procedures
works under comparatively drastic conditions in the pres- described recently. The use of DMSO at higher tempera-
ence of hydrochloric acid at high temperature). With the tures seems to be especially problematic since it often leads
knowledge that hydroxide coordinated to platinum(IV) has to decomposition of the platinum complexes. The subse-
nucleophilic properties and therefore can be carboxylated quent derivatization of 2 was carried out in DMF by acti-
with classical agents known from synthetic organic chemis- vation of the carboxylic acid with 1,1Ј-carbonyldiimidazole
try, a new class of platinum(IV) complexes was accessible, (CDI). The formed imidazolide was used directly without
which resulted in the development of satraplatin. Carboxyl- isolation for the next reaction step. Contrary to our syn-
ation of trans-dihydroxoplatinum(IV) by anhydrides, pyro- thetic procedure, Lippard and co-workers have used an-
carbonates, isocyanates, and even by carboxylic acid chlo- other typical peptide coupling reagent, namely diisopro-
rides in the presence of pyridine has recently been described pylcarbodiimide/4-(dimethylamino)pyridine, which could
in the literature,[17–21] leading to numerous new and interest- cause problems in the workup of the reaction mixture and
ing platinum(IV) derivatives. Very recently, the carboxyla- may lead to unfavorable side-reactions. Reaction of the imid-
tion with cyclic anhydrides (succinic, maleic, glutaric, and azolide with amines afforded the corresponding amides,
phthalic anhydride) under different reaction conditions was whereas the use of alcohols, which were converted in part
reported. Carboxylation in CH2Cl2 over 1–2 days,[22] reac- to the alkoxides by catalytic amounts of sodium, produced
tion in DMSO at 70 °C with a considerably large amount the esters. In the case of ethanolamine (in the absence of a
(3.3 g) of the dihydroxoplatinum(IV) starting complex,[23] strong base), only the amide was produced, thus demon-
and the unsuccessful use of molten phthalic anhydride[24] strating the selectivity of the reaction.
have been reported. The yields were reported to be in the
The new complexes 2, 3a–c, 4a, and 4b were charac-
range of 40 to 70%. The use of cyclic anhydrides offers a terized in detail by elemental analysis, IR, 1H, 13C, 15N, and
further advantage, besides the fact that novel platinum(IV) 195Pt NMR spectroscopy, mass spectrometry, and also by
compounds are prepared: it provides an uncoordinated car- X-ray diffractometry in the case of 2. The carboxylation of
boxylic acid moiety for subsequent derivatization, although 1 and its subsequent derivatization to the amide or ester
in only one case has derivatization to the amide been de- can be followed by significant changes in the infrared spec-
scribed; amine-modified estrogens were coupled to the un- tra. The trans-dihydroxoplatinum(IV) starting complex ex-
coordinated carboxylic acid by the use of a common pep- hibits a characteristic very sharp and intense O–H stretch
tide coupling reagent, namely diisopropylcarbodiimide/4- at 3483 cm–1, which disappears after carboxylation with
(dimethylamino)pyridine.
succinic anhydride. As a result, two C=O stretches, at
Here we report an improved carboxylation method based 1654 cm–1 for the coordinated carboxylato moiety and at
on succinic anhydride. Additionally, reaction of the uncoor- 1719 cm–1 for the uncoordinated carboxylic acid group, are
Eur. J. Inorg. Chem. 2006, 2612–2617
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2613

M. Reithofer, M. Galanski, A. Roller, B. K. Keppler
FULL PAPER
Figure 2. Synthesis of novel bis(carboxylato)platinum(IV) complexes and NMR numbering scheme.
detectable. The shift of the C=O band of the coordinated the proton resonances of the amide protons are found at
carboxylate to smaller wavenumbers is in good agreement around δ = 7.96 ppm, with 15N chemical shifts in the region
with previously published data for analogous complexes between δ = 90 and 109 ppm (typical region for amide ni-
(1633–1669 cm–1).[19] Derivatization with amines, leading to trogens: δ = 63–113 ppm). Values between δ = 1 and 3 ppm
complexes 3a–c, is reflected by two characteristic absorp- (1H) and –15 to +15 ppm (15N) are found in the free
tions (1633–1640 and 1664–1675 cm–1) for the coordinated amines, thus demonstrating the success of amide formation.
carboxylate and the amide C=O stretch, respectively, In both 3a–c and 4a/4b, long-range shift correlation signals
whereas the ester formation is accompanied by C=O ab- between the derivatized C=O quaternary carbon atom and
sorption bands in the range of 1650 and 1658 cm–1 for the the amine- or alcohol-derived residue could also be de-
PtOC=O stretch and between 1739 and 1745 cm–1 for the tected, additionally proving the amide or ester formation.
C=O stretch of the ester moiety. Remarkably, in the case of Furthermore, these cross peaks in the two-dimensional shift
ethanolamine the amide formation (vs. ester formation) correlated spectra allowed us unequivocally to distinguish
could be confirmed by infrared spectroscopy.
between the two 13C=O resonances.
1H, and 195Pt as well as gradient-enhanced two-dimen-
1
1
sional H,13C- and H,15N-COSY NMR spectra of com-
plexes 2, 3a–c, 4a, and 4b were acquired in [D7]DMF. The
ligand sphere around the platinum center can best be
judged by the chemical shift of the 195Pt nucleus, which
spans a wide range of several thousand ppm, depending on
the coordinated atoms, the geometry, and the oxidation
state of the metal center. The 195Pt resonances of the novel
platinum(IV) complexes were found between δ = 2621 and
2630 ppm, which is indicative of a cis,cis,trans-PtIVN2Cl2O2
ligand sphere (Table 1). These values are in good agreement
Table 1. 1H, 13C, 15N, and 195Pt NMR spectroscopic data for the
new complexes 2, 3a–c, 4a, and 4b.
1H
13C
C-2
15N
NH2 NH
195Pt
NH2 NH
C-5
2
8.93
–
180.0 172.3
180.3 170.0
180.3 169.9
180.2 170.3
179.7 170.8
179.7 170.9
–3.8
–
2630
2622
2622
2621
2629
2628
3a
3b
3c
4a
4b
8.89 7.95
8.88 7.94
8.88 7.98
8.92
8.92
–3.3 94.6
–3.7 108.5
–4.2 90.1
–3.6
–3.5
–
–
–
–
with literature data {δ
= 2658 ppm for [PtCl2(en)-
(OCOCH3)2]}.[26] As expected, the 195Pt chemical shifts as
Crystals suitable for X-ray diffraction analysis were
1
well as the H (δ = 8.88–8.92 ppm) and 15N resonances (δ grown by vapor diffusion of diethyl ether into a solution of
= –3.3 to –4.2 ppm) of the coordinated amine moiety are 2 in acetone. The result of the X-ray diffraction study of
not significantly influenced by derivatization at the uncoor- complex 2·2(CH3)2CO is shown in Figure 3. Crystal data,
dinated carboxylic acid group. Nevertheless, a trend in the data collection parameters and structure-refinement details
1
195Pt and H (of the NH2 group) chemical shifts seems to are given in the Experimental Section. The compound crys-
be obvious. In the 13C NMR spectra, two resonances for tallizes in the monoclinic space group P2/c, with the plati-
the quaternary carbon atoms of the coordinated carboxyl- num atom lying on a twofold rotation axis that also goes
ate (C-2 at around δ = 180 ppm and C-5 in the region be- through the center of the C–C bond of the ethane-1,2-di-
tween δ = 169.9 and 172.3 ppm) are detected, with an ap- amine ring. The platinum(IV) atom has an octahedral coor-
parent upfield shift of C-5 upon derivatization of the unco- dination geometry with ethane-1,2-diamine and two chloro
ordinated carboxylic acid. Amide formation, especially in ligands bound in the equatorial plane and two succinic
the case of the bifunctional ethanolamine, was verified by acids coordinated in a monodentate fashion in the axial
1
significant H and 15N shift differences. In complexes 3a–c positions. The Pt–N1, Pt–Cl1, and Pt–O1 bond lengths
2614
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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An Entry to Novel Platinum Complexes
FULL PAPER
DPX 400 spectrometer (UltrashieldTM Magnet) at 400.13, 86.11,
100.62, and 40.55 MHz, respectively, in [D7]DMF at 25 °C, using
standard pulse programs; two-dimensional spectra were measured
in a gradient-enhanced mode. 15N and 195Pt chemical shifts are
referenced relative to external NH4Cl and K2PtCl4, respectively.
Half-height line widths of 195Pt resonances are given in parentheses.
IR spectra were measured in a KBr matrix (4000–400 cm–1) with a
Perkin–Elmer Spectrum 2000 FT-IR spectrometer. Mass spectra
(ESI-MS) were recorded with a Bruker ESQUIRE3000 ion-trap
mass spectrometer in the negative- as well as in the positive-ion
[2.0541(10), 2.3175(5), and 2.0113(12) Å, respectively] are
well comparable with those in cis,trans-[Pt(en)Cl2-
(OCOCH3)2] [2.040(5), 2.315(1), and 2.017(5) Å, respec-
tively].[27] A five-membered chelate ring, with a bite angle
of 83.66(6)°, is formed upon coordination of ethane-1,2-
diamine to PtIV. A zigzag arrangement of the ligand atoms
alternately above and below the mean least-squares
plane through PtCl2N2 is observed. The dihedral angle
ΘN1–C1–C1i–N1i (superscript i denotes –x + 1, y, 1/2 – z),
which serves as a measure of the deviation of the corre- mode. The elemental analyses were performed with a Perkin–Elmer
2400 CHN elemental analyzer by the microlaboratory of the Insti-
tute of Physical Chemistry, University of Vienna. Silica gel 60
(Fluka) was used for column chromatography. (OC-6-33)-Dichloro-
(ethane-1,2-diamine)dihydroxoplatinum(IV) (1) was synthesized ac-
cording to standard literature procedures by mixing equivalent
amounts of ethane-1,2-diamine and K2PtCl4 in aqueous solution
and subsequent oxidation with H2O2.[16]
sponding chelate ring from planarity, is –55.8°.
(OC-6-33)-Bis(3-carboxypropanoato)dichloro(ethane-1,2-diamine)-
platinum(IV) (2): Succinic anhydride (114 mg, 1.139 mmol) was
added to a suspension of 1 (100 mg, 0.278 mmol) in DMF (2 mL)
and the reaction mixture was stirred at 70 °C for 24 h. During this
time the solid material dissolved to form a yellow-brown solution.
DMF was then removed under reduced pressure. The residue was
dissolved in acetone and filtered to give a clear, yellow solution.
This solution was concentrated under reduced pressure, and subse-
quent addition of diethyl ether led to precipitation of a pale-yellow
solid. The product was dried in vacuo. Yield: 131.5 mg (85%).
C10H18Cl2N2O8Pt (560.24): calcd. C 21.44, H 3.24, N 5.00; found
C 21.72, H 3.18, N 4.89. ESI-MS: m/z 561.1 [M + H+]+, 583.1
Figure 3. ORTEP diagram of 2 displaying thermal ellipsoids at
50% probability (the solvent molecule has been omitted). Selected
bond lengths [Å] and angles [°]: Pt–N1 2.0541(10), Pt–Cl1
2.3175(5), Pt–O1 2.0113(12), O1–C2 1.3095(16), C2–O2 1.2235(16),
C2–C3 1.5122(19), C3–C4 1.519(2), C4–C5 1.497(2), C5–O3
1.234(2), C5–O4 1.3070(18); O1–C2–O2 126.42(13), O3–C5–O4
123.13(15).
[M + Na+]+, 598.1 [M + K+]+, 559.1 [M – H+]–. IR: ν = 3445
˜
(νCOO–H), 3202 (νN–H), 3039–2927 (νC–H), 1719, 1654 (νas C=O
)
2
cm–1 1H NMR: δ = 12.52 (s, 2 H, COOH), 8.93 (s, JH,Pt
. =
52.7 Hz, 4 H, NH2), 3.15 (s, 4 H, 1-H), 2.70 (m, 4 H, 3-H/4-H),
2.67 (m, 4 H, 3-H/4-H) ppm. 13C NMR: δ = 180.0 (C-2), 172.3 (C-
5), 47.6 (C-1), 28.1, 29.5 (C-3/C-4) ppm. 15N NMR: δ = –3.8 ppm.
195Pt NMR: δ = 2630 (420 Hz) ppm. Crystals suitable for X-ray
data collection were grown by vapor diffusion of diethyl ether into
a solution of 2 in acetone.
Conclusions
(OC-6-33)-Dichloro(ethane-1,2-diamine)bis{(4-propylamino)-4-
oxobutanoato}platinum(IV) (3a): 1,1Ј-Carbonyldiimidazole (CDI;
237.3 mg, 1.464 mmol) in DMF (16 mL) was added to a solution
of 2 (400 mg, 0.714 mmol) in DMF (8 mL) and the mixture heated
to 60 °C. After 10 min stirring, the solution was cooled down to
room temperature and CO2 was removed by flushing with argon.
Propylamine (120.8 µL, 1.464 mmol) in DMF (24 mL) was added
to the solution and stirred for 24 h at room temperature. DMF was
then removed under reduced pressure to form a yellow-brown oil.
The crude product was purified by column chromatography
(EtOAc/MeOH, 4:1) to yield a white powder. Yield: 253.1 mg
(55%). C16H32Cl2N4O6Pt (642.43): calcd. C 29.91, H 5.02, N 8.72;
found C 30.12, H 4.89, N 8.67. ESI-MS: m/z 643.1 [M + H+]+,
665.1 [M + Na+]+, 681.0 [M + K+]+, 641.1 [M – H+]–, 677 [M +
It has been demonstrated that carboxylation of (OC-6-
33)-dichloro(ethane-1,2-diamine)dihydroxoplatinum(IV)
with succinic anhydride results in a platinum complex with
coordinated carboxylato ligands, which contains further un-
coordinated carboxylic acid groups for subsequent derivati-
zation. Improved reaction conditions have allowed synthe-
sis of this new complex in a pleasingly high yield of 85%.
Reaction of the uncoordinated carboxylic acid with simple
amines and alcohols, which leads to the corresponding
amides and esters in the presence of 1,1Ј-carbonyldiimid-
azole, has been shown to be generally applicable to this kind
of platinum complex, and provides entry to a new class of
kinetically inert platinum(IV) complexes with potentially
useful anticancer properties.
Cl–]–. IR: ν = 3300, 3206 (νN–H), 2963, 2929–2873 (νC–H), 1664,
˜
1640 (νas C=O) cm–1. 1H NMR: δ = 8.89 (br. s, 4 H, NH2), 7.95 (br.
s, 2 H, NH), 3.25 [q, 3JH,H = 6.3 Hz, 4 H, 6-H], 3.16 (br. s, 4 H, 1-
3
3
H), 2.66 (t, JH,H = 7.0 Hz, 4 H, 3-H/4-H), 2.55 (t, JH,H = 7.0 Hz,
4 H, 3-H/4-H), 1.62 (m, 4 H, 7-H), 1.03 (t, 3JH,H = 7.4 Hz, 6 H, 8-
H) ppm. 13C NMR: δ = 180.3 (C-2), 170.0 (C-5), 47.5 (C-1), 39.1
(C-6), 30.0, 30.5 (C-3/C-4), 21.0 (C-7), 9.4 (C-8) ppm. 15N NMR:
δ = 94.6 (NH), –3.3 (NH2) ppm. 195Pt NMR: δ = 2622 (440 Hz)
ppm.
Experimental Section
All chemicals were obtained from commercial suppliers and were
used as received. The H, 195Pt and two-dimensional 1H,13C- and
1
1H,15N-COSY NMR spectra were recorded with a Bruker Avance
Eur. J. Inorg. Chem. 2006, 2612–2617
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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M. Reithofer, M. Galanski, A. Roller, B. K. Keppler
FULL PAPER
(OC-6-33)-Dichlorobis{(4-cyclopentylamino)-4-oxobutanoato}-
(ethane-1,2-diamine)platinum(IV) (3b): The synthesis was carried
out as described for 3a. The crude product was purified by column
chromatography (EtOAc/MeOH, 4:1) and recrystallized from
MeOH to yield a white powder. Yield: 102.3 mg (21 %).
C20H36Cl2N4O6Pt (694.51): calcd. C 34.59, H 5.22, N 8.07; found
C 34.56, H 5.02, N 7.89. ESI-MS: m/z 717.1 [M + Na+]+, 733.0 [M
6 H, 13-H) ppm. 13C NMR: δ = 179.7 (C-2), 170.9 (C-5), 62.6 (C-
6), 47.7 (C-1), 29.5, 28.1 (C-3/C-4), 26.9 (C-7), 30.1, 27.52, 27.48,
24.1, 20.8 (C-8 to C-12), 12.0 (C-13) ppm. 15N NMR: δ =
–3.5 ppm. 195Pt NMR: δ = 2628 (420 Hz) ppm.
X-ray diffraction measurements were performed on a Bruker
X8APEX II CCD diffractometer at 100 K. Single crystals were po-
sitioned 37.5 mm from the detector and 813 frames were measured,
each for 80 s over a 1° scan. The data were processed using the
Denzo-SMN software package.[28] Crystal data, data collection pa-
rameters, and structure-refinement details for 2·2CH3COCH3 are
given in Table 2. The structures were solved by direct methods and
refined by full-matrix least-squares techniques. Non-hydrogen
atoms were refined with anisotropic displacement parameters. H
atoms were calculated and allowed to ride. Computer programs:
structure solution: SHELXS-97;[29] refinement: SHELXL-97;[30]
molecular diagrams: ORTEP.[31] Computer: PC, Pentium II; scat-
tering factors taken from the literature.[32]
+ K+]+, 693.1 [M – H+]–. IR: ν = 3251, 3199 (νN–H), 2947–2865
˜
1
(νC–H), 1664, 1638 (νas C=O) cm–1. H NMR: δ = 8.88 (br. s, 4 H,
3
NH2), 7.94 (d, JH,H = 6.8 Hz, 2 H, NH), 4.23 (m, 2 H, 6-H), 3.17
3
(br. s, 4 H, 1-H), 2.65 (t, JH,H = 7.1 Hz, 4 H, 3-H/4-H), 2.52 (t,
3JH,H = 7.1 Hz, 4 H, 3-H/4-H), 1.99 (m, 4 H, 7-H), 1.82 (m, 4 H,
8-H), 1.68 (m, 4 H, 8-H), 1.60 (m, 4 H, 7-H) ppm. 13C NMR: δ =
180.3 (C-2), 169.6 (C-5), 49.1 (C-6), 47.6 (C-1), 30.9 (C-7), 30.0,
30.5 (C-3/C-4), 21.9 (C-8) ppm. 15N NMR: δ = 108.5 (NH), –3.7
(NH2) ppm. 195Pt NMR: δ = 2622 (433 Hz) ppm.
(OC-6-33)-Dichloro(ethane-1,2-diamine)bis{[4-(2-hydroxyethyl)-
amino]-4-oxobutanoato}platinum(IV) (3c): The synthesis was car-
ried out as described for 3a. The crude product was purified by
column chromatography (MeOH) to yield a pale-yellow powder.
Yield: 87.7 mg (38%). C14H28Cl2N4O8Pt (646.38): calcd. C 26.01,
H 4.37, N 8.67; found C 25.81, H 4.07, N 8.43. ESI-MS: m/z 669.3
Table 2. Crystallographic data for 2·2CH3COCH3.
Empirical formula
Fw
C16H30Cl2N2O10Pt
676.41
[M + Na+]+, 645.2 [M – H+]–. IR: ν = 3592, 3530 (νO–H), 3309,
Space group
a [Å]
b [Å]
P2/c
˜
1
3213 (νN–H), 1675, 1633 (νas C=O) cm–1. H NMR: δ = 8.88 (br. s,
15.128(3)
7.9108(16)
10.745(2)
110.72(3)
1202.8(4)
2
NH2), 7.98 (br. s, 2 H, NH), 4.88 (br. s, 2 H, OH), 3.70 (m, 4 H,
c [Å]
3
7-H), 3.42 (m, 4 H, 6-H), 3.16 (br. s, 4 H, 1-H), 2.67 (t, JH,H
=
β [°]
6.8 Hz, 4 H, 3-H/4-H), 2.57 (t, 3JH,H = 6.8 Hz, 4 H, 3-H/4-H) ppm.
13C NMR: δ = 180.2 (C-2), 170.3 (C-5), 59.1 (C-7), 47.6 (C-1), 40.3
(C-6), 30.4, 29.9 (C-3/C-4) ppm. 15N NMR: δ = 90.1 (NH), –4.2
(NH2) ppm. 195Pt NMR: δ = 2621 (440 Hz) ppm.
V [Å3]
Z
λ [Å]
0.71073
1.868
0.18×0.10×0.04
100
61.06
0.0108
ρcalcd. [gcm–3]
Crystal size [mm]
T [K]
(OC-6-33)-Dichloro(ethane-1,2-diamine)bis{(4-ethoxy)-4-oxo-
butanoato}platinum(IV) (4a): CDI (59.3 mg, 0.365 mmol) in abs.
DMF (4 mL) was added to a solution of 2 (100 mg, 0.178 mmol)
in abs. DMF (2 mL) and heated to 60 °C. After 10 min stirring, the
solution was cooled down to room temperature and CO2 was re-
moved by flushing with argon. Sodium ethanolate (4 mg of Na in
10 mL of abs. ethanol) in abs. ethanol was added to the solution
and stirred for 24 h at room temperature. Ethanol and DMF were
removed under reduced pressure to form a yellow-brown oil. The
crude product was purified by column chromatography (EtOAc/
MeOH, 7:1) to yield a white powder. Yield: 41.5 mg (38 %).
C14H26Cl2N2O8Pt (616.35): calcd. C 27.28, H 4.25, N 4.55; found
C 27.58, H 4.09, N 4.50. ESI-MS: m/z 616.1 [M + H+]+, 639.1 [M
µ [cm–1]
[a]
R1
[b]
wR2
0.0259
1.061
GOF[c]
2
2 2
[a] R1 = Σ||Fo| – |Fc||/Σ|Fo|. [b] wR2 = {Σ[w(Fo – Fc2)2]/Σ[w(Fo ) ]}1/2
.
[c] GOF = {Σ[w(Fo – Fc ) ]/(n – p)}1/2, where n is the number of
reflections and p is the total number of parameters refined.
2
2 2
CCDC-297226 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Center via
www.ccdc.cam.ac.uk/data_request/cif.
+ Na+]+, 655.0 [M + K+]+, 615.2[M – H+]–. IR: ν = 3203 (νN–H);
˜
2985, 2929 (νC–H); 1739, 1654 (νas C=O) cm–1. H NMR: δ = 8.92
1
2
3
(t, JH,Pt = 53.6 Hz, 4 H, NH2), 4.25 (q, JH,H = 7.1 Hz, 4 H, 6- Acknowledgments
H), 3.16 (br. s, 4 H, 1-H), 2.73 (m, 4 H, 3-H/4-H), 2.68 (m, 4 H,
3-H/4-H), 1.37 (t, JH,H = 7.1 Hz, 6 H, 7-H) ppm. 13C NMR: δ = The support of the FWF (Fonds zur Förderung der wissen-
3
179.7 (C-2), 170.8 (C-5), 58.4 (C-6), 47.6 (C-1), 28.2, 29.3 (C-3/C- schaftlichen Forschung), Faustus Forschungs Compagnie Transla-
4), 12.1 (C-7) ppm. 15N NMR: δ = –3.6 ppm. 195Pt NMR: δ =
2629.1 (460 Hz) ppm.
tional Cancer Research GmbH, and COST (European Co-opera-
tion in the Field of Scientific and Technical Research) is gratefully
acknowledged. We are thankful to Prof. Arion for the discussion
of X-ray data.
(OC-6-33)-Dichloro(ethane-1,2-diamine)bis{(4-octyloxy)-4-oxo-
butanoato}platinum(IV) (4b): The synthesis was carried out as de-
scribed for 4a. The crude product was purified by column
chromatography (EtOAc) to yield a white powder. Yield: 143.9 mg
(34%). C26H50Cl2N2O8Pt (784.67): calcd. C 39.80, H 6.42, N 3.57;
found C 39.69, H 6.26, N 3.49. ESI-MS: m/z 807.3 [M + Na+]+,
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2616
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Inorg. Chem. 2006, 2612–2617

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Received: February 7, 2006
Published Online: April 26, 2006
Eur. J. Inorg. Chem. 2006, 2612–2617
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjic.org
2617