Studies on the oral anticancer drug JM-216: Synthesis and characterization of isomers and related complexes

Article abstract of DOI:10.1021/ic951548n

The complex cis,trans,cis-[PtCl₂(OAc)₂NH₃(c-C ₆H₁₁NH₂)] (JM-216) is currently undergoing clinical evaluation as an antitumor agent. In support of characterization and analysis of this complex a study of its isomers and other complexes [PtCl_m(OAc)_4-mNH₃(c-C₆H ₁₁NH₂)] (m = 0-4) has been undertaken. The complexes have been obtained by a variety of synthetic routes which now extend the scope for the preparation of platinum(IV) antitumor complexes. As platinum(IV) complexes are very stable to substitution in the absence of catalysis, use has been made of both light and base catalysis to promote substitution. Oxidative addition to platinum(II) using hypervalent iodine reagents has also been used. The stereochemistry of the complexes has been confirmed by spectroscopic studies, primarily NMR including natural abundance ¹⁵N NMR spectroscopy.

Full text of DOI:10.1021/ic951548n

3280
Inorg. Chem. 1996, 35, 3280-3284
Studies on the Oral Anticancer Drug JM-216: Synthesis and Characterization of Isomers
and Related Complexes
Christopher F. J. Barnard*
Johnson Matthey Technology Centre, Sonning Common, Reading RG4 9NH, U.K.
Jean F. Vollano
Johnson Matthey Biomedical Research, West Chester, Pennsylvania 19380
Penny A. Chaloner and Shaliza Z. Dewa
School of Chemistry and Molecular Sciences, University of Sussex, Falmer, Brighton BN1 9QJ, U.K.
ReceiVed December 6, 1995X
The complex cis,trans,cis-[PtCl2(OAc)2NH3(c-C6H11NH2)] (JM-216) is currently undergoing clinical evaluation
as an antitumor agent. In support of characterization and analysis of this complex a study of its isomers and
other complexes [PtClm(OAc)(4-m)NH3(c-C6H11NH2)] (m ) 0-4) has been undertaken. The complexes have
been obtained by a variety of synthetic routes which now extend the scope for the preparation of platinum(IV)
antitumor complexes. As platinum(IV) complexes are very stable to substitution in the absence of catalysis, use
has been made of both light and base catalysis to promote substitution. Oxidative addition to platinum(II) using
hypervalent iodine reagents has also been used. The stereochemistry of the complexes has been confirmed by
spectroscopic studies, primarily NMR including natural abundance 15N NMR spectroscopy.
Introduction
The oxidation of platinum(II) complexes with hydrogen
peroxide has been shown to proceed with the addition of trans
hydroxide ligands and retention of the stereochemistry of the
platinum(II) complex.6,7 For the trans-ammine complexes
[PtCl2(OH)2(NH3)2], it has been found that rearrangement of
the anionic ligands may occur readily, leading to conversion of
the all-trans complex to the cis,cis,trans isomer.8 Complexes
containing trans chloride ligands and a chelating carboxylate
ligand can be obtained by oxidation of the platinum(II)
carboxylate complex. One or both axial chloride ligands may
then be replaced by reaction of this species with silver
carboxylates.9 The formation of a platinum(IV) complex
containing trans chloride and cis sulfate and water ligands has
also been reported as the product of reaction of the tetrachloro
complex with silver sulfate, although no evidence was presented
to confirm the stereochemistry of the product.10 The scope of
reactions for the preparation of complexes of the type
[PtClm(OAc)(4-m)NH3(c-C6H11NH2)] (m ) 0-4) is thus limited,
and alternate routes are required to obtain further isomers.
There are six geometric isomers of [PtCl2(OAc)2NH3(c-C6H11-
NH2)] as shown in Figure 1 with the all-cis isomers existing as
stereoisomers. The fac isomers of the trisacetato and trichloro
complexes (Figure 2) also exist as stereoisomers. No attempt
has been made in this study to separate the individual enanti-
omers for these compounds.
The preparation of platinum(IV) carboxylate complexes has
been described recently.1,2 Compounds of this type containing
cis amine ligands have shown potential as antitumor agents
suitable for oral administration.3 One compound of this class,
cis,trans,cis-[PtCl2(OAc)2NH3(c-C6H11NH2)] (JM-216), is cur-
rently undergoing clinical evaluation in USA, Europe, and
Japan.4 As part of the chemical studies of this compound, its
isomers and related complexes have been synthesized and
characterized.
Previous studies of platinum(IV) bis(amine) antitumor com-
plexes have been largely based on hydroxo complexes obtained
by oxidation of platinum(II) complexes with hydrogen peroxide
and chloro complexes obtained by oxidation of the platinum-
(II) compounds with chlorine or treatment of the hydroxo
compounds with chloride under strongly acidic conditions.5 The
recent reporting of the carboxylation of hydroxo-complexes has
extended the range of platinum(IV) complexes, but the examples
given are limited to cis,trans,cis stereochemistry.2
* Author to whom correspondence should be addressed.
X Abstract published in AdVance ACS Abstracts, May 1, 1996.
(1) Giandomenico, C. M.; Abrams, M. J.; Murrer, B. A.; Vollano, J. F.;
Barnard, C. F. J.; Harrap, K. R.; Goddard, P. M.; Kelland, L. R.;
Morgan, S. E. In Platinum and Other Metal Coordination Compounds
in Cancer Chemotherapy; Howell, S. B., Eds.; Plenum Press: New
York, 1991; p 93.
(2) Giandomenico, C. M.; Abrams, M. J.; Murrer, B. A.; Vollano, J. F.;
Rheinheimer, M. I.; Wyer, S. B.; Bossard, G. E.; Higgins, J. D. Inorg.
Chem. 1995, 34, 1015.
Here we report the use of a variety of reactions to obtain
novel isomers of complexes [PtClm(OAc)(4-m)NH3(c-C6H11-
(3) Kelland, L. R.; Abel, G.; McKeage, M. J.; Jones, M.; Goddard, P.
M.; Valenti, M.; Murrer, B. A.; Harrap, K. R. Cancer Res. 1993, 53,
2581.
(4) McKeage, M. J.; Mistry, P.; Ward, J.; Boxall, F. E.; Loh, S.; O’Neill,
C.; Ellis, P.; Kelland, L. R.; Morgan, S. E.; Murrer, B. A.; Santabar-
bara, P.; Harrap, K. R.; Judson, I. R. Cancer Chemother. Pharmacol.
1995, 36, 451.
(6) Harrigan, T. D.; Johnson R. C. Inorg. Chem. 1977, 16, 1741.
(7) Dunham, S. O.; Larsen, R. D.; Abbott, E. H. Inorg. Chem. 1993, 32,
2049.
(8) Kuroda, R.; Neidle, S.; Ismail, I. M.; Sadler, P. J. Inorg. Chem. 1983,
22, 3620.
(9) Kidani, Y. In SeVenth International Symposium on Platinum and Other
Metal Coordination Compounds in Cancer Chemotherapy, Abstracts;
Van Zuiden Communications: Netherlands, 1995; Abstract S006.
(10) European Patent Application 357 108.
(5) Hartley, F. R. The Chemistry of Platinum and Palladium; John Wiley
and Sons: New York, 1973.
S0020-1669(95)01548-5 CCC: $12.00 © 1996 American Chemical Society

The Oral Anticancer Drug JM-216
Inorganic Chemistry, Vol. 35, No. 11, 1996 3281
Table 1. 13C NMR Data for Complexes
[PtCl2(OAc)2NH3(c-C6H11NH2)]
acetatea δ
cyclohexylaminea δ
C1 C2,C6 C3,C5 C4
complex O2CCH3 O2CCH3
1
2
182.6 (29) 23.09 (35) 56.15 (∼10) 33.85 (16) 26.07 26.43
182.0 (24) 23.45 (32) 57.68
181.7 (29) 23.88 (29)
34.05 (17) 26.11 26.36
33.64 (15) 25.98
3
4
182.7 (21) 24.17 (29) 56.06 (11) 33.73 (19) 26.31 26.38
182.1 (28) 24.02 (34)
182.9 (17) 24.17
24.37
33.40 (13) 26.18
33.40 (17) 26.02 26.43
57.56
5
6
181.7 (28) 23.40 (35) 55.60 (<8) 33.93 (13) 26.16 26.50
181.2 (29) 23.86 (34) 55.00 (<6) 33.87 (12) 26.16 26.50
a 13C-195Pt coupling constants are indicated in parentheses.
C6 (and C3 and C5) carbons of the cyclohexylamine ring.
Equivalence of the acetate ligands arises when these are trans
to one another or trans to the chloride ligands. The trans,cis,-
cis isomer 4 is therefore defined by the observation of two
resonances for the acetate methyl groups but single resonances
for C2 and C6 (and C3 and C5) of the cyclohexylamine ring
(Table 1). The two trans amine isomers 5 and 6 are distin-
guished by their high symmetry but cannot be differentiated
from each other by their 13C spectra. Similarly, the two all-cis
isomers 2 and 3 are identified by the lack of equivalences in
their 13C spectra but cannot be differentiated from one another.
The trans amine isomers are distinguished by their vibrational
Figure 1. Isomers of [PtCl2(OAc)2NH3(c-C6H11NH2)].
spectra using the Pt-Cl bands. For 6 these occur at 358 (νsym
)
and 301 (νasym) cm-1 in the IR spectrum and at 359 + 367
(probably one band split by solid state effects) and 301 cm-1
in the Raman spectrum, consistent with cis chloride ligands.12
For 5 there is only a single strong band at 356 cm-1 in the IR
spectrum as expected for trans chloride ligands. This assign-
ment is also consistent with the chromatographic behavior of
the complexes.
The two all-cis isomers present a more complex problem for
structural assignment which has been resolved by 15N NMR
spectroscopy. The high solubility (ca. 100 g L-1) of these
complexes in polar aprotic solvents such as N,N-dimethyl-
formamide permits satisfactory INEPT spectra to be obtained
overnight using a high-field (500 MHz) instrument. The
complexes 1 and 4 provide the basic data on the chemical shift
and 15N-195Pt coupling constants for nitrogen trans to chloride
and acetate, respectively. The resonances for the amine and
cyclohexylamine are assigned by the proton coupling observed
in the DEPT spectrum (NH3 quartet 1JN-H 75 Hz, c-C6H11NH2
Figure 2. Complexes [PtClm(OAc)(4-m)NH3(c-C6H11NH2)] (m ) 0, 1,
3, or 4).
NH2)] (m ) 1-3). Carboxylation of trans-hydroxo complexes
has been used to obtain trans acetate ligands. Oxidations with
(diacetoxyiodo)benzene have been used to add acetate ligands
in cis positions. Light catalysis has been used to promote
substitution in platinum(IV) complexes. This can lead to
isomerization or substitution if suitable alternate ligands are
available. Base catalysis has also been used to achieve
stereoselective substitution in platinum(IV) complexes.
NMR spectroscopy using both 13C and 15N nuclei has been
used to characterize these complexes and, in particular, to
confirm their stereochemistry.
1
triplet JN-H 74 Hz for both complexes). The data (Table 3)
for 1 and 4 show a clear shift of ca. -16 ppm with a larger
15N-195Pt coupling constant for nitrogen trans to acetate
compared with nitrogen trans to chloride. The data for 2 and
3 then confirm their stereochemistries as cyclohexylamine trans
to acetate and chloride, respectively.
The 13C NMR spectra for the trisacetato complexes 8, 9, and
10 and trichloro-complexes 11, 12, and 13 distinguish the fac
isomers by their lack of symmetry and hence inequivalent
cyclohexylamine ring carbon atoms (Table 2). Distinction
between the two mer isomers in each case is not possible by
13C NMR spectroscopy alone and again the 15N spectra are
required to identify the ligands trans to each amine. From the
data in Table 3 it can be seen that complexes 9 and 12 are related
to 1 and have cyclohexylamine trans to chloride, while 8 and
11 have cyclohexylamine trans to acetate.
Results and Discussion
Characterization. The stereochemistry of the isomers of
[PtCl2(OAc)2NH3(c-C6H11NH2)] has been determined with
reference to that of the cis,trans,cis complex for which a single
crystal X-ray diffraction study has been published.11 In the 13
C
NMR spectra a trans pair of acetate or chloride ligands creates
a symmetry plane which results in equivalence of the C2 and
HPLC has also been used to characterize these complexes
and to assist in following the course of the reactions. The
(11) Neidle, S.; Snook, C. F.; Murrer, B. A.; Barnard C. F. J. Acta.
Crystallogr. 1995, C51, 822.
(12) James, D. W.; Nolan, N. J. J. Raman Spectrosc. 1973, 1, 271.

3282 Inorganic Chemistry, Vol. 35, No. 11, 1996
Barnard et al.
Table 2. 13C NMR Spectral Data for Complexes [PtClm(OAc)(4-m)NH3(c-C6H11NH2)] (m ) 0, 1, 3 or 4)
acetatea δ
cyclohexylaminea δ
complex
O2CCH3
O2CCH3
C1
56.55
C2, C6
C3, C5
26.20
C4
7
182.2 (17, eq)
181.3 (27, ax)
181.2 (20, eq)
182.3 (28, ax)
181.0 (23, eq)
182.1 (22, eq)
182.0 (28, ax)
182.7 (16, eq)
182.1 (17, eq)
180.8 (29, ax)
182.9 (23)
23.74 (29, eq)
23.20 (29, eq)
22.32 (38, ax)
23.50 (29, eq)
22.62 (35, ax)
23.90 (29, eq)
22.89 (37, ax)
24.10 (29, eq)
23.77 (28, eq)
23.18 (35, ax)
24.38 (29)
33.28 (17)
26.36
8
9
57.21 (8)
56.01 (12)
56.50 (11)
33.58 (16)
33.51 (17)
25.95
26.27
26.36
26.38
26.34
10
33.40 (∼17)
33.30 (∼17)
26.14
26.07
11
12
13
58.43 (9)
56.64 (8)
56.69
33.85 (16)
33.67 (17)
34.57 (18)
33.82 (12)
34.36 (15)
26.00
26.09
25.98
26.16
26.02
26.37
26.36
26.36
182.8 (22)
182.4 (30)
24.24 (28)
24.08 (33)
14
57.20 (8)
26.38
a 13C-195Pt coupling constants indicated in parentheses; eq ) equatorial, ax ) axial, see Figure 2.
Table 3. 15N NMR Spectral Data for Complexes
[PtClm(OAc)(4-m)NH3(c-C6H11NH2)] (m ) 1-3)
exposure to light, and therefore it seems likely that in that case
also photoinduced reduction initiates the isomerization and that
the addition of hydrogen peroxide prevents this by trapping the
intermediate before rearrangement can take place.
complex
amminea δ
cyclohexylaminea δ
1
4
2
3
8
9
11
12
-402.8 (254)
-419.6 (267)
-404.9 (246)
-418.9 (270)
-408.0 (254)
-422.7 (278)
-399.8 (234)
-414.1 (277)
-370.7 (245)
-386.3 (262)
-382.7 (271)
-369.7 (241)
-387.4 (272)
-372.8 (248)
-380.0 (271)
-369.9 (234)
Hypervalent iodine compounds are versatile reagents which
have been widely applied in organic chemistry.13,14 However,
they have been little used in inorganic chemistry. For the
oxidation of platinum(II) complexes we have found that
(diacetoxyiodo)benzene can give somewhat cleaner reactions
than manganese(III) or lead(IV) acetates. As for many other
oxidative additions to platinum(II) an intermediate species is
formed by attack of the platinum complex on the oxidizing agent
with the second trans ligand being acquired in a subsequent
step.15 This may either be a solvent molecule or another added
ligand if the solvent is a poorly coordinating one. To obtain
diacetate products we have investigated dichloromethane, chlo-
robenzene, acetone, and N,N-dimethylacetamide as noncoordi-
nating solvents. (In ethanol ethoxide products are formed.) Only
minor differences in the product distribution were noted between
the solvents. For reaction of cis-[PtCl2(NH3)(c-C6H11NH2)] with
(diacetoxyiodo)benzene a mixture of products is formed with
three species predominating. The major product is 2, but
significant amounts of 8 and 13 are also formed. Evidently
the lifetime of the five-coordinate intermediate is sufficient for
it to rearrange to give the cis addition product in contrast to the
more normal trans oxidative addition reaction. The evidence
of halide exchange suggests that the lifetime of the intermediate
is sufficient for it also to participate in intermolecular exchange
reactions. Reaction of trans-[PtCl2(NH3)(c-C6H11NH2)] with
(diacetoxyiodo)benzene in dichloromethane gives good yields
of 4, further emphasizing the rearrangement of the intermediate
prior to coordination of the second acetate ligand.
a 15N-195Pt coupling constants indicated in parentheses.
Table 4. Relative Retention of Complexes on Reverse Phase HPLC
complex
relative retention
complex
relative retention
7
9
10
3
8
12
4
0.45
0.61
0.61
0.74
0.80
0.84
0.86
2
1
13
11
14
6
0.90
1.00
1.07
1.10
1.17
2.38
3.00
5
relative retention times versus 1 for reverse phase conditions
are given in Table 4. The complexes are eluted in order of
decreasing polarity. Thus trans isomers elute much later than
cis isomers and the all-trans isomer 5 has the longest retention
time of these complexes. Retention is increased by replacing
acetates with chloride ligands. Comparing the behavior of
isomers it can be seen that complexes with ammonia trans to
chloride elute after those with ammonia trans to acetate.
Synthesis. The complex 1 is prepared by the acetylation of
the corresponding hydroxo complex with acetic anhydride.2
Treatment of the trans-amine hydroxo complex [PtCl2(OH)2-
NH3(c-C6H11NH2)] with acetic anhydride in the dark yields 5.
This reaction in itself provides evidence that the hydroxo
complex has all-trans stereochemistry, which is otherwise
difficult to establish, and that the complex has not undergone
isomerization to a cis,cis,trans form as described for trans-
[PtCl2(OH)2(NH3)2] complexes. However, if the reaction is
carried out in light the product obtained is the cis,cis,trans
isomer 6. HPLC analysis of the mixture during the course of
the reaction indicated that the initial product was 5 which
subsequently rearranged to 6, i.e., isomerization of the acetato
rather than the hydroxo complex. No mechanism was described
for the isomerization of trans-[PtCl2(OH)2(NH3)2], but it was
noted that it was prevented by the addition of hydrogen peroxide
during recrystallization of all-trans-[PtCl2(OH)2(NH3)2].8 No
indication was given that precautions were taken to prevent
In contrast with the reactions of (diacetoxyiodo)benzene, the
reaction of (dichloroiodo)benzene with cis-[Pt(OH)2NH3(c-
C6H11NH2)] and subsequent treatment with acetic anhydride
generates a mixture in which 4 is the dominant species, i.e.,
the product of trans oxidative addition. Since ligand exchange
products are still formed, this suggests a thermodynamic
preference for the initial intermediate, so that there is a reduced
tendency to isomerization.
A study of the photolysis of amminehaloplatinum(IV) com-
plexes in water has been previously reported.16 Although an
(13) Moriarty, R. M.; Vaid, R. K. Synthesis 1990, 6, 431.
(14) Varvoglis, A. Chem. Soc. ReV. 1981, 10, 377.
(15) Hodges, K. D.; Rund, J. V. Inorg. Chem. 1975, 14, 525.
(16) Loginov, A. V.; Yakovlev, V. A.; Shagisultanova, G. A. Koord. Khim.
1979, 5, 733.

The Oral Anticancer Drug JM-216
Inorganic Chemistry, Vol. 35, No. 11, 1996 3283
initial reduction to platinum(III) arising from ligand to metal
charge transfer was believed to occur, platinum(II) products were
rarely observed, with ligand substitution by water predominating.
Substitution trans to chloride was found to be favored, with
chloride trans to OH or H2O being photostable.
isomers of complexes [PtXmZ(4-m)LL′] (m ) 1-3). In the
absence of crystals suitable for X-ray diffraction studies we have
demonstrated that multinuclear NMR spectroscopy may be used
to assign structures to these complexes and that significant
structural information may be inferred from reverse phase HPLC
data.
We have made use of this photochemistry to obtain substitu-
tion products of cis-[PtCl4(NH3)(c-C6H11NH2)]. As for oxida-
tive addition reactions, an added ligand can compete with a
poorly donating solvent. To obtain acetate products the
photolysis was carried out in ethanol containing potassium
acetate. The course of the reaction was followed by HPLC.
The initial products show little selectivity with respect to the
different chloride ligands in the molecule. The favored product
is 13, which is obtained by substitution of either of the axial
chloride ligands, while substitution of the equatorial ligands
yields 11 and 12. Further substitution continues with loss of a
second chloride ligand, generating 2, 3, and 4. A third chloride
is then lost, in each case forming 8. The absence of 1 and
triacetate isomers other than 8 is in agreement with the previous
conclusion that chloride trans to hydroxide or water is photo-
stable. The final yield of 8 in these reactions is poor (<40%)
suggesting that other products are formed which elute at the
solvent front or which do not elute at all during HPLC. Solvated
platinum(II) complexes would be expected to give this behavior.
Although the reactions described above give sources for all
complexes [PtClm(OAc)(4-m)NH3(c-C6H11NH2)] (m ) 1-3),
poor yields and the unwieldy preparative HPLC isolation
procedure led us to explore alternative routes to the some of
these complexes. Base-catalyzed solvolysis of platinum(IV)
complexes has received little attention in comparison with the
work on cobalt(III) complexes.17 The reactions of platinum-
(IV) acidoamine complexes with hydroxide were found to be
very slow and complicated by reduction to platinum(II).18
However, given the potential for stereospecific substitution we
have explored this possibility. We have found that 1 reacts
readily with base leading to chloride substitution.19 When the
reaction is carried out in an aqueous solvent the products are
hydroxo-complexes formed by deprotonation of the coordinated
water ligand. By carrying out the reaction with approximately
1 equiv of hydroxide the selective substitution of one chloride
ligand can be achieved. Treatment of the product [PtCl(OH)-
(OAc)2NH3(c-C6H11NH2)] (15) with acetic anhydride yields 8,
indicating that it is the chloride trans to cyclohexylamine which
is lost. As for the oxidative addition reactions of platinum, if
a ligand is present at sufficient concentration it may compete
effectively with a poorly coordinating solvent for binding to
the metal. This has been exploited for the formation of 9. The
reaction was carried out in N,N-dimethylacetamide using lithium
chloride as the source of incoming ligand. Triethylamine was
used as the base. Reaction of 7 under these conditions gave
substitution of the acetate group trans to cyclohexylamine with
the formation of 9 in good yield. It should be noted that
treatment of 14 with base (hydroxide or carbonate) gave a
mixture of products including a significant amount of reduction
to platinum(II), consistent with the previous work in this area.18
The antitumor activity of platinum(II) complexes is known
to be dramatically influenced by stereochemistry with only a
few examples of active trans isomers while there are many
active cis complexes.20-23 The different isomers of the com-
plexes [PtCl2(OAc2)NH3(c-C6H11NH2)] may be expected to have
different pharmacokinetics and metabolism on administration
to animals, and this may result in significant variations in their
antitumor properties. This is currently being investigated.24
Experimental Section
General Methods. Organic solvents were obtained from Merck Ltd.
(BDH). Organic reagents were obtained from Aldrich Chemical Co.
and used without further purification. (Dichloroiodo)benzene was
prepared by passing dry chlorine into a solution of iodobenzene in
chloroform cooled in an ice-salt bath.25
IR spectra were recorded as KBr disks using a Perkin-Elmer 1720X
spectrometer. Raman spectra were obtained using Innova 70 CRL Ar+
and 90 CRL Kr+ lasers with a Spex Ramalog 5 instrument and Spex
Datamate data acquisition unit. 1H and 13C NMR spectra were recorded
for solutions in CD3OD using a Jeol GSX 270 instrument. 15N NMR
spectra were recorded using solutions in freshly distilled N,N-dimeth-
ylformamide using a Bruker AMX 500 spectrometer operating at 50.70
MHz for 15N. Chemical shifts are reported in ppm downfield from
external nitromethane. Elemental microanalyses were performed at the
University of Strathclyde.
For analytical HPLC, samples were chromatographed on Hypersil
ODS 5 µm (250 × 4.8 mm) using aqueous acetonitrile solutions (range
10%-50% v/v) as eluent and UV detection. For preparative HPLC,
samples dissolved in 50% aqueous acetonitrile were chromatographed
on PLRP-S 100 Å 5 µm (300 × 30 mm) with aqueous acetonitrile
eluent (ca. 30% v/v) using a Waters Prep 2000 chromatograph. The
eluent composition was adjusted slightly to optimize the separation for
each sample. Samples were recovered by evaporation to dryness under
reduced pressure with the exclusion of light. The solids were washed
with diethyl ether and dried in Vacuo.
Preparation of Complexes. cis,trans,cis-[PtCl2(OAc)2NH3(c-
C6H11NH2)] (1), (OC-6-43)-Bis(acetato-O)amminedichloro(cyclo-
hexylamine)platinum(IV). This was prepared as described by Gian-
domenico et al.2
all-cis-[PtCl2(OAc)2NH3(c-C6H11NH2)] (2), (OC-6-42)-Bis(acetato-
O)amminedichloro(cyclohexylamine)platinum(IV). A suspension of
cis-[PtCl2(NH3)(c-C6H11NH2)] (2 g, 5.2 mmol) in dichloromethane (50
mL) was treated with (diacetoxyiodo)benzene (2 g, 6.2 mmol) and the
mixture stirred at room temperature for 20 h. The solution was
evaporated under reduced pressure to yield an oil which was triturated
with diethyl ether to yield a solid. This was purified by preparative
HPLC. Yield 0.5 g (20%). Anal. Calcd for C10H22N2Cl2O4Pt: C,
24.01; H, 4.43; N, 5.60; Cl, 14.18. Found: C, 24.16; H, 4.67: N,
5.57: Cl, 14.2. IR νmax 698 (δ O-C-O) 343 (ν Pt-Cl) cm-1 1H
.
4
4
NMR δ 2.04 (3H, JPt-H ) 2.3 Hz, OCOCH3) 2.08 (3H, JPt-H ) 3.2
Hz, OCOCH3).
trans,cis,cis-[PtCl2(OAc)2NH3(c-C6H11NH2)]‚H2O (4), (OC-6-14)-
Bis(acetato-O)amminedichloro(cyclohexylamine)platinum(IV) Mono-
(20) Farrell, N.; Ha, T. T. B.; Souchard, J.-P.; Wimmer, F. L.; Cros, S.;
Johnson, N. P. J. Med. Chem. 1989, 32, 2240.
Conclusion
(21) Van Beusichem, M.; Farrell, N. Inorg. Chem. 1992, 31, 634.
(22) Farrell, N.; Kelland, L. R.; Roberts, J. D.; Van Beusichem, M. Cancer
Res. 1992, 52, 5065.
(23) Coluccia, M.; Nassi, A.; Loseto, F.; Boccarelli, A.; Mariggio, M. A.;
Giordano, D.; Intini, F. P.; Caputo, P.; Natile, G. J. Med. Chem. 1993,
36, 510-512.
(24) Kelland, L. R.; Barnard, C. F. J.; Evans, I. G.; Murrer, B. A.; Theobald,
B. R. C.; Wyer, S. B.; Goddard, P. M.; Jones, M.; Valenti, M.; Bryant,
A.; Rogers, P. M.; Harrap, K. R. J. Med. Chem. 1995, 38, 3016.
(25) Lucas, H. J.; Kennedy, E. R. Organic Syntheses; Wiley: New York,
1955; Collect Vol. 3, p 482.
Platinum(IV) complexes are inert to substitution in the
absence of catalysis, e.g., by light. We have demonstrated that
this need not be a barrier to the synthesis of the full range of
(17) Tobe, M. L. AdV. Inorg. Bioinorg. Mech. 1983, 2, 1.
(18) Johnson, R. C.; Basolo, F.; Pearson, R. G. J. Inorg. Nucl. Chem. 1962,
24, 59.
(19) Neidle, S.; Murrer, B. A.; Barnard, C. F. J. Bioorg. Med. Chem. Lett.
1996, 6, 421.

3284 Inorganic Chemistry, Vol. 35, No. 11, 1996
Barnard et al.
Cl, 7.07. IR νmax 702 (δ O-C-O) 341 (ν Pt-Cl) cm-1 1H NMR δ
2.04 (6H, JPt-H ) 3 Hz, OCOCH3) 2.06 (3H, JPt-H ) <2.5 Hz,
OCOCH3).
hydrate. The complex trans-[PtCl2(NH3)(c-C6H11NH2)] was prepared
as previously described.24 This compound (1 g, 2.6 mmol) was
suspended in dichloromethane (20 mL) and treated with (diacetoxy-
iodo)benzene (1 g, 3.1 mmol). The mixture was stirred at room
temperature for 20 h and a pale yellow solid collected by filtration and
washed with dichloromethane. The solid was recrystallized from N,N-
dimethylacetamide and water, and the product was recovered as a
monohydrate. Yield 0.3 g (22%). Anal. Calcd for C10H24N2Cl2O5Pt:
C, 23.18; H, 4.67; N, 5.41; Cl 13.69. Found: C, 23.07; H, 4.60; N,
5.30; Cl, 14.2. IR νmax 3537 (ν O-H) 703, 690 (δ O-C-O) 354 (ν
.
4
4
mer-[PtCl(OAc)3NH3(c-C6H11NH2)] (9), (OC-6-34)-Tris(acetato-
O)amminechloro(cyclohexylamine)platinum(IV). Triethylamine (0.7
mL) and 7 (1.1 g) were added to a solution of lithium chloride in N,N-
dimethylacetamide (2 M, 5 mL). The mixture was stirred at room
temperature for 50 min and then diluted with acetone to precipitate
excess lithium chloride. The solution was filtered and evaporated to
an oil which was purified by preparative chromatography. Yield 0.55
g (52%). Anal. Calcd for C12H25N2ClO6Pt: C, 27.51; H, 4.81; N,
5.35; Cl, 6.77. Found: C, 27.64; H, 4.99; N, 5.20; Cl, 6.76. IR νmax
Pt-Cl) cm-1 1H NMR δ 2.07 (3H, OCOCH3) 2.08 (3H, OCOCH3).
.
all-trans-[PtCl2(OAc)2NH3(c-C6H11NH2)] (5), (OC-6-12)-Bis-
(acetato-O)amminedichloro(cyclohexylamine)platinum(IV). A sus-
pension of all-trans-[PtCl2(OH)2NH3(c-C6H11NH2)] (1 g, 2.4 mmol)
in a mixture of acetic anhydride (5 mL) and diethyl ether (3 mL) was
stirred in the dark for 3 days. The yellow product was collected by
filtration and washed with diethyl ether. Yield 0.75 g (62%). Anal.
Calcd for C10H22N2Cl2O4Pt: C, 24.01; H, 4.43; N, 5.60; Cl, 14.18.
706, 698 (δ O-C-O) 343 (ν Pt-Cl) cm-1
.
1H NMR δ 2.04 (6H,
4
4JPt-H ) 3.2 Hz, OCOCH3) 2.09 (3H, JPt-H ) <2.1 Hz, OCOCH3).
fac-[PtCl(OAc)3NH3(c-C6H11NH2)]‚H2O (10), (OC-6-24)-Tris-
(acetato-O)amminechloro(cyclohexylamine)platinum(IV) Mono-
hydrate. This complex was obtained by preparative HPLC. Mixtures
containing the complex were obtained in two ways: (i) stirring 14 and
silver acetate (1 equiv) in acetone at 40 °C in the dark for 7 days and
(ii) stirring 14 (3 g, 6.6 mmol) in ethanolic potassium acetate (0.5 M,
100 mL) for 3 days in the light. The solution was evaporated,
redissolved in acetone, and filtered three times to remove KOAc/KCl
before chromatography. Typical yield ca. 5%. Anal. Calcd for
C12H27N2ClO7Pt: C, 26.60; H, 5.02; N, 5.17; Cl, 6.55. Found: C,
26.46; H, 4.88; N, 5.03; Cl, 6.86. IR νmax 703, 693 (δ O-C-O) 357
Found: C, 24.02; H, 4.35; N, 5.53; Cl, 14.4. IR νmax 712 (δ O-C-
4
O), 356 (ν Pt-Cl) cm-1
OCOCH3).
.
1H NMR δ 2.01 (6H, JPt-H ) <3 Hz,
cis,cis,trans-[PtCl2(OAc)2NH3(c-C6H11NH2)] (6), (OC-6-22)-Bis-
(acetato-O)amminedichloro(cyclohexylamine)platinum(IV). The com-
plex was prepared as previously described.24 A suspension of all-trans-
[PtCl2(OH)2NH3(c-C6H11NH2)] (2 g, 4.8 mmol) in acetic anhydride (10
mL) was stirred at ambient temperature for 5 days without protection
from daylight. The cream-colored product was collected by filtration
and washed with diethyl ether. Yield 1.72 g (72%). Anal. Calcd for
C10H22N2Cl2O4Pt: C, 24.01; H, 4.43; N, 5.60; Cl, 14.18. Found: C,
24.16; H, 4.33; N, 5.52; Cl, 14.1. IR νmax 695 (δ O-C-O) cm-1. 1H
NMR δ 2.04 (6H, OCOCH3).
cis-[Pt(OAc)4NH3(c-C6H11NH2)] (7), (OC-6-32)-Tetrakis(acetato-
O)amminecyclohexylamineplatinum(IV). An aqueous suspension of
cis-[PtCl2(NH3)(c-C6H11NH2)] (4.5 g, 11.8 mmol) was stirred with silver
nitrate (3.92 g, 23.1 mmol) overnight with protection from light. The
suspension was filtered to remove AgCl and the filtrate passed down
a column of Amberlite IRA-400 resin (OH form, 100 mL) to remove
nitrate. The eluent was treated with activated charcoal and filtered,
hydrogen peroxide (30% w/v; 8 mL, 70 mmol) was added to the eluent,
and the mixture heated at 80 °C for 30 min. The solution was allowed
to cool and evaporated under reduced pressure to low volume using
additions of ethanol to minimize foaming. [Caution: Solutions
containing residual hydrogen peroxide should not be reduced to
dryness]. The solution was treated with acetone to yield white cis-
[Pt(OH)4NH3(c-C6H11NH2)]. This was washed with diethyl ether and
dried in Vacuo. Yield 2.95 g (66%). A sample (0.6 g) was stirred in
acetic anhydride for 16 h at room temperature. Evaporation of the
solution yielded an oil which was dissolved in acetone to precipitate
the white crystalline product. This was recrystallized from ethanol and
diethyl ether. Yield 0.3 g (35%). Anal. Calcd for C14H28N2O8Pt: C,
(ν Pt-Cl) cm-1
. )
1H NMR δ 2.05 (3H, OCOCH3) 2.075 (3H, 4JPt-H
3 Hz, OCOCH3) 2.09 (3H, OCOCH3).
cis-[PtCl4NH3(c-C6H11NH2)] (14), (OC-6-32)-Ammine(tetra-
chloro)cyclohexylamineplatinum(IV). A solution of cis,trans,cis-
[PtCl2(OH)2NH3(c-C6H11NH2)] was heated in dilute hydrochloric acid
(1 M) at 80 °C for 2 h. The product precipitated on cooling (typical
yield 50%). The complex may also be obtained by oxidation of cis-
[PtCl2(NH3)(c-C6H11NH2)] with chlorine at room temperature (typical
yield 46%). Anal. Calcd for C6H16N2Cl4Pt: C, 15.91; H, 3.56; N,
6.14; Cl, 31.30. Found: C, 15.90; H, 3.44; N, 6.10; Cl, 31.4. IR νmax
346 (ν Pt-Cl) cm-1
.
all-cis-[PtCl2(OAc)2NH3(c-C6H11NH2)] (3), (OC-6-32)-Bis(acetato-
O)amminedichloro(cyclohexylamine)platinum(IV); mer-[PtCl3(OAc)-
NH3(c-C6H11NH2)] (11), (OC-6-41)-(Acetato-O)amminetrichloro-
(cyclohexylamine)platinum(IV); mer-[PtCl3(OAc)NH3(c-C6H11NH2)]
(12), (OC-6-31)-(Acetato-O)amminetrichloro(cyclohexylamine)-
platinum(IV); fac-[PtCl3(OAc)NH3(c-C6H11NH2)] (13), (OC-6-43)-
(Acetato-O)amminetrichloro(cyclohexylamine)platinum(IV). A so-
lution of 14 in ethanolic potassium acetate (0.5 M, 100 mL) was stirred
in daylight for 3 h. The mixture was evaporated to dryness and
redissolved in acetone. This mixture was filtered to remove potassium
chloride and excess potassium acetate. Evaporation, dissolution, and
filtration was repeated twice more and the final residue was separated
using preparative HPLC.
3: Yield ca. 4%. Anal. Calcd for C10H22N2Cl2O4Pt: C, 24.01; H,
4.43; N, 5.60; Cl, 14.18. Found: C, 24.22; H, 4.25; N, 5.42; Cl, 14.4.
IR νmax 697 (δ O-C-O) 352 (ν Pt-Cl) cm-1
.
1H NMR δ 2.07 (3H,-
30.72; H, 5.16; N, 5.12. Found: C, 31.03; H, 5.19; N, 5.09. IR νmax
OCOCH3) 2.08 (3H, OCOCH3).
4
706, 687 (δ O-C-O) cm-1
.
1H NMR δ 2.03 (6H, JPt-H ) 3.2 Hz,
11: Yield ca. 5%. Anal. Calcd for C8H19N2Cl3O2Pt: C, 20.16; H,
OCOCH3) 2.06 (3H, OCOCH3) 2.10 (3H, OCOCH3).
4.02; N, 5.88; Cl, 22.31. Found: C, 20.30; H, 3.73; N, 5.77; Cl, 22.4.
IR νmax 694 (δ O-C-O) 349 (ν Pt-Cl) cm-1
.
1H NMR δ 2.04 (3H,
[PtCl(OH)(OAc)2NH3(c-C6H11NH2)]‚H2O (15), (OC-6-52)-Bis-
(acetato-O)amminechloro(cyclohexylamine)hydroxoplatinum(IV)
Monohydrate. A solution of 1 (5 g, 10 mmol) in 75/25 acetonitrile/
water (800 mL) was treated with KOH (1 M, 12 mL). The mixture
was stirred for 3 h in the dark at room temperature and then evaporated
under reduced pressure until precipitation was initiated. The white
product was washed with acetone and dried in Vacuo. Yield 2.1 g
(44%). Anal. Calcd for C10H25N2ClO6Pt: C, 24.03; H, 5.04; N, 5.60;
Cl, 7.09. Found: C, 24.13; H, 5.00; N, 5.52; Cl, 7.35. IR νmax 712 (δ
4JPt-H ) 2.4 Hz, OCOCH3).
12: Yield ca. 3%. Anal. Calcd for C8H19N2Cl3O2Pt: C, 20.16; H,
4.02; N, 5.88; Cl, 22.31. Found: C, 20.36; H, 4.03; N, 6.03; Cl, 20.8.
IR νmax 695 (δ O-C-O) 349 (ν Pt-Cl) cm-1
OCOCH3).
.
1H NMR δ 2.05 (3H,
13: Yield ca. 10%. Anal. Calcd for C8H19N2Cl3O2Pt: C, 20.16;
H, 4.02; N, 5.88; Cl, 22.31. Found: C, 20.13; H, 3.96; N, 5.72; Cl,
22.2. IR νmax 696 (δ O-C-O) 347 (ν Pt-Cl) cm-1
.
1H NMR δ 2.04
4
O-C-O) 562 (Pt-OH) 331 (ν Pt-Cl) cm-1
.
(3H, JPt-H ) 3.2 Hz, OCOCH3).
mer-[PtCl(OAc)3NH3(c-C6H11NH2)] (8), (OC-6-43)-Tris(acetato-
O)amminechloro(cyclohexylamine)platinum(IV). A suspension of
15 (0.5 g) in acetic anhydride (3 mL) was stirred at room temperature
for 16 h. The solution was evaporated under reduced pressure and the
resultant oil triturated with diethyl ether to yield the white crystalline
product. Yield 0.5 g (92%). Anal. Calcd for C12H25N2ClO6Pt: C,
27.51; H, 4.81; N, 5.35; Cl, 6.77. Found: C, 27.72; H, 4.85; N, 5.44;
Acknowledgment. We thank Mr. Brian Moore (JMTC) and
Dr. Tony Avent (Univ. of Sussex) for obtaining NMR spectra.
We are grateful to Professor W. P. Griffith, Imperial College,
London, for assistance in obtaining and interpreting Raman
spectra.
IC951548N