Enantiomers of Platinum(II) Complexes
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 22 3509
a substituent to the primary amine would give a ligand
with the features shown in Scheme 1. Upon coordina-
tion, a second chiral center on the exocyclic amine is
generated. In the present paper we report the synthesis
of two such ligands (meahaz ) 3-(N-methylamino)-
hexahydroazepine, Scheme 2, R′ ) H, R′′ ) Me, and
etahaz ) 3-(N-ethylamino)hexahydroazepine, Scheme
volume of water (30 mL) and shaken with sodium carbonate
(2.50 g, 0.025 mol). Absolute ethanol (475 mL) was then added
and the solvent removed by rotary evaporation to leave a
yellow/white residue. More absolute ethanol (250 mL) was
added to azeotropically remove any residual water present.
The resulting solid, which consisted of sodium chloride and
sodium carbonate, was filtered off, and the solvent was again
removed by rotary evaporation. The product R-amcap was
collected as a clear yellow oil: yield 7.00 g, ∼100%.
2
, R′ ) H, R′′ ) Et) and their platinum complexes. We
S-amcap‚HCl was liberated as described above to produce
S-amcap, again in almost quantitative yield. Both enantio-
merically pure compounds were used as precursors in the
syntheses of the following ligands.
have also synthesized the ligand with two methyl
substituents on the primary amine of ahaz (dimeahaz
)
3-(N,N-dimethylamino)hexahydroazepine, Scheme 2,
R′ ) Me, R′′ ) Me, and its complex to assess the effect
of increasing the steric bulk and removing the amine
proton. The crystal structures of these three complexes
and the in vitro cytotoxicities of the three pairs of
enantiomers are also reported.
P r ep a r a tion of 3-(N-Meth yla m in o)h exa h yd r oa zep in e
(m ea h a z). The synthesis of meahaz was adapted from the
procedure published by Kashiwabara et al. for the dimeth-
ylation of 1,2-cyclohexanediamine. The enantiomerically pure
amcap‚HCl (7.00 g, 0.046 mol) solid was added to an ice-cold,
magnetically stirred solution of sodium hydroxide (5.60 g,
8
0
.14 mol) in water (40 mL). A solution of ethyl chloroformate
Exp er im en ta l Section
(3.7 mL, 0.046 mol) in benzene (20 mL) was added dropwise
In str u m en ta l. The H and 13C NMR analyses were carried
out on either a Bruker AMX 400 MHz spectrometer or a
Bruker AC 200F spectrometer. The solvents were com-
mercially obtained and were of 99.6% isotopic purity or better.
The polarimetric studies of the ligands and their intermediates
were carried out on an Optical Activity Polaar 2001 automatic
polarimeter, using a 1 dm cell and were recorded at ambient
temperature. The mass spectroscopic analysis of the ligands
was carried out on a Kratos MS9 (updated to an MS50);
ionization energy was achieved by physical electron impact
at 70 eV. The samples were run on a direct insertion probe
with a source temperature of 150-200 °C. The data collection
system used was a Kratos DS90. The circular dichroism
measurements for all the complexes were carried out on a
J ASCO J -710 spectropolarimeter equipped with J -700 software
for Windows. The instrument was calibrated with camphor
sulfonate (188.7 mdeg at λmax 291.5 nm) prior to running the
1
to the cooled mixture over a period of 1 h. The reaction
mixture was allowed to stand at room temperature for 3 h,
and then the crude product was extracted with dichlo-
romethane (3 × 100 mL), dried over anhydrous sodium sulfate,
and filtered. The solvent was removed from the filtrate by
rotary evaporation, and the residual oil was then cooled in an
acetone/ice bath to induce crystallization. The solid was
washed with 60/90 petroleum ether to remove a soluble yellow
impurity, leaving a pale-yellow solid: yield 7.00 g, 82%, based
on the ethyl chloroformate amcap intermediate; MS m/z 200,
calcd 200.
The (R)-ethyl chloroformate amcap intermediate (7.00 g,
0.035 mol) was added to sodium dried tetrahydrofuran (200
mL) and stirred. Freshly crushed lithium aluminum hydride
(10.3 g) was slowly added to the cooled mixture, and the
reaction mixture was allowed to warm to room temperature
and was then refluxed for 48 h. Upon cooling, a solution of
water (30 mL) in tetrahydrofuran (70 mL) was added dropwise
to the reaction solution. The resultant mixture was gently
refluxed for 0.5 h, and the solid was then removed by suction
filtration and washed with boiling tetrahydrofuran (2 × 100
mL). The combined filtrates were condensed on a rotary
evaporator, and benzene was used to azeotropically remove
any residual water. The crude R-meahaz ligand was collected
as a yellow oil: yield: 4.58 g, 92%. The ligand was further
purified by vacuum distillation (Kugelrohr) at ca. 80 °C, 0.05
mmHg, to produce R-meahaz as a colorless oil: yield 3.32 g;
-3
spectra. All spectra of the complexes were recorded using 10
M N,N-dimethylformamide (DMF) solutions, with a sensitivity
setting of 50 mdeg and spectral band width at 1.0 nm, between
2
60 and 500 nm. Diffuse reflectance infrared Fourier trans-
form spectra (DRIFTS) of the platinum complexes were
collected on a Bio-Rad FTS-40 spectrophotometer equipped
with Win-IR Windows based software. KBr was used for a
-
1
background and as a matrix, over a range of 400-4000 cm
.
All melting points were measured on a Gallenkamp model
digital melting point apparatus and are reported uncorrected.
The microanalysis of each complex was carried out by the
National Analytical Laboratories Pty Ltd.
MS m/z 128, calcd 128. NMR (solvent CDCl , ppm) 1.49 (m,
3
2H), 1.65 (m, 5H), 1.83 (m, 1H), 2.40 (s, 3H), 2.60 (m, 1H),
Resolu tion of Ra cem ic r-Am in o-E-ca p r ola cta m (r a c-
a m ca p ). The resolution of the precursor, rac-amcap (Sigma-
Aldrich), was necessary as the R-enantiomer is not commer-
cially available. The resolution procedure used was a modifi-
2.73 (q, 1H), 2.85 (m, 2H), 2.91 (dd, 1H), [R] +10.9 (c ) 0.1,
D
methanol). A similar procedure was followed to synthesize the
S-meahaz ligand; the NMR spectrum of this compound was
identical to that reported above for R-meahaz: yield: 7.51 g,
75%; distillation at ca. 80 °C, 0.05 mmHg; yield 6.52 g; MS
7
cation of the method described by Boyle et al. A vigorously
stirred solution of dimethoxyethane (300 mL) and rac-amcap
m/z 128, calcd 128; [R] -11.0 (c ) 0.1, methanol).
D
(51.2 g, 0.4 mol) was heated to 70 °C, and over a period of 10
P r ep a r a tion of 3-(N-Eth yla m in o)h exa h yd r oa zep in e
(eta h a z). Acetic anhydride (40 mL, 0.36 mol) was slowly
added to R-amcap (10 g, 0.078 mol), followed by 3 drops of
pyridine. The mixture was stirred for 1 h and allowed to stand
for a further 4 h, after which the solvent was removed by
rotary evaporation. The crude product was broken up in ethyl
acetate (20 mL), filtered, washed with ethyl acetate (2 × 10
mL), and air-dried. The white solid (R)-R-(acetylamino)-ꢀ-
caprolactam was collected at the pump: yield 9.00 g, 67%; mp
min, (S)-2-oxopyrrolidin-5-carboxylic acid (L-PCA) (26.9 g, 0.21
mol) was added. The mixture was refluxed for 0.5 h, cooled
to 30 °C, and then filtered. The yellowwhite filter cake was
boiled in ethanol (500 mL), filtered, and washed with ethanol
to give the white S-amcap.L-PCA salt (37.9 g). This was
suspended in methanol (600 mL) and treated with concen-
trated hydrochloric acid (24.2 mL) to precipitate (S)-R-amino-
ꢀ
-caprolactam as a white hydrochloride salt (S-amcap‚HCl).
The solid was filtered, washed with ethanol, and dried in
vacuo: yield: 17.1 g, 67%; [R] -27.7° (c ) 4, 1 M HCl).
155-157 °C; [R] -12.27 (c ) 1, methanol); MS m/z 170, calcd
D
D
170.
The filtrate was condensed on a rotary evaporator to leave
R-amcap‚L-PCA as a dark yellow oil (22.40 g). This oil was
dissolved in methanol (150 mL) and treated with concentrated
hydrochloric acid (14.5 mL) to precipitate (R)-R-amino-ꢀ-
caprolactam as the hydrochloride salt (R-amcap‚HCl). The
solid was filtered, washed with a little ethanol followed by
(R)-R-(Acetylamino)-ꢀ-caprolactam (9.00 g, 0.053 mol) was
added to sodium-dried tetrahydrofuran (250 mL) and stirred.
Freshly crushed lithium aluminum hydride (31.0 g) was slowly
added to the cooled mixture. The reaction mixture was
allowed to reach room temperature and then refluxed for 48
h. The mixture was cooled, a solution of water (62 mL) in
tetrahydrofuran (38 mL) was added dropwise, and the result-
ant mixture was gently refluxed for 0.5 h. The solid was
removed by suction filtration and washed with boiling tet-
diethyl ether, and dried in vacuo: yield 11.51 g, 45%; [R]
D
7
+
26.8° (c ) 4, 1 M HCl) (lit. [R]
D
+26.4°).
R-amcap‚HCl (7.50 g, 0.05 mol) was dissolved in a minimum