Synthesis and structures of 9-oxabispidine analogues of cisplatin, carboplatin, and oxaliplatin

Article abstract of DOI:10.1021/acs.inorgchem.6b01690

The literature synthesis of 9-oxabispidine [OC₆H₁₀(NH)₂, C] has been revisited and optimized, which includes determination of the crystal structures of C, the secondary component trans-(PhSO₂)NC₄H

Full text of DOI:10.1021/acs.inorgchem.6b01690

Article
pubs.acs.org/IC
Synthesis and Structures of 9‑Oxabispidine Analogues of Cisplatin,
Carboplatin, and Oxaliplatin
David Pollak, Richard Goddard, and Klaus-Richard Porschke*
̈
Max-Planck-Institut fur Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mulheim an der Ruhr, Germany
̈
̈
S
* Supporting Information
ABSTRACT: The literature synthesis of 9-oxabispidine [OC6H10(NH)2, C] has been
revisited and optimized, which includes determination of the crystal structures of C, the
secondary component trans-(PhSO2)NC4H6O(CH2I)2 (trans-III), and the unexpected solute
intermediate OC6H10(NSO2Ph)2·1/2py (V·1/2py). The reaction of (1,5-hexadiene)platinum
dichloride with C yields {OC6H10(NH)2}PtCl2 (C1), which is converted to {OC6H10(NH)2}-
Pt(cbdca)·5H2O (C2) and {OC6H10(NH)2}Pt(C2O4) (C3). In the crystal, C1 forms a planar
2D network by N−H··Cl and N−H··O hydrogen bonding. In the crystal structure of C2,
which is isomorphous to the parent bispidine compound (A2), all complex molecules are
encapsulated by a water shell. While complexes C1 and C3 are virtually insoluble in water, C2
dissolves quite well. The low cytotoxicity of compounds C1−C3 is explained by an increased polarity of the bonds in the C
skeleton as a consequence of the electronegative O atom.
platinum drugs is not curative. Oxaliplatin appears to be
particularly potent for colon cancer and is the treatment of
choice for tumors that prove to be resistant to cisplatin or
carboplatin by virtue of the different structural demand of the
trans-(R,R)-1,2-diaminocyclohexane ligand.
1. INTRODUCTION
The serendipitous discovery of the cytostatic properties of
cisplatin, cis-(NH3)2PtCl2, by Rosenberg and co-workers1 in the
mid-1960s has unleashed an enduring interest in the advance-
ment of Pt-based anticancer drugs. The most notable
developments were carboplatin, in which the labile chloride
anions of cisplatin are replaced by 1,1-cyclobutanedicarboxylate
(cbdca),2 and oxaliplatin, trans-(R,R)-1,2-diaminocyclohexane-
platinum(II) oxalate.3 Until today, these three compounds
represent the only worldwide-approved platinum drugs for
cancer therapy (Chart 1).
In the quest to overcome the problems associated with
cisplatin-based therapy, countless platinum complexes have
been tested for their cytostatic activity. On the basis of such
empirical studies, structure−activity rules (SARs) have been
established and were first formulated by Cleare and Hoeschele.4
According to SARs, activity is generally found for platinum(II)
complexes that are neutral and planar and adhere to the general
formula cis-PtIIA2X2, in which A represents a neutral amine
ligand bearing 1−3 protons. X or X2 represents an anionic
leaving group such as halide, oxalate, and malonate, which
allows slow hydrolysis. Platinum compounds that conform to
these rules are considered as “classical” or “traditional”
platinum cytostatics.
Chart 1. Worldwide-Approved Platinum Drugs for Cancer
Therapy
A series of essential properties are accredited to the amine
ligand, which is assumed to remain coordinated during the
whole action time of the drug. First, the amine appears to
function as a “carrier ligand” for transport of the drug from the
bloodstream through the cell membrane of the cancer cells.
The amine is thought to identify cancer cells by preferably
penetrating the membranes of certain cancer cells and sparing
the healthy tissue. This feature allows the drug to accumulate in
the cancer cells, minimizing side effects. In order to optimally
penetrate the lipophilic cell membrane, the drug molecule must
be neutral and sufficiently lipophilic but not exceedingly bulky.
In this way, the “carrier ligand” should provide a route to
enlargement of the so-far-rather-limited scope of treatable
There are numerous serious side effects associated with
cisplatin and its congeners. Further pressing problems are
inherent or acquired platinum resistance and narrow limitations
in the profile of responding cancers. For example, the
prototypical cisplatin is particularly curative in the case of
testicular cancer with a cure rate of up to 95%. However, for
about 5% of the patients, the cancer shows no response to the
treatment, attributed to an inherent and not yet fully
understood platinum resistance. Even for those patients who
respond to the initial treatment, a recurring cancer may not
react to subsequent treatment due to acquired platinum
resistance. Unfortunately, for some major cancers such as
lung, breast, and head cancers, therapy with the current
Received: July 14, 2016
© XXXX American Chemical Society
A
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cancers. Second, once inside the cancer cells, the drug molecule
must be able to move through the cell fluid with its countless
ingredients and find its way to bind selectively to DNA.
Migration to and along DNA with selection of the DNA purine
bases for coordination occurs by reversible hydrogen bonding
of the N−H functions, which therefore appear indispensable.
While the anionic ligands are cleaved off by hydrolysis, the
remaining aminoplatinum(II) species latches onto the DNA
and causes its denaturation.5 Third, coordination of the amine
ligand to both platinum and the purine bases must be strong
enough to hold platinum at its ultimate position, avoiding efflux
from the cell by reverse migration. Finally, as DNA repair
mechanisms responsible for “Pt resistance” come into action,
these therapy-counteracting mechanisms cope most efficiently
with the small (H3N)2PtII moiety of cisplatin and carboplatin,
which therefore cannot prevent “Pt resistance”. Amino-
platinum(II) moieties of disk shape and larger bulk, as is the
case for oxaliplatin, appear to withstand such mechanisms more
effectively and therefore appear to thwart an upcoming “Pt
resistance”.
According to the SARs, platinum complexes bearing
secondary amines, which are usually sterically more demanding,
are expected to be less potent than those with ammine or
primary amines. However, because the traditional platinum
cytostatics do not appear to provide a remedy for the adverse
effects and limitations of the current platinum-based treat-
ments, current research focus is set on “non-traditional”
platinum drugs, molecules that are not necessarily consistent
with SARs.6 So far, little attention has been given to the
intermolecular hydrogen bonding extended by the carrier
ligands by self-association of the complexes and to water.7
Some years ago, we studied complexes of nickel(0) with 3,7-
dimethylbispidine (bispidine = 3,7-diazabicyclo[3.3.1]-
nonane).8 The unexpected stability of these complexes, which
runs contrary to the hard and soft acids and bases concept, can
be explained by the principles of preorganization (ligand) and
prepositioning (ligand atoms) as the essential features of the
macrocyclic effect.9 The bispidine−metal entity comprises an
adamantane-type structural unit, featuring four six-membered
rings. We note that many herbal alkaloids [(−)-sparteine,
(+)-lupanine, (−)-cytisine, etc.] contain such a bispidine core.
The relevance of the bispidine scaffold in biologically active
systems is well documented.10 Such considerations raised the
question of whether simple bispidines, unsubstituted at both N
atoms, could provide useful “carrier ligands” for platinum
cytostatics.
Chart 2. Bispidine-Type Modified Analogues of Cisplatin,
Carboplatin, and Oxaliplatin
potency on the micromolar concentration level. Particular
potency was found with respect to A2780 CisR, suggesting that
overcoming “Pt resistance” might be a possible feature.
In a continuation of these studies, we became interested in
what effect might follow from the incorporation of oxygen in
the bispidine skeleton, as is the case for 9-oxabispidine (C).
The bridging O atom was expected to result in a balancing of
the hydrophilicity and lipophilicity and, at the same time, to
reduce the size of the bispidine ligand by virtue of the short C−
O bonds. It was considered an open question as to how the
additional basic sites of the O atom would alter the properties
of (bispidine)platinum(II)-type complexes.
We therefore revisited the previous synthesis of C by Stetter
and Meissner, prepared and characterized complexes C1−C3 as
the C derivatives of cisplatin, carboplatin, and oxaliplatin, and
probed their cytotoxic potency (Chart 3). A subsequent paper
will deal with related complexes of 9,9-difluorobispidine
(complexes D1−D3).16
Chart 3. New (9-Oxabispidine)platinum(II) Complexes
2. RESULTS AND DISCUSSION
Synthesis and Properties of 9-Oxabispidine (C). The
synthesis of C was performed by modification of the route
outlined by Stetter and Meissner (Scheme 1; retained
notation).17 After protection of the N atom in diallylamine
by phenylsulfonate to obtain I, the CC bonds were
On the basis of an improved synthesis of the parent bispidine
(C7H12(NH)2, A)11,12 and knowledge of its properties so
gained,13 we recently synthesized the series of cisplatin,
carboplatin, and oxaliplatin analogues A1−A3 (Chart 2).14
Similarly, in a subsequent series, the 9,9-dihydroxy-substituted
derivatives B1−B3 were prepared.15
Scheme 1. Synthesis of C (after Stetter and Meissner)
The cytotoxic potency of these compounds has been tested
against the ovarian cancer line A2780, the cisplatin-resistant
subline A2780 CisR, and the leukemia cell line K562. While a
general decrease of the cytotoxic potency was noted compared
to that of the reference compounds, the complexes still retained
B
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oxygenated with mercury diacetate/water to give a cis/trans
mixture of mercuric morpholine (II), which was converted to
the iodide III. Ring closure with ammonia afforded (non-
isolated) 3-(phenylsulfonyl)-9-oxabispidine (IV), which in a
pyridine solution was converted to crystalline 3,7-bis-
(phenylsulfonyl)-9-oxabispidine (V). Final cleavage of the
protection groups with LiAlH4 afforded 9-oxabispidine (VI,
denoted as C in this paper).
pressure of the compound. Fragmentation of the molecular ion
[M]+ (m/e 128, 48%) occurs in a fashion similar to that of
parent A,12 in that the initial ionization at N is followed by 2-
fold α-C−C bond cleavage18 and two proton-transfer steps to
afford, inter alia, the 2,3-dehydromorpholinium cation
[C4H6NO]+ (m/e 84) as a prominent ion (eq 1). Moreover,
We encountered several pitfalls during the synthesis of C,
which call for special attention. (i) Stetter and Meissner
anticipated that during the formation of the morpholine
intermediates II and III the cis isomers would prevail. We
found, however, while investigating the iodide III by NMR, that
cis-III is actually the minor isomer in the reaction mixture, with
the cis/trans ratio being as low as 1:2. From the oily raw
product, large chunks of cis/trans-III can be crystallized.
Repeated recrystallization from ethanol leads to extraction of
pure trans-III and enrichment of cis-III in the mother liquor.
Both isomers have been characterized by their NMR spectra,
and the structure of trans-III has been established by single-
crystal X-ray structure analysis (Table S1 and Figure S1 in the
Supporting Information, SI). The crude cis/trans-III can be
used for further reactions. (ii) Carrying out step IV → V in
pyridine did not produce pure V but the pyridine solute
V·1/2py as a crystalline product. We have verified the identity of
V·1/2py by X-ray structure analysis (see below). The thermal
effect reported to occur at 150 °C appears to be caused by the
elimination of solute pyridine rather than devitrification
(“Kristallumwandlung”),17 which we were able to rule out for
pyridine-free V. The presence of pyridine complicated the next
reaction step because it results in [C5H5NH]Cl as a byproduct,
which is tedious to remove. We were able to avoid this problem
by carrying out step IV → V in a tetrahydrofuran (THF)
solution. Nevertheless, NEt3 was necessary as a base, which
afforded [Et3NH]Cl. The latter was effectively removed by
aqueous KOH to yield pure V. (iii) We recommend that the
reduction V → VI be carried out with freshly recrystallized
(colorless) LiAlH4, which markedly increases the yield. (iv)
Quenching the reaction mixture with methanol (MeOH)
instead of water allowed direct sublimation of the strongly
hygroscopic VI (OC6H10(NH)2, C) from the reaction mixture,
thus avoiding tedious workup. The full protocol of the modified
synthesis, including the NMR characterization of intermediate
cis/trans-III, is described in the SI (Figures S2−S5).
The melting point of C is 76 °C and thus much lower than
that of parent A (198 °C).13 A differential scanning calorimetry
(DSC) investigation rules out any phase transition prior to
melting for the ordered-crystalline C, whereas the parent A
seems to transform into a dynamically disordered phase. Similar
to A, solid C sublimes under vacuum before melting. It
dissolves well in pentane at ambient temperature, from which it
can be recrystallized at 0 °C. The compound has a particularly
unpleasant and characteristic odor when finely divided. The
odor is also noticeable for its solutions in THF, acetone, and
water but is substantially reduced in solutions of N,N-
dimethylformamide (DMF) and dimethyl sulfoxide (DMSO)
(hardly noticeable). This fact may be explained by the effective
hydrogen bonding of the NH protons to the increasingly basic
O of the latter solvents. Solid C is strongly hygroscopic and
liquefies within minutes when exposed to air.
electrospray ionization mass spectrometry in positive operation
mode (ESI+ MS) of a solution of C in MeOH shows [M + H]+
as the sole cation. Keeping a solution of C in CH3OD for 2
days resulted in H/D exchange at NH with the formation of
OC6H10(ND)2 (C-d2), which was isolated by vacuum
evaporation of the solvent below 0 °C. The IR spectra of C
and C-d2 (see the SI) are described below, together with those
of complexes C1−C3.
The 1H NMR spectrum (THF-d8) of C shows for the
3
bridgehead OCH [δ(H) 3.23; J = 3.6 Hz] a triplet because of
coupling to two NCHax. The OCH signal occurs expectedly at
low field due to the neighboring O atom, in contrast to the
situation observed for parent A [δ(H) 1.45].13 NCHeqHax gives
rise to AB-type signals with typical geminal coupling. The
higher field doublet [δ(H) 2.84, 2J = 12 Hz] lacks further visible
coupling and can be assigned to NCHeq, while the lower field
2
signal for NCHax is a doublet of doublets [δ(H) 3.13, J = 12
3
Hz, J = 3.6 Hz] due to coupling with the bridgehead OCH.
Intriguingly, in C, the signal of NCHax is shifted downfield and
that of NCHeq upfield so that the order of the signals is
reversed compared to that of A (it is again reversed for
complexes C1 and C2; see below).19 The assignment of the
NCHeqHax signals of A and C ensues from correlation of the
dihedral angles with H2/5 (see the molecular structures) and
the coupling constants according to the Karplus equation.
Because of flattening of the chair conformation of the six-
membered rings at N, the dihedral angle between CH2/5 and
NCHax (54°) is relatively small, and the corresponding 3J
coupling is larger and hence resolved. This relationship is
3
different for NCHeq (64°, J ≤ 2 Hz).
The NH signal at δ(H) 2.34 (w1/2 = 1.7 Hz) occurs at lower
field than that for A [δ(H) 2.10]. The NH signal is markedly
broadened at −80 °C [δ(H) 2.61, w1/2 = 22 Hz], which is
explained by the slow exchange of the bonding situations of the
endo- and exo-NH protons according to eq 2.
The electron impact mass spectrometry spectrum (25 °C) of
C was recorded by means of gas chromatography−mass
spectrometry (GC−MS) coupling because of the high vapor
13C NMR displays for C merely two sharp signals in the 1:2
intensity ratio [δ(C) 66.8 (OCH), 47.5 (NCH2); δ(C) 28.9
(CH), 52.1 (NCH2) for A].
C
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When C is dissolved in CH2Cl2, it slowly reacts with the
solvent by nucleophilic displacement of Cl by N to eventually
(after several days) give pure 1,3-diaza-6-oxaadamantane
dihydrochloride [OC7H12N2(HCl)2, VII-2HCl; eq 3]. This
intermediate reacts further with full conversion of the initial C
into VII-2HCl.
When the reaction of eq 3 by 1H NMR for a solution of C in
CD2Cl2 is monitored, reaction steps a−d can be distinguished
depending on the base in action (Scheme 2).13 In the first step
(a), attack of C on CH2Cl2 (CD2Cl2) formally generates VII-
2HCl, which in the presence of C immediately becomes fully
deprotonated, forming 1,3-diaza-6-oxaadamantane (VII) and
soluble C-1HCl. This step takes about 12−24 h and is
distinctly slower than the analogous reaction of A with CH2Cl2
(E = CH2; 90 min). The lower reactivity of C compared to that
of A is consistent with the electron-withdrawing effect of O,
which reduces the nucleophilicity of the N atoms while
increasing the acidity of the NH protons. In the course of step
a, the NMR signals of C/C-1HCl (in rapid exchange) move to
lower field due to an increasing amount of C-1HCl, and the
new signals of VII arise at constant chemical shifts.
When all C is consumed (mostly in its function as a base),
the generated C-1HCl undergoes a similar but still slower
reaction (steps b and c). In step b, 0.5 equiv of C-1HCl reacts
with 0.5 equiv of CH2Cl2, and all of intermediate VII serves as a
base to give VII-1HCl. During this step, the NMR signals of
VII/VII-1HCl (in rapid exchange) shift to lower field, while
the signals of C-1HCl retain their chemical shifts but decrease
in intensity. In step c, when all of VII is consumed, a further 0.5
equiv of C-1HCl reacts with 0.5 equiv of CH2Cl2, with C-1HCl
acting as base to partially deprotonate intermediate VII-2HCl,
producing a further 0.5 equiv of VII-1HCl. The concomitantly
formed C-2HCl associates to give polymeric chains and so
precipitates from the solution. In this step, the signals of VII-
deceptively simple reaction proceeds in a multistage cascading
fashion because of the action of alternating bases. The stepwise
nature of the reaction is clearly apparent by the formation of
colorless needles of 9-oxabispidine dihydrochloride
[OC6H10(NH)2(HCl)2, C-2HCl], within 1 day, which
redissolve to be replaced by the colorless precipitate of VII-
2HCl. The reaction is analogous to that of A with CH2Cl2,
which comes to a halt at the stage of the insoluble bispidine
dihydrochloride (A-2HCl).13 However, because the 9-oxabis-
pidine analogue C-2HCl is moderately soluble in CH2Cl2, this
Scheme 2. Generalized Stepwise Reaction of Bispidines with CH2Cl2 To Give 1,3-Adamantane Derivatives [for C, E = Oxygen]
D
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Table 1. Crystal Data for V·1/2py, C, C1, and C2
V·1/2py
C
C1
C2
internal identification 8721
8789
9221
8865
CCDC no.
empirical formula
color
1491344
1491345
C6H12N2O
colorless
128.18
1491346
1491347
C18H20N2O5S2·1/2C5H5N
colorless
C6H12Cl2N2OPt
colorless
C12H28N2O10Pt
colorless
555.45
fw (g mol−1
)
448.03
394.17
temp (K)
100(2)
100(2)
100(2)
100(2)
wavelength (Å)
cryst syst
space group
unit cell dimens
a (Å)
1.54178
0.71073
monoclinic
0.71073
0.71073
monoclinic
P21/n (No. 14)
orthorhombic
Pnma (No. 62)
triclinic
P21/c (No. 14)
P1 (No. 2)
̅
9.7890(6)
16.0478(10)
12.7315(8)
90.0
6.3990(17)
9.167(2)
11.334(3)
90.0
9.074(3)
9.0848(9)
11.483(3)
90.0
9.2354(19)
12.847(3)
17.067(4)
69.229(3)
89.034(3)
78.774(3)
1854.2(7)
4
b (Å)
c (Å)
α (deg)
β (deg)
96.1711(15)
90.0
95.314(5)
90.0
90.0
γ (deg)
90.0
V (Å3)
1988.4(2)
4
662.0(3)
4
946.6(4)
4
Z
V/Z (Å3)
497.1
165.5
236.7
463.6
calcd density
1.497
1.286
2.766
1.990
(Mg m−3
)
abs coeff (mm−1
)
2.766
0.090
15.341
7.619
F(000)
940
280
728
1088
cryst size (mm3)
0.49 × 0.29 × 0.16
4.449−67.640
0.42 × 0.29 × 0.04
2.863−33.727
0.11 × 0.06 × 0.05
2.859−35.984
0.39 × 0.27 × 0.11
2.522−28.280
θ range for data
collecn (deg)
index ranges
−11 ≤ h ≤ 11, −19 ≤ k ≤ 19,
−15 ≤ l ≤ 15
−9 ≤ h ≤ 9, −14 ≤ k ≤ 13,
−17 ≤ l ≤ 17
−14 ≤ h ≤ 14, −15 ≤ k ≤ 15,
−18 ≤ l ≤ 18
−12 ≤ h ≤ 12, −17 ≤ k ≤ 17,
−22 ≤ l ≤ 22
no. of rflns collected
no. of indep rflns
87888
21667
31678
44173
3574 (Rint = 0.0368)
2645 (Rint = 0.0907)
2288 (Rint = 0.0259)
9197 (Rint = 0.0492)
no. of rflns with I >
2σ(I)
3561
1938
2275
8384
completeness (%)
abs corrn
99.3 (θ = 67.679°)
Gaussian
100.0 (θ = 25.242°)
Gaussian
93.9 (θ = 25.242°)
Gaussian
99.9 (θ = 25.242°)
Gaussian
max/min transmn
0.72113/0.35454
F2
0.99599/0.96575
F2
0.52144/0.22697
F2
0.42254/0.13855
F2
full-matrix least
squares
no. of data/restraints/ 3574/0/271
param
2645/0/90
1.175
2288/0/70
1.178
9197/12/539
1.028
GOF on F2
1.059
final R indices [I >
2σ(I)]
R1
0.0285
0.0744
0.0780
0.2146
0.0127
0.0309
0.0227
0.0549
wR2
R indices (all data)
R1
0.0286
0.0745
0.1098
0.0128
0.0261
wR2
0.2276
0.0309
0.0568
largest diff peak/hole 0.296/−0.455
0.621/−0.385
1.563/−1.231
1.696/−2.341
(e Å−3
)
1HCl increase in their relative intensity with retained chemical
shifts and the signals of C-1HCl largely disappear from the
spectrum. In the last step (d), solid C-2HCl redissolves to
similarly react with CH2Cl2, and all of VII-1HCl acts as a base,
affording the complete formation of VII-2HCl. During this
step, the NMR signals of VII-1HCl/VII-2HCl shift further to
lower field until the spectrum of VII-2HCl is reached. Thus, in
steps a−c, VII-2HCl is a transient intermediate but eventually
reappears as the product in step d. Four different bases come
into action and are consumed in the various steps.
intermediate V persistently contained pyridine. In order to
clarify the nature of the compound, we carried out an X-ray
structure analysis. Details of the structure analysis are given in
Table 1, and a drawing of the compound is shown in Figure 1.
3,7-Bis(phenylsulfonyl)-9-oxabispidine crystallizes from pyr-
idine in the monoclinic crystal system, space group P21/n (No.
14), together with half a pyridine molecule, hence V·1/2py.
There are four identical asymmetric 3,7-bis(phenylsulfonyl)-9-
oxabispidines (V) and two pyridine molecules in the unit cell.
The two pyridine molecules reside on inversion centers located
at b/2 and the center of the ac plane. Owing to the positions of
the solute pyridine molecules about inversion centers, the
C r y s t a l a n d M o l e c u l a r S t r u c t u r e o f
OC6H10(NSO2Ph)2·1/2py (V·1/2py). The isolated crystalline
E
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Figure 2. Molecular structure of C in the crystal, showing two
consecutive molecules of opposite environmental chirality in a chain
and the intramolecular and intermolecular hydrogen-bonding
interactions. Selected distances (Å) and angles (deg): N1−H1 =
0.88(4), N2···H1 = 2.28(4), N2−H2 = 0.88(4), N1···H2* = 2.19(4),
N1···N2 = 2.88(4), N1···N2* (intermolecular) = 3.055(3), C2···C5 =
2.344(3); C2−O1−C5 = 109.0(2), N1−H1···N2 = 125(2), N2−H2···
N1* = 169(2).
Figure 1. Molecular structure of V·1/2py (pyridine molecules and H
atoms are omitted). Shown are two identical molecules of V, related by
an inversion center. Selected bond distances (Å), nonbonding
distances (Å), and bond angle (deg): O1−C2 = 1.4319(2), O1−C5
= 1.4352(2), C2···C5 = 2.336(2), N1···N2 = 2.968(2), O1···O1* =
3.423(2); C2−O1−C5 = 109.1(1).
Å]. Within the morpholine rings in C, the C−O bonds at 1.44
Å (mean) are much shorter than their geometric C−C bond
equivalent (1.53 Å, mean) in A and are even shorter than N−C
(1.47 Å, mean). As a consequence of the oxygen tie, the
(nonbonding) C2···C5 distance reflecting the “thickness” of the
molecule is reduced to 2.344(3) Å in C [from 2.462(2) Å in A
and 2.435(3) Å in D] and is now distinctly shorter than the
C1···C6 and C3···C4 distances at 2.41 Å (mean). This results in
a “squeezed” and concave geometry of the C skeleton, together
with a widened N1···N2 bite.
The C2−O1−C5 [109.0(2)°] and C−N−C [110.2(4)°,
mean] angles in C are closer to the tetrahedral ideal than the
corresponding angles in A (C2−C7−C5 107.4° and C−N−C
112.0°, mean). While the chair conformation of the morpholine
ring involving N2 is close to what is expected (dihedral angles
55−63°), that of the ring involving N1 is flattened at N1
(dihedral angles 47−64°), which appears to result from the
intramolecular N1−H1···N2 hydrogen bridge, similar to the
situation in A.
In the crystal, the asymmetric molecules are head−tail
associated with alternating chirality, albeit weakly manifested,
and arranged to both sides of a glide plane (parallel to ac),
forming chains that extend along the c axis. Association is given
by intermolecular N2−H2···N1* hydrogen bonds [H2···N1*
2.19(4) Å and N2−H2···N1* 169(2)°]. The short intermo-
lecular N2···N1* distance at 3.055(3) Å [A, 3.114(2) Å; D,
3.192(2) Å] suggests relatively strong hydrogen bonding,
indicating an increased acidity of the NH protons. Interestingly,
the ethereal O1 is not involved in any N−H···O bonding,
which appears to be in agreement with the concept of Etter22
that in complex systems the strongest hydrogen-bond donor
(NH) will interact with the strongest base, viz., the secondary
amine.
Such chains are piled up along the b axis, forming pads
extending parallel to the bc plane. Neighboring chains run in
the opposite direction. Molecules that are “atop” one another
are related by a 2-fold screw axis parallel to b, and these
molecules interact by a hydrogen-bonding interaction, N2C4−
H4B···O1* 2.61(4) Å [145(2)°], involving one NCHeq proton
(out of four) and the ethereal O atom of the adjacent chain.
These C−H···O bonds appear slightly shorter than the sum of
the Bondi van der Waals (vdW) radii of H (1.20 Å)23a and O
(1.52 Å).23
isoelectronic N3 and the C20H20 entities of the pyridine
molecules are disordered in a 1:1 ratio.
Both morpholine rings of the C skeleton adopt a slightly
flattened chair conformation, resulting in a relatively large
intramolecular N1···N2 distance of 2.968(2) Å. The two PhSO2
substituents at N1 and N2 formally occupy equatorial (exo)
positions in the six-membered oxa rings, which leaves the
electron pairs in axial (endo) positions, pointing toward one
another. Because the orientation of the phenyl substituents is
antiperiplanar to the N lone pairs, as is typical for this structural
entity,20 the molecules assume a W-shaped conformation of
which the three top tips are given by the central O1 bridge and
p-CH of the flanking phenyl rings, whereas the two bottom tips
can be represented by S1O2O3 and S2O3O4.
Around the center and origin (viz. corners) of the unit cell,
each two nonsymmetric molecules form an inversion-related
racemic pair by mutual alignment of the W top tips [the
intermolecular O1···O1* distance is 3.423(2) Å]. Such pairs are
related to one another by the four 2-fold screw axes parallel to
b; the same holds for the pyridine molecules at different
positions. Because there is no π−π stacking in the structure, the
pyridine molecules appear to fill the voids in the lattice of V.
Crystal and Molecular Structure of 9-Oxabispidine
(C). Single crystals of C were obtained by sublimation. C
crystallizes in the monoclinic space group P21/c (No. 14),
different from that of the parent bispidine A (Figure 2).13,21 We
will show later that 9,9-difluorbispidine (D)16 crystallizes in the
same space group as that for C. The unit cell of C contains four
equivalent asymmetric molecules, which pairwise belong to two
chains created by N−H···N hydrogen bonding. The NH H
atoms were located on a difference Fourier synthesis and
refined with the isotropic atomic displacement parameter;
nevertheless, the relatively high R indices of the structure
solution indicate that the positions of the H atoms should be
treated with caution and are therefore not discussed in detail.
Similar to the situation in A, C exhibits a chair−chair
conformation of the two morpholine rings, with the N1−H1
proton in an endo orientation and the N2−H2 proton in an
exo orientation with respect to the core of the molecule. N1−
H1 forms an intramolecular hydrogen bond, N1−H1···N2, with
a (nonbonding) N1···N2 distance of 2.875(3) Å, which is
slightly longer than those in A [2.849(2) Å] and D [2.830(2)
F
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There is a discernible decrease in the molecular volume upon
going from parent bispidine A (180.2 Å3 at 200 K) to C (165.5
Å3 at 100 K; ΔVm = −14.7 Å3), which exceeds that calculated
(ΔVcalc = −12.64 Å3) for the replacement of CH2 by O based
on the Hofmann atom volume increments [V(C) = 13.87 Å3,
V(H) = 5.08 Å3, and V(O) = 11.39 Å3],24 thus indicating an
overall tighter packing of the molecules in C.
Synthesis of the (9-Oxabispidine)platinum Com-
plexes C1−C3. The synthesis of the (9-oxabispidine)platinum
complexes largely followed that of the parent bispidine
complexes A1−A3.14 Thus, (1,5-hexadiene)platinum dichlor-
ide25 was reacted with 1 equiv of C in DMF at 65 °C to afford a
yellow precipitate of {OC6H10(NH)2}PtCl2 (C1; Scheme 3).
Displacement reactions at platinum(II) by DMSO have been
studied before.14,15,26,27 The mutual Cl−/DMSO replacement
reactions of eq 5 are slow, as evidenced by the sharp NMR
signals for C1 and C1-DMSO. In contrast, exchange of the
DMSO ligand in C1-DMSO with the solvent appears to be fast
1
because no separate H and 13C NMR signals were found for
the coordinated DMSO. The presence of the cation
[{OC6H10(NH)2}PtCl(DMSO)]+ (m/e 436) was verified by
ESI MS. No dication [{OC6H10(NH)2}Pt(DMSO)2]2+ was
detected by either NMR or ESI MS. DMSO solutions of C1
can be diluted with water.
Scheme 3
Unlike C1, the cbdca derivative C2 is quite soluble in water,
from which it forms the pentahydrate. After removal of water
under vacuum, the complex still dissolves in DMSO and DMF
but not in acetone or THF. The relatively high solubility of C2
can be attributed to its “nutshell” structure, which appears to
impede association with neighboring molecules by strong
hydrogen bonds.
The clearly more planar oxalate C3 is again virtually insoluble
in all solvents including DMSO and DMF, also when heated.
Thus far, we have been unable to obtain crystals suitable for X-
ray structure analysis. Taking into account various forms of N−
H···O bonding, we assume that C3 adopts a polymeric planar
chain structure like A314 or a planar 2D network structure
similar to that of C1. The addition of oxalic acid to a
suspension of C3 in water appears to increase its solubility.
All of the platinum complexes are odorless, despite the
intense odor of the free C. The complexes (C2 after
dehydration) are thermally extraordinarily stable up to about
320 °C, and no change in the appearance was noticed. No
thermal effect was detected by DSC below this temperature.
The [M + Na]+ ions were observed in the ESI MS spectra of
solutions of the complexes in MeOH, recorded in a positive
operation mode.
IR Spectra of C, C-d2, and C1−C3. The IR spectra of the
compounds are included in the SI (Figures S12−S16). The
spectra of C and C-d2 may be compared with the spectra of the
other isolated N-unsubstituted bispidines A13 and D,16 and the
spectra of C1−C3 to those of A1−A3,14 B1−B3,15 and D1−
D3.16 The extraordinary hygroscopy of A and C may have
resulted in incidental uptake of some moisture during recording
of the spectra. Some residual water is also contained in the
pentahydrate C2 after drying under vacuum. The spectra of the
malonate C2 and oxalate C3 are dominated by very strong
bands due to carbonyl stretching (1700−1600 cm−1) and ν(C−
O/C−C) coupling vibrations (1400−1300 cm−1). The assign-
ment of the IR bands was made by a comparison with the
literature values.28
The isolated C1 was then further reacted with Ag2(cbdca) in
water to obtain, after removal of AgCl, an aqueous solution of
{OC6H10(NH)2}Pt{(O2C)2C4H6}·5H2O (C2), which was
isolated after concentration. Complex C2 crystallizes from
water as a pentahydrate but largely loses the water under
vacuum. The reaction of C1 with sodium oxalate in water
afforded {OC6H10(NH)2}Pt(C2O4) (C3) as an off-white
precipitate.
The dichloride C1 is practically insoluble in DMF (from
which it is obtained during the synthesis) and dissolves only
scarcely in water, even when heated. We will show below that
the molecules of C1 form a planar 2D network in the crystal by
intermolecular N1−H1···O1 and N2−H2···Cl2 hydrogen
bonding, and these bonds are apparently not readily cleaved
by water. When forced to dissolve in hot water (D2O), a series
of species is formed according to NMR, which suggests partial
or full hydrolysis, as depicted in eq 4.
While A and D exhibit relatively small ν(NH) vibrational
humps in the 3320−3260 cm−1 region, C features a prominent
ν(NH) band at 3213 cm−1. For C-d2, this band is shifted to the
2400 cm−1 region and is multifold split. Because C and the 9,9-
difluorinated D are exempt from containing bridging 9-CH2
and because ν(CtertH) is usually weak, the bands at 2916 and
2820 cm−1 can be safely attributed to νas(CH2) and νs(CH2) of
NCH2. The weak bands at 2800−2700 cm−1 can be considered
Compound C1 dissolves slowly in DMSO (DMSO-d6) at
ambient temperature, but dissolution may be spurred on by
sonication. In the 1H and 13C NMR spectra (see below) of such
a solution, in addition to the signals of the C2v-symmetrical C1
(33%), the signals of the ionic C1-DMSO (67%) of lower
symmetry are observed, demonstrating displacement of one
chloride by DMSO in an equilibrium reaction (eq 5).
G
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to be ν(NCHax) Bohlmann bands.29 A series of bands at 1500−
1200 cm−1 are attributed to δ(CH2) and δ(CH) bending
vibrations. All CH ν and δ bands remain unaltered for C-d2.
Most bands of C in the 1200−450 cm−1 region are shifted to
lower wavelengths for C-d2 and gain sharpness, suggesting the
occurrence of NH (respectively ND)-coupled vibrations. Upon
going from C to C1−C3, the ν(NH) bands are shifted to
3200−3100 cm−1. No Bohlmann bands ν(NCHax) ≤ 2850
cm−1 are visible because the lone electron pairs at N, now
binding to PtII, are no longer free. For C and C1−C3, we find
sharp bands of medium intensity at 1160−1100 cm−1 assigned
to νas(C−O−C) and a further sharp band at 980−960 cm−1
assigned to νs(C−O−C) of the oxygen bridge. While the
uncoordinated C exhibits a very strong broad band at 880−780
cm−1 (centered at 828 cm−1), C1−C3 agree in a very strong
sharp band at 860 cm−1. These bands appear unique and
characteristic for the C-derived compounds, and we attribute
them to δas(C−O−C) bending of the C skeleton. While the
skeleton of the uncoordinated C still exhibits slight flexibility,
which includes chair−boat conformational changes and entails
lower-energy vibrations and a broader distribution profile, the
adamantane-type structures of complexes C1−C3 are fully
rigid, accounting for higher energy and sharper νas/s(C−O−C)
vibrations.
amino groups and is thus of lower symmetry (Cs). For the ionic
C1-DMSO, the two NH signals at δ(H) 7.39 and 6.30 flank
that of C1 with very similar intensity. There are two sets of
signals for NCHeqHax and N′CHeqHax well separated from
another and for which Hax occurs at higher field than Heq. In
the 13C NMR spectrum of C1-DMSO, three signals of equal
intensity are found for CH, NC, and N′C. The assignments of
the 1H signals of C1 and C1-DMSO were verified by H,H- and
C,H-correlated NMR (Figures S8 and S9).
Crystal and Molecular Structure of {OC6H10(NH)2}PtCl2
(C1). A summary of the crystal structure determination of C1 is
included in Table 1, and representations of the structure are
shown in Figure 3. The compound crystallizes in the
NMR Spectra of C1 and C2. Because of the low solubility,
1H and 13C NMR spectra were recorded only for solutions of
C1 in DMSO-d6 and C2 in DMSO-d6 and D2O. We describe
first the spectra of C2.
The 13C NMR spectra of C2 in DMSO-d6 and D2O are
1
inconspicuous and feature six singlets. The H NMR spectrum
of C2 in DMSO-d6 is somewhat broadened. The NH signal at
δ(H) 7.48 is flanked in the 300 MHz spectrum by a pair of
humps, but these vanish at 600 MHz (Figure S10) and thus
appear to be due to the 14N quadrupole. Compared to
uncoordinated C (solvent of THF-d8), all C signals are shifted
to lower field, and the order of the NCHeqHax signals is
reversed so that the NCHax signal is now at higher field. The 1H
NMR spectrum of C2 in D2O is much better resolved (Figure
S11), although here no NH signal is found, owing to H/D
exchange. The other C signals are shifted to still lower field.
2
The signal of NCHeq is a doublet [δ(H) 3.51; J(HH) = 13.1
Hz] because of the geminal coupling and small vicinal coupling
[3J(HH) ≤ 2 Hz] ensuing from the large torsional angle with
OCH (63.0°, mean; see the X-ray structure). The higher field
signal for NCHax [δ(H) 3.37; 2J(HH) = 13.1 Hz; 3J(HH) = 3.5
Hz] shows additional fine splitting by coupling with OCH, in
agreement with the small torsional angle (55.5°, mean). The
bridgehead OCH signal [δ(H) 4.35] is a broad triplet, resulting
from the coupling with NCHeqHax and “w” coupling to its
Figure 3. Crystal and molecular structure of C1: (a) drawing of the
structure of the molecule; (b) view along the b axis, showing the 2D
network of molecules in a plane parallel to ac. Selected bond distances
(Å), nonbonding distances (Å), and bond angles (deg): Pt1−N1 =
2.029(2), Pt1−N2 = 2.032(2), Pt1−Cl1 = 2.3115(9), Pt1−Cl2 =
2.3107(7), C2−O1 = 1.440(2), C1−N1 = 1.490(2), C3−N2 =
1.490(2), N1···N2 = 2.779(2), C2···C2* = 2.357(2), C1···C1* =
2.433(2), C3···C3* = 2.421(2), C1···C3 = 2.579(2); C2−O1−C2* =
109.8(2), N1−Pt1−N2 = 86.36(7), Cl1−Pt1−Cl2 = 94.92(2).
1
sibling proton. The H signals of the cbdca ligand are the
typical triplet (δ 2.87) and quintet (δ 1.90); however, these
become overlaid over time by other multiplets, which appear to
follow from the slow H/D exchange of the cyclobutane ring
with the solvent. The assignments have been confirmed by
C,H-correlated NMR.
orthorhombic crystal system, space group Pnma (No. 62),
with four identical molecules in the unit cell. The space group
of solid C1 is different from that of the homologues
{C7H12(NH)2}PtCl2 (A1)14 and {F2C7H10(NH)2}PtCl2 (D1)
[both P21/n (No. 14)]16 and {(HO)2C7H10(NH)2}PtCl2 [B1;
C2/c (No. 15)].15
The Pt−N bond lengths in C1 are 2.029(2) and 2.032(2) Å
and thus lie within the typical range for (bispidene)platinum-
(II) complexes (2.02−2.04 Å); the same holds for the Pt−Cl
bonds at 2.311(2) Å (mean). Upon coordination of C to PtCl2,
the N···N distance reduces from 2.875(3) Å (C) to 2.779(2) Å
The 1H and 13C NMR spectra of a solution of C1 in DMSO-
d6 (Figures S6 and S7) revealed the presence of two
components in a 1:2 ratio (eq 5). The minor component is
considered to be the neutral and C2v-symmetrical C1. While its
NH signal is at δ(H) 6.90, all other C signals of C1, including
the 13C signals, concur with those of C2. The signals of the
major component are attributed to the ionic [{OC6H10(NH)2}-
PtCl(S(O)Me2)]Cl (C1-DMSO), which displays inequivalent
H
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in C1, which marks the upper limit of the range of distances
(2.76−2.78 Å)14 for complexes of this kind. Accordingly, the
N−Pt−N angle opens to 86.4(1)° (from 85.3 to 85.8° in A1,
B2, and D2). Coordination of C at PtCl2 goes along with slight
widening of the C2···C5 distance from 2.344(3) Å in C to
2.357(2) Å in C1 (here C2···C2*), but this distance,
nevertheless, remains markedly shorter than that for (9-C-
bispidine)platinum(II) complexes (2.46−2.47 Å). Thus, all in
all, the C ligand in C1 appears quite contracted compared to
the other bispidines.
In the crystal of C1, molecules reside on crystallographic
mirror planes that pass through the atom O1, both NH groups,
the Pt atom, and the two chloride ligands. Neighboring
molecules in each plane are related by two 2-fold screw axes
along a and the glide planes parallel to ab. The molecules are
hydrogen-bonded to their neighbors to one side by N−H···Cl
hydrogen bonds {N2−H2···Cl2 = 2.60(4) Å [137(2)°; N2···
Cl2 = 3.239(2) Å]} and to the other side by N−H···O
hydrogen bonds {N1−H1···O1 = 2.21(4) Å [145(2)°; N1···O1
= 2.847(2) Å]}. In this way, strictly planar 2D networks are
formed (Figure 3b).
Contiguous planes are stacked along b at a distance of b/2 =
4.5424 Å to one another. The molecules are related to their
closest neighbors in the adjacent planes by 2 × 2 screw axes
along b. There appears to be only a weak vdW interaction
between the molecules in different planes, probably supported
by additional N2C3−H3B···Cl1 = 2.67(4) Å [148(2)°; C3···
Cl1 = 3.550(2) Å] hydrogen-bonding interactions involving the
chloride Cl1, which is not taking part in the planar networks.
According to the structural data, the molecular volume of C1
is V/Z = Vm = 236.7 Å3, which is distinctly less than that of
parent A1 at Vm = 252.2 Å (ΔVm = −15.5 Å3).14 The reduction
of the volume reflects roughly the difference in the molecular
volumes of the uncoordinated bispidines A (Vm = 180.2 Å3)13
and C (Vm = 165.5 Å3; ΔVm = −14.7 Å3).
Figure 4. Crystal and molecular structure of C2: (a) drawing of the
structure of molecule 1; (b) packing of the molecules in the crystal.
Selected bond distances (Å), nonbonding distances (Å), and bond
angles (deg); molecule 1, Pt1−N1 = 2.025(2), Pt1−N2 = 2.026(2),
Pt1−O1 = 2.036(2), Pt1−O2 = 2.017(2), N1···N2 = 2.788(3), C2···
C5 2.351(4), N1−Pt1−N2 = 87.0(1), O1−Pt1−O2 = 90.4(1);
molecule 2, Pt2−N3 = 2.019(2), Pt2−N4 = 2.024(3), Pt2−O5 =
2.027(2), Pt2−O6 = 2.025(2), N3···N4 = 2.790(3), C15···C18
2.360(4), N3−Pt2−N4 = 87.3(1), O5−Pt2−O6 = 89.3(1).
derivatives. (ii) The C−O20/21 bonds of C2 [1.444(2) Å,
mean] are shorter than the respective C−C bonds in A2
[1.532(2) Å, mean] and D2 [1.517(5) Å, mean], involving the
bridging atom of the bispidine ligands. This leads to
compression of the ligand, as is evident from the shorter
intramolecular distances between the bridgehead atoms C2···
C5 = 2.351(4) Å and C15···C18 = 2.360(4) Å, as has also been
found for the dichloride C1 [2.357(2) Å]. (iii) As is evident
from the larger nonbonding N···N distances at 2.789(3) Å
(mean) and the larger N−Pt−N angles at 87.1(2)°, the “bite”
of the C ligand in C2 is still further increased compared to
those of C1 [2.779(2) Å and 86.4(1)°] and the parent A2
[2.77(1) Å and 86.4(3)°]. (iv) As a consequence of 9-O, the
volume of the formula unit (V/Z) of C2 at 463.6 Å3 is lower
than that of A2 (471.0 Å3),14 but the difference (ΔV = −7.4 Å3)
is less than that expected from the Hofmann atom volume
increments (ΔVcalc = −12.64 Å3; see C), so the hydrate shell
appears to cancel out part of the effect of replacement of the
groups at 9-C.
Crystal and Molecular Structure of {OC6H10(NH)2}Pt-
{C4H6(CO2)2}·5H2O (C2). The crystal structure of the (9-
oxabispidine)platinum complex C2 [Table 1; triclinic crystal
system, space group P1 (No. 2)] is isomorphous to those of the
̅
parent bispidine {C7H12(NH)2}Pt{C4H6(CO2)2}·5H2O (A2;
compound 2b in ref 14), and 9,9-difluorobispidine
{F2C7H10(NH)2}Pt{C4H6(CO2)2}·5H2O (D2),16, whereas the
corresponding 9,9-diol {(HO)2C7H10(NH)2}Pt{C4H6(CO2)2}·
2H2O [B2; tetragonal, P4/n (No. 85)] differs in the hydrate
content. There are two independent platinum complexes and
10 water molecules in the asymmetric unit of C2, so the unit
cell (Z = 2) contains a total of four platinum complexes and 20
water molecules (Figure 4). The packing of the molecules in
the crystal is essentially based on hydrogen bonding between
the complex molecules and water and is determined by the
eight inversion centers of the space group. Each platinum
complex is completely surrounded by a shell of water
molecules, and there are no direct bonds between neighboring
platinum complexes. The easy hydration of the Pt(cbdca)
complexes may be due to their strongly curved structure, which
impedes crystallization without the incorporation of solute
molecules. The structure and packing have been described in
detail for A2.14
3. CONCLUSIONS
Continuing our ongoing study of the (bispidine)platinum(II)
analogues of cisplatin, carboplatin, and oxaliplatin, we have
revisited the literature synthesis of C and prepared and
investigated a series of new platinum(II) complexes containing
C as the carrier ligand. Essential findings from this study are as
follows:
While the structure of C2 is very similar to that of A2 and
D2, in particular with respect to hydrogen bonding, some
features are noteworthy. (i) The ethereal O atom of the C
ligand in C2 is not involved in any hydrogen bonding, thus
illustrating the structural similarity with the other 9-substituted
(i) The literature synthesis of C has been improved. Pure C
can now be prepared efficiently on a gram scale. C has been
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2
3
Hz, 4H, NCHaxHeq), 3.37 (dd, J(HH) = 13.2 Hz, J(HH) = 3.5 Hz,
4H, NCHaxHeq), oxabispidine; 2.87 (t, 3J(HH) = 8 Hz, 4H, CH2), 1.90
characterized in detail, including the determination of its X-ray
crystal structure.
(ii) The 9-oxabispidine complexes C1−C3 have been
synthesized. Both C1 and C2 have been characterized by
crystal structure analysis. While the dichloride C1 is only
sparingly soluble in water and the oxalate C3 is practically
insoluble, the pentahydrate C2 dissolves well.
(iii) An important feature of C and its complexes is the
reduced size of C (uncoordinated or as a ligand) compared to
the usual bispidines because of the short C−O bonds. The
intramolecular distance between the tertiary C atoms and the
molecular volume Vm determined from structural data allow the
bulk of C to be assessed.
(iv) The introduction of the ether group into the bridging
position of bispidine causes an increase of the acidity of the NH
protons, which strengthens the N−H···X (X = N, Cl, O) bridge
bonds in the solid. The strengthening of these bonds appears to
contribute to reduced solubility, in particular of C1 and C3, in
all solvents, including water.
(v) Although the ethereal 9-O atom of C is a base and
possible hydrogen-bond acceptor for NH, it is only partially
involved in the packing of the molecules in the crystals, either
uncoordinated (C) or as a ligand (in C2). The most notable
interaction is in the 2D network structure of C1.
(vi) We found that the (9-oxabispidine)platinum complexes
C1−C3 express markedly lower cytotoxic potency to the
ovarian cancer cell line A2780 than the parental bispidine
complexes A1−A3.30 This feature is attributed to an increased
polarity of the bonds in the C skeleton caused by the high
electronegativity of O, which appears to decrease the
lipophilicity of the compounds.
(quint, J(HH) = 8 Hz, 2H, CH2), cbdca. 13C NMR (D2O): δ 65.4
3
(2C, CH), 51.9 (4C, NCH2), oxabispidine; 181.8 (2C, CO2), 56.2
(1C, Cquat), 31.0 (2C, CH2), 15.3 (1C, CH2), cbdca. Anal. Calcd for
C12H18N2O5Pt·H2O (483.4): C, 29.82; H, 4.17; N, 5.80; O, 19.86; Pt,
40.36. Found: C, 29.38; H, 4.14; N, 5.88; Pt, 41.03.
(9-Oxabispidine)platinum(II) Oxalate (C3). Na2C2O4 (145 mg,
1.08 mmol) was added to a light-yellow suspension of C1 (394 mg,
1.00 mmol) in 100 mL of H2O. The mixture was stirred at 40 °C
overnight, whereupon the color faded. The nearly white solid was
isolated by filtration, washed with water, and dried under vacuum:
yield 275 mg (67%). Recrystallization from hot water (70 °C) afforded
off-white microcrystals of C3, however with a marked loss of material.
ESI+ MS (MeOH): m/e 434 ([M + Na]+, 100%) (high background
noise due to low solubility). Anal. Calcd for C8H12N2O5Pt (411.3): C,
23.36; H, 2.94; N, 6.81; Pt, 47.43. Found: C, 23.40; H, 2.96; N, 6.78;
Pt, 47.41. No NMR spectra were recorded owing to insolubility.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.inorg-
chem.6b01690.
■
S
Protocols for the synthesis of I−VI, including the NMR
characterization of cis-III and trans-III and the X-ray
structure analysis of trans-III, IR spectra of all new
compounds, and NMR spectra of C1 and C2 (PDF)
X-ray crystallographic data in CIF format for V·1/2py
(CCDC 1491344), C (CCDC 1491345), C1 (CCDC
1491346), C2 (CCDC 1491347), and trans-III (CCDC
1491348) (CIF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: poerschke@kofo.mpg.de.
Author Contributions
4. EXPERIMENTAL SECTION
■
The reactions were performed with Schlenk-type glassware under
argon. (1,5-Hexadiene)platinum dichloride25 was prepared according
to the literature. A revised protocol for the synthesis of 9-oxabispidine
(C, C6H12N2O, fw 128.2) is included in the SI.
All authors contributed to the writing of this manuscript.
(9-Oxabispidine)platinum(II) Dichloride (C1). A solution of C
(0.555 g, 4.33 mmol) in 100 mL of DMF was added to (1,5-
hexadiene)platinum dichloride (1.66 g, 4.77 mmol), and the mixture
was heated to 65 °C overnight. The solution adopted a light-green
color, and a greenish-yellow solid precipitated: yield 1.17 g (2.97
mmol, 69%). ESI+ MS (MeOH): m/e 416 ([M + Na]+, 100%), 809
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Angelika Dreier and Alexander Zwerschke for
technical assistance, Dr. Christophe Fares
and Dr. Alexandra Hamacher and Professor Mathias U. Kassack
■
1
([2M + Na]+, 45%). H NMR (DMSO-d6, 600 MHz): δ 6.90 (s, 2H,
̀
for NMR support,
NH), 4.09 (“s”, 2H, CH), 3.27 (d, 4H, NCHaxHeq), 3.07 (m, 4H,
NCHaxHeq). 13C NMR (DMSO-d6): δ 64.2 (2C, CH), 51.1 (4C,
NCH2). Anal. Calcd for C6H12Cl2N2OPt (394.2): C, 18.28; H, 3.07;
Cl, 17.99; N, 7.11; O, 4.06; Pt, 49.49. Found: C, 18.31; H, 3.04; Cl,
17.95; N, 7.07; Pt, 49.47.
from the University of Dusseldorf for the cell studies. General
̈
funding by the Max Planck Society is gratefully acknowledged.
1
[{OC6H10(NH)2}PtCl(DMSO)]Cl (C1-DMSO). H NMR (DMSO-
REFERENCES
■
d6, 600 MHz): δ 7.39, 6.30 (each s, 1H, NH), 4.23 (“s”, 2H, CH), 3.48
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