Synthesis of chiral β-aminoalcohol palladium complexes exhibiting cytotoxic properties

Article abstract of DOI:10.1039/c0dt00328j

Original palladium complexes involving (-)-ephedrine, (-)-norephedrine, L-prolinol, L-valinol and L-isoleucinol have been rapidly prepared in neutral or basic medium and simply purified. They have been fully characterized by classical analytical methods a

Full text of DOI:10.1039/c0dt00328j

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www.rsc.org/dalton | Dalton Transactions
Synthesis of chiral b-aminoalcohol palladium complexes exhibiting cytotoxic
properties†
Fabien Accadbled, Bernard Tinant, Eric H e´ non, Dani e` le Carrez, Alain Croisyc,d and Sandrine Bouquillon*a
a
b
a
c,d
Received 19th April 2010, Accepted 12th July 2010
DOI: 10.1039/c0dt00328j
Original palladium complexes involving (-)-ephedrine, (-)-norephedrine, L-prolinol, L-valinol and
L-isoleucinol have been rapidly prepared in neutral or basic medium and simply purified. They have
been fully characterized by classical analytical methods and four of them were characterized by X-Ray
analysis. In parallel with the experimental work, HF-DFT(B3LYP/PCM) computations were
performed to obtain additional structural information. Their antiproliferative properties have been
evaluated and some complexes showed small activities especially towards HT29 human cancer cells.
Introduction
the Pd-complexes similar to the Pt ones showed low cytotoxic
activity. In 1984, Gill et al. described some amine containing
24
Chiral aminoalcohols play an important role in modern chemistry,
in medicinal chemistry or as chiral ligands and auxiliaries in
Pd-complexes which showed similar activity compared to the
25
activity of cisplatin. Since then, many Pd-complexes containing
1
organic chemistry. Syntheses of 1,2 aminoalcohols and their
amines or amino acids revealed some interesting antitumor and
2,3
derivatives as chiral moieties have already been largely reported.
In medicinal chemistry, they revealed particular interests in
26
antiviral properties. In the course of our studies in Pd-catalyzed
27
enantioselective hydrogenation of enones, we described the
4
5
cardiovascular diseases, in intracellular mechanisms and also
as antidepressive agents.
Most applications in catalysis focused particularly on asym-
formation of palladium complexes involving (-)-ephedrine as
6
28
chiral aminoalcohol (Scheme 1). Since preliminary biological
evaluation of complexes 1b and 2 (see Table 3 later) was promising,
we decided to extend this study to other aminoalcohol ligands.
Herein, we report:
7
8
metric transfer hydrogenation of ketones associated to Zn, Ni,
9
10
11
12
13
Ru or Ir, B, and Rh salts or complexes. Some V or Ti
complexes were also used for asymmetric sulfoxidation or Streker
reactions. Recently, the implication of 1,3-aminoalcohols and their
derivatives associated to transition metals (Pd, Rh, Ti and Cu) in
(
a) the synthesis of new palladium complexes (PdCl
Pd(OAc) and PdL ),
b) the unusual behaviour in solution of Pd(OAc)
that exhibit different conformations in solution,
c) the evaluation of the cytotoxicity of these new palladium
complexes.
2
L
2
,
2
L
2
2
(
2
L complexes,
2
14
asymmetric organic synthesis was also reviewed.
In the field of materials, aminoalcoholates are good ligands for
(
15
metals such as Cd or Ta in LPCVD or MOCVD processes. As
16
many complexes of transition metals have been reported, a large
contribution of Cu, Sn or Pt ones is noticed in the field of biology
17
as DNA cleavers or cytotoxic agents.
In fact, since three decades, a considerable amount of interest
has been also devoted to the chemistry of Pd and Pt complexes,
mostly focusing on their structural diversities and activities.
Concerning antitumor agents, Pt chemistry has been largely
18
developed since the discovery of the cytotoxic activity of cisplatin
19
by Rosenberg in 1969. Most of the time, ligands associated to
20
Pt are amines, diamines or N-containing heterocycles and di-
or poly-nuclear complexes which revealed to be generally more
2
1
22a–c
22d
active. Other ligands such as thiosemicarbazones,
thiourea,
17
23
aminoalcohols or aminosugars are also employed.
In this field of application, palladium complexes have been
also developed but received less attention. Until the 1980s,
Scheme 1 Synthesis of Pd complexes with (-)-ephedrine.
a
Institut de Chimie Mol e´ culaire de Reims, CNRS UMR 6229, Universit e´ de
Reims Champagne-Ardenne, BP 1039, 51687, Reims Cedex, France
b
CSTR 1, Place Louis Pasteur, 1348, Louvain-la-Neuve, Belgique
c
INSERM U759, B aˆ timent 112, Centre Universitaire, 91405, Orsay, France
Results and discussion
d
Centre de Recherche de l¢Institut Curie, 91405, Orsay, France
†
7
CCDC reference numbers CCDC 767180 (3, PdCl
45869 (6, Pd(OAc) (valinol) ), 745867 (11, PdCl (prolinol)
). For crystallographic data in CIF or other electronic format
see DOI: 10.1039/c0dt00328j
2
(norephedrine)
2
),
Aminoalcohols with primary amine function were used to see the
influence of the substitution of the nitrogen atom on complexation
or biological properties.
2
2
2
2
), 745868 (13,
Pd(prolinato)
2
8
982 | Dalton Trans., 2010, 39, 8982–8993
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Scheme 2 Synthesis of Pd complexes with (-)-norephedrine (3, 4), L-valinol (5, 6, 9) and L-isoleucinol (7, 8, 10).
So, for the first time, the coordination of (-)-norephedrine to
palladium was performed in dichloromethane (Scheme 2) to yield
complexes 3 and 4. These complexes were isolated by precipitation
with diethylether with respectively a yield of 97% and 99%.
eluting mixture that decomposed the chelate structure. Other bases
(NaOH, Ag
reactions conditions (CH
2
CO
3
, Et
3
N, t-BuOK . . . ) instead of Cs
2
CO and other
3
◦
2
Cl
2
, 40 C) were employed referring to
28a
previous reported work but did not proceed in a clean cyclization
of the norephedrinate.
Slightly better yields were obtained from Pd(OAc)
2
precursor
compared to PdCl one that was already described with the
2
Next, referring to the antitumor properties of aminosugars, we
explored the coordination of the L-prolinol to palladium. In fact,
the L-prolinol was considered as a model for the aminosugars
we want to prepare in the future. As previously described,
the complexation of palladium with L-prolinol or L-prolinolate
ligands was conducted using similar conditions (Scheme 3).
General characteristics from IR or NMR spectroscopies help us
to propose such structures for all complexes (3–13) before having
X-Ray analyses of some suitable crystals of four of them (3, 6, 11
and 13).
coordination of (-)-ephedrine to the palladium. The reason we
could give is the better solubility in the reaction medium of the
palladium diacetate compared to the palladium chloride.
26
Next, in relation with the work of Srivastava on Pd complexes
involving amino acids, we chose some aminoalcohols derived from
natural amino acids such as the L-valinol and the L-isoleucinol.
Using similar complexation conditions, four PdX
2
L
2
complexes 5–
8
were obtained with good to high yields and here again, reactivity
with Pd(OAc) seems to be a little more proper (Scheme 2).
2
In order to have in hand bichelated complexes, we explored
the complexation reaction in basic medium (Scheme 2). Com-
plexes 9 and 10 were obtained with good yields using caesium
carbonate as the base in THF. However, with (-)-norephedrine as
ligand, we could not isolate a pure bichelate complex using the
same conditions. Purification of this complex was attempted by
chromatography over silica but the acidic and polar properties
In IR spectroscopy, concerning the complexation of Pd salts as
-
1
PdCl
2
or Pd(OAc)
2
, we always observed a band between 1100 cm
-
1
and 1120 cm . More precisely, a strong band appeared between
1109 cm and 1115 cm for PdCl
and a weaker one between 1115 cm and 1121 cm for analogous
-
1
-1
2
L
2
complexes (3, 5, 7 and 11)
-
1
-1
Pd(OAc)
2
2
L complexes (4, 6, 8 and 12). These bands correspond
to the deformation of the C–O bond of the aminoalcohol. The
differences observed between the two classes of complexes in term
of this support led us to use MeOH associated to Et N as
3
Scheme 3 Synthesis of Pd complexes with L-prolinol and L-prolinolate ligands.
Dalton Trans., 2010, 39, 8982–8993 | 8983
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of absorption value and intensity are probably due to the nature
of the salt, the acetate group having a greater influence on the C–
O–H moiety through hydrogen bond than the chloride atom. For
PdCl
2
L complexes, two strong intensive bands are also observed
2
-
1
around 2930 and 2874 cm . A large band around 3300–3400
is also observed relative to the OH bond and masks the band
relative to the N–H stretching. In contrary, this one is generally
clearly observed for Pd-aminoalcoholate complexes around 3200–
300 cm- and another characteristic band at 1460 cm appeared
1
-1
3
and constitutes the principal differences for bichelate complexes
in IR spectroscopy.
We could also follow the complexation reaction through NMR
spectroscopy. If we consider a general formula for the aminoal-
cohols employed in our reaction (Fig. 1), the coordination of the
ligand can be established by chemical shifts of the protons or
1
Fig. 2 H NMR Spectra of 4 n at different temperatures (successively 27,
◦
4
5, 60 and 45 C in DMSO-d
6
).
1
13
carbons in position (a) and (b) in H NMR and C NMR.
Fig. 1 General formula of aminoalcohols.
For PdCl
2
L
2
or Pd(OAc)
2
2
L complexes, the chemical shifts of
the proton(s) in position (a) are strongly modified to higher values.
3
Furthermore, when R = H, the two protons on the nitrogen
1
3
atom became unequivalent. In C NMR, we observed shifts,
respectively to lower field for Ca (around 10 ppm) and higher
field for Cb (between 4 and 7 ppm).
For Pd-aminoalcoholate complexes, no difference is observed
1
3
compared to the free ligand. In C NMR, no general conclusions
can be made because, according to the aminoalcohol, carbons
shifts are randomly modified.
1
Fig. 3 H NMR Spectra of 4 at different concentration (1, 5, 10, 25, 50,
00 and 200 g L- in CDCl
1
from bottom to top).
1
3
But what is more interesting to observe is that NMR spectra
At least a cap of 130 molecules (50 g L-1 in chloroform) is needed
of Pd(OAc)
2
2
L with L as prolinol, valinol, isoleucinol and
to obtain a solvent layer of about two or three molecules around
the solute. This unambiguously shows that self-association driven
by strong electrostatic and hydrogen bonding forces and leading
to solute–solute interactions is very likely to occur at such high
norephedrine obtained at room temperature, revealed the presence
of a mixture of various products or forms corresponding to
the same MS and elemental analyses. So we first supposed the
formation in solution of several stable conformers differing only
by hindered internal rotation around the Pd–N or/and Pd–O
bonds (because the complex having acis configuration could not be
envisaged); this assumption was addressed by means of quantum
calculations (see below). To our knowledge, cis Pd-complexes
could be formed only with bidentate chelating ligands.
-1
concentrations. For a higher dilution (25 g L , 5–6 shells of
chloroform solvent), solute–solute clustering cannot be excluded.
Molecular calculations were then attempted especially on
complex 4 to determine the most stable conformers.
Molecular calculations
To confirm this hypothesis, we carried out NMR experiments
◦
on complex 4 at different temperatures (27, 45 and 60 C). As
Collaterally with the experimental work, a computational ap-
no differences were observed using CDCl
3
or CD
2
Cl
2
, we chose
proach helped us to examine the structure of complex 4.
29
DMSO-d as solvent. The spectra shown in Fig. 2 revealed a
6
Calculations were performed using the Gaussian 09 package.
The structure of similar palladium complexes has suitably been
coalescence phenomena but no coalescence temperature could be
28b
evaluated because of the formation of black palladium beyond
obtained in a previous study using the methodology HF-DFT
◦
30–33
6
0 C revealing the instability of the complex at this temperature.
with the B3LYP
hybrid functional. The same methodology was
Furthermore, spectra at different concentrations were per-
applied in the present study to the real system. The combination
of a relativistic effective core potential (ECP) with the appropriate
formed and revealed also an influence of the concentration on
the chemical shift (Fig. 3). With increasing molar fraction of
34–36
double-zeta valence basis, referred to as LANL2DZ,
was
-
1
the complex up to 1/65 (100 g L in chloroform), solute–solute
intermolecular interactions are expected in solution and can be
responsible for such an effect. To estimate the averaged size of the
solvation shell around the complex, a pre-equilibrated simulated
cap of 65 chloroform molecules was created around complex 4. As
a result, it appears that the first solvation shell is still incomplete.
employed for the Pd atom, while the all-electron valence double
37
zeta basis sets developed by Dunning (D95V ) were used for
the other atoms (basis set I). For the nitrogen and oxygen
atoms, a set of diffuse and polarization functions (D95V+(d))
was also added (basis set II). Actually, the extension of the basis
set with diffuse functions is recommended, especially for the
8
984 | Dalton Trans., 2010, 39, 8982–8993
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negatively charged species. The restricted approach was used. As
the molecule investigated is relatively large, it was not possible
to carry out ab initio methods such as MP2 for comparison.
38–40
Full PCM
geometry optimization calculations were performed
to account for the solvent effects on structures. Minima and
first-order saddle points were fully optimized in the field of
dimethyl sulfoxide (DMSO) using the standard dielectric constant
of DMSO implemented in the Gaussian 2009 program (e = 46.826).
Vibrational frequencies were determined within the harmonic
approximation, at the same level of theory (PCM). All transition
states were characterized by one imaginary frequency associated
with the desired reaction pathway.
Starting from a square-planar environment as commonly con-
sidered for Pd-complexes, the cis arrangement was first considered.
Two conformers were found differing in the orientation of the
amine substituent as depicted in Fig. 4.
Fig. 5 trans structures obtained at the B3LYP/basis set II/PCM level of
˚
theory; selected distances in A; non-polar hydrogen atoms are removed for
clarity.
Compared with the cis-structures, very similar deviations from
square-planar geometry are predicted for these trans-complexes.
Due to the presence of the acetate groups acting as hydrogen-
bond acceptors and of the amine and alcohol groups, all the
complexes feature intramolecular hydrogen bonding, the role
of which is discussed below. The trans structures have been
found to be energetically more stable than the cis isomers, which
agrees favourably with what was previously found for the Bis-
-
1 28b
[
(-)ephedrinate]-palladium(II) complex (DH0 K = 11 kcal mol
).
However, the cis/trans energy difference is predicted to be
considerably smaller here within the PCM model (DH0 K = 5–
-
1
28b
8
kcal mol ) than in our previous gas-phase study of bidentate
Fig. 4 cis structures obtained at the B3LYP/basis set II/PCM level of
theory; selected distances in A; non-polar hydrogen atoms are removed for
clarity.
ligands. From a methodological point of view, comparison with
the gas-phase results indicates that the non-specific interaction
of the solvent exerts a substantial effect lowering the cis/trans
isomerisation energy by 6 kcal mol . The addition of a set of
polarization and diffuse functions to nitrogen and oxygen atoms
leads to only minor changes in the structures and relative energies
of all complexes.
˚
-
1
˚
The Pd–O distances are larger (2.09 A) than the corresponding
ones previously predicted in the Bis-[(-)ephedrinate]-palladium(II)
˚
28b
complex (2.00 A). Instead, Pd–N distances are predicted to be
˚
smaller in the present norephedrine cis-complex (2.07–2.08 A)
than in the N,O-chelate cis-complex
2.15 A). Only small deviations from planarity are predicted (3 at
As further described, the NMR spectra of 4 have provided
28b
with ring constraints
evidence for the existence of several stable isomers (at least three)
◦
◦
˚
(
even at high temperature (up to 60 C in DMSO-d
6
). Our cis
the most) while the geometry around the metal centre is slightly
and trans structures generate chemical distinct environments for
the a and b positions (Fig. 1), what could explain the separated
signals observed experimentally. Two questions must however be
addressed. Are the predicted relative energies in line with the
observed intensity ratio? Is the interconversion (between these
structures) slow enough to see separate peaks rather than an
averaged peak on the NMR time scale? According to the energetic
◦
distorted square with O–Pd–O angles differing from 90 by 7–
◦
9
. Several structures were found for the trans isomer. Starting
from the geometry trans-a shown on Fig. 5, five supplementary
conformers were found by rotation either about the single Pd–O
(
structures trans-a,b,c) or about the Pd–N (structures trans-c,d,e)
bonds.
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Table 1 Isomers and conformers ZPE corrected relative energies and free
X-Ray analysis
-1
energies (given in kcal mol ); results obtained at the B3LYP/PCM level
of theory; basis set II is deduced from basis set I (LANL2DZ) with one
polarization function and one diffuse function added on N and O atoms
As shown on Fig. 7–10, in each complex, the Pd is coordinated in a
trans square planar configuration which is commonly observed for
similar complexes. The coordinated atoms are the N terminal of
41
H
0 K
G
298 K
H
0 K
G
298 K
-
the aminoalcohol in all the four complexes but with the CH COO
3
-
-
basis set I
basis set II
in 6, Cl in 3 and 11 and CH O in 13. The values of the
2
coordinating bond lengths are as expected and they are similar in
the four complexes . For compounds 3, 6, 11 and 13 respectively,
cis-syn
cis-anti
trans-a
trans-b
trans-c
trans-d
trans-e
trans-f
8.0
5.8
1.0
1.4
0.7
2.5
0.0
1.2
9.0
6.2
0.0
1.2
1.3
2.1
0.5
0.9
7.7
5.2
0.4
1.6
1.8
2.2
0.0
0.7
8.1
4.7
0.4
1.8
2.4
2.2
0.6
0.0
˚
˚
˚
the mean values for Pd–N are 2.046(2) A, 2.068(6) A, 2.051(3) A
˚
˚
˚
and 2.049(4) A, for Pd–O 2.019(5) A in 6, 2.020(3) A in 11, for
˚
Pd–Cl 2.300(1) A in both 3 and 11.
values in Table 1, the resulting Boltzmann distribution is such that
only trans structures are expected to have populations. Actually,
the trans isomers are predicted to be more stable than the cis
-
1
counterpart by at least 5 kcal mol . Hence, only the energetically
lower trans complexes have been considered. Then, a critical
element in assessing the rate of trans/trans conversion is the barrier
height between each species. Relaxed rotational energy profiles for
internal rotation around Pd–O and Pd–N were performed and
the resulting trans/trans transitions states display small barrier
heights, in the range 4–5 kcal mol . Thus, although these rotations
involve breaking intramolecular hydrogen bonds the trans/trans
exchange process is expected to be fast in the NMR time scale
43
Fig. 7 ORTEP view and atom labelling of 3. Displacement ellipsoids
are drawn at the 50% probability level. Hydrogen were omitted.
-
1
(
500 MHz NMR). As a result, proton signals of all trans complexes
are likely averaged.
However the question remains whether hydrogen bonding might
cause the observed signal separation since analogue complexes
with chloride and without acetate ligands exhibit only one peak.
An explicit solvent effect induced by intermolecular hydrogen
bonding or (and) interaction between metal and solvent molecule
might contribute to increase the barrier to ligand rotation. The
result of a preliminary calculation achieved at the B3LYP/Basis
set II level of theory (vacuum) is shown Fig. 6 and emphasizes
such explicit hydrogen bond interactions. Thus, a slow trans/trans
exchange process cannot be rigorously excluded. The inclusion of
micro-solvation in our PCM model system would be needed to
get better estimations of the activation energy properties, but is
computationally prohibitive.
43
Fig. 8 ORTEP view and atom labelling of 6. Displacement ellipsoids
are drawn at the 50% probability level.
The absolute configuration of the asymmetric C of the aminoal-
cohol in 3 and 6 is confirmed by the structure determinations.
In compound 3, only one Pd(Cl)
2
(norephedrine) complex in
2
the asymmetric part of the unit cell can be observed. The two
OH, two Cl and one of the two N are involved in a H-bonding
network parallel to the (a,b) plan explaining the high value of the
c parameter.
In compound 6, only one Pd(OAc)
2
(valinol) complex in the
2
asymmetric part of the unit cell can be observed. One intramolec-
ular H bond N1–H ◊ ◊ ◊ O4 is present. Five intermolecular H bonds
involving the hydroxyl, amino and carbonyl groups contribute to
the packing of the structure.
Fig. 6 B3LYP/basis set II (vacuum) trans structures microsolvated with
two DMSO molecules; non-polar hydrogen atoms are removed for clarity.
8
986 | Dalton Trans., 2010, 39, 8982–8993
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Table 2 Data collection and refinement parameters of compounds 3, 6, 11 and 13
3
6
11
13
Formula
Mr
C
479.71
18
H
26Cl
2
N
2
O
2
Pd
C
14
H
32
N
2
O
6
Pd
C
379.60
10
H
22Cl
2
N
2
O
2
Pd
17 37 3 4
C H N O4.,5Pd1,5Cl
656.90
430.82
Monoclinic
P2
7.873(3)
10.736(4)
11.073(4)
95.92(2)
930.9(6)
1.537
System
Space group
Orthorhombic
P212121
6.3630(2)
9.0651(2)
34.8315(9)
90
2009.12(9)
1.586
4
0.71073
100(2)
976
1.203
0.40 ¥ 0.10 ¥ 0.40
37.02
Orthorhombic
P212121
9.5874(2)
20.0334(3)
23.3478(4)
90
4484.4(1)
1.687
12
0.71073
293(2)
2304
1.592
0.40 ¥ 0.12 ¥ 0.10
27.9
Orthorhombic
C2221
15.444(5)
16.302(5)
20.352(7)
90
5124(3)
1.703
8
0.71069
120(2)
2664
1.511
0.50 ¥ 0.50 ¥ 0.45
26.4
1
˚
a/A
˚
b/A
˚
c/A
◦
b ( )
˚
3
V/A
-
3
D
Z
x
/g cm
2
˚
l/A
0.71069
120(2)
448
1.026
0.40 ¥ 0.18 ¥ 0.04
24.7
-9 £ h £ 9
-12 £ k £ 12
-13 £ l £ 12
13971
T/K
F(000)-
1
m/mm
Crystal size/mm
◦
qmax ( ) for data collection
Range of hkl
-10 £ h £ 5
-12 £ h £ 10
-25 £ k £ 26
-30 £ l £ 30
34505
-19 £ h £ 19
-20 £ k £ 20
-25 £ l £ 25
89627
-
15 £ k £ 15
58 £ l £ 58
-
No. of measured refl.
57870
No. of independent refl. (R int)
9723 (0.0227)
9637
99.7
3163 (0.10)
3078
99.8
9622 (0.024)
5785
92.9
5219 (0.051)
5207
99.0
No. of observed refl. [I ≥ 2s(I)]
Completeness (%)
No. of parameters
Flack parameter
230
221
0.01(6)
0.0637
0.0646
0.169
1.203
3.41–1.12
471
0.00(3)
0.0321
0.0697
0.0658
1.047
0.36–0.40
292
0.01(3)
0.0288
0.0288
0.0812
1.159
0.53–1.00
0.03(2)
0.0317
0.0320
0.0825
1.310
R
R (all data)
wR
S
˚
-3
Dr(max, min) (e A )
1.916–2.717
43
Fig. 9 ORTEP view and atom labelling of 11. Only one complex entity
is represented. Displacement ellipsoids are drawn at the 50% probability
level.
4
3
Fig. 10 ORTEP view and atom labelling of 13. Only one complex entity
is represented. Displacement ellipsoids are drawn at the 50% probability
level.
The asymmetric part of the unit cell of 11 is more complicated.
It contained three independent complex entities but no co-
crystallized solvent molecule. These three entities differ by the
orientation of the aminoalcohol lateral arm as shown by the
The structure of complex 13 is rather complicated: the asym-
metric part of the unit cell contained one and half Pd(prolinato)
complexes with one in general position, the other one with the Pd
atom on a twofold axis. Also solvent molecules are observed: one
O in general positions, one other H O and two
Cl , with one which is disordered, on a twofold axis. The
O and NH groups are involved in three H bonds contributing to
the packing of the structure. Because of the twofold symmetry of
the second entity, there are only three independent prolinol rings.
2
◦
torsion angles N–C–C–O: they are 177 and -49 in the first entity
◦
(
labelled N1 to C10), -64 and 73 in the second (labelled N3 to
◦
C20) and finally 64 and 180 in the third one (labelled N5 to C30).
Also the conformations of the 5-membered heterocycles are quite
different: from a nearly perfect envelope with N6 at the flap for one
ring in entity 2 to a deformed half-chair with C7 on the twofold
axis observed in entity 1. All the six OH and six Cl are involved in
the H-bonding network.
CH
2
Cl
2
and one H
2
2
other CH
2
2
-
The side arm CH
2
–O has a similar orientation as one observed
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Fig. 11 Biological evaluation of compounds 3–7, 9, 11 and 13.
Table 3 Cytostatic activities of complexes 1b, 2 and cisplatin on L1210
diacetate ones (4 and 6), and that complexes with aminoalcoholate
ligands are also more active than the ones with aminoalcohol
ligands. These observations deserve further study on a wider panel
of complexes to establish a possible structure–activity relationship
within this class of compounds.
and HT29 cells
Compounds
IC50 (mM) - L1210
IC50 (mM) - HT29
1
2
b
47
34
2
100
29
21
Considering the very marginal activity of these compounds,
nothing can justify a more detailed study with these compounds
on other tumoral lines. However, we can discuss the fact that
the antitumoral platinum-based compounds are all in a cis
configuration and that our products here described are on the
contrary in the trans conformation. The weak activity of our
palladium-based complexes could be explained by the fact the
trans configuration does not allow suitable interactions with
the DNA, while the cisplatin acts by building adducts on two
neighboring purines 1,2 (Fig. 12a) or two purines separated by
the third base (1,3) (Fig. 12b), or finally, more marginally, by the
decking between two guanines belonging to two strands (Fig. 12c).
In conclusion we have prepared new palladium complexes
involving aminoalcohols or aminoalcoholates features. Four of
them have been also characterized by X-Ray analysis. The results
of the computational investigation give theoretical support to the
existence of structures featuring strong intramolecular hydrogen
bonding in the complexes involving acetate ligands. The predicted
relative energies emphasize a net preference for the trans structure.
From a methodological point of view, the inclusion of the non-
specific solvent effect has a large influence on the difference in
energy between cis and trans isomers. Two complexes revealed an
Cisplatin
◦
◦
◦
N–C–C–O torsion angles values of -52 , -50 and -43 . However,
the conformations of the 5-membered ring are different: a regular
◦
half-chair DC
2
(C3) = 1.1 is observed for the one labelled from
N1 to C4, a deformed envelope for the two others heterocycles:
◦
◦
42
DCs(N11) = 6.4 and DCs(N21) = 2.3 .
Biological evaluation
Preliminary cytotoxic evaluations of compounds 1b and 2, towards
L1210 and HT29 (human colon cancer) cells gave promising
44
results if we compared to the activity of the cisplatin (Table 3).
Evaluation are realized after solubilization of the complexes in
DMSO and NMR studies confirm their stability in such medium.
After this preliminary study, several other representative com-
plexes were tested on the HT29 cells. However, as shown on Fig. 11,
these compounds displayed only marginal activities. Actually, we
can propose that the presence of an unsaturated core increases the
activity of the complexes. On the other hand, it is noteworthy that
the dichloride derivatives (3 and 5) appear more active than the
Fig. 12 Interaction between cisplatin and DNA.
8
988 | Dalton Trans., 2010, 39, 8982–8993
This journal is © The Royal Society of Chemistry 2010

View Article Online
interesting behavior as cytostatic agents for HT29 cells so consec-
utive work on the preparation of more biological active complexes
is already underway by associating the different characteristics
required for the ligand and the nature of the metal.
(ws, OH–X), 5.97 (ws, CH–OH–X, CH–OH–Y or CH–OH–Z),
1
3
1
6.06 (ws, CH–OH–Y or CH–OH–Z), 7.1–7.5 (m, Ph–H). C{ H}
NMR (125 MHz, CDCl , 100 g L , 20 C): d 14.7 (CH –X), 15.0
(CH –Y or CH –Z), 15.5 (CH –Y or CH –Z), 22.0 (OAc–Y or
OAc–Z), 23.5 (OAc–X, OAc–Y or OAc–Z), 55.1 (CH–NH –X,
CH–NH –Y or CH–NH –Z), 59.6 (CH–NH –Y or CH–NH –Z),
4.7 (CH–OH–X), 75.1 (CH–OH–Y or CH–OH–Z), 75.4 (CH–
OH–Y or CH–OH–Z), 125.9 (Ph–C), 126.5 (Ph–C), 127.4 (Ph–C),
128.4 (Ph–C), 139.9 (Ph–C –Y or Ph–C –Z), 141.1 (Ph–C –X),
141.5 (Ph–C –Y or Ph–C –Z), 176.0 (OAc–Y or OAc–Z), 180.2
(OAc–X, OAc–Y or OAc–Z). FT-IR KBr (cm ): 3376, 3292, 3240,
2978, 2932, 1581, 1383, 1326, 701. Anal. Calc. for C22 Pd,
1H O: C 48.49; H 6.29; N 5.14. Found: C 48.06; H 5.89; N 5.45.
-
1
◦
3
3
3
3
3
3
2
2
2
2
2
Experimental
7
Unless specified otherwise, all experiments are handled under
an argon atmosphere using standard Schlenk line technique.
Diethylether, ethyl acetate and chloroform are used as received.
q
q
q
q
q
-
1
Dichloromethane was distilled on CaH
2
and tetrahydrofuran on
sodium/benzophenone. L-prolinol, L-valinol, L-isoleucinol and
H
32
N
2
O
6
(
-)-norephedrine are commercial and used as received.
2
+
TLC were performed on silica 60 F254 Fluka and chromatogra-
MS (m/z) [M+H - 2AcOH] : Calc. 407.1. Found 407.1.
˚
phies on SDS silica 60 A (0.060–0.200 mm). NMR spectra were
1
13
recorded on an AC 250 Bruker ( H NMR, 250.13 MHz; C-NMR,
(SP-4-1)-Bis[(S)-2-amino-3-methyl-1-butanol-jN]-dichloro-
palladium(II) 5
1
6
2.89 MHz) and on a DRX 500 Bruker ( H NMR, 500.13 MHz;
1
3
1
13
1
C-NMR, 125.76 MHz) spectrometers. For H and C{ H} NMR
General procedure with respectively the L-valinol (50 mg,
spectra, the residual solvent peak was used as an internal reference.
IR spectra were recorded on an AVATAR 320 FT-IR apparatus
0
.48 mmol), PdCl
2
(43 mg, 0.24 mmol) in CH
2
Cl (3 mL). Orange
2
◦
20
crystals. Yield: 67% (62 mg). mp: dec. >159 C. [a] = -43.4 (1.23
CHCl
1
D
(
KBr pellets or films). Elemental analysis (C, H, N) were obtained
1
3
). H NMR (250 MHz, CDCl
3
): d 0.92–1.13 (m, 12H, CH
3
),
using Flash EA-1112 Series.
3
3
.94 (dt, 2H, J = 13.9 Hz, J = 6.9 Hz, CH–CH
3
), 2.68 (m, 2H,
CH–NH
2
), 2.79 (m, 2H, OH), 2.98 (m, 2H, NH2a), 3.23 (d, 2H,
General procedure for the preparation of the PdCl or
2
2
3
J = 8.5 Hz, NH2b), 3.87 (m, 2H, CH2a–OH), 4.56 (d, 2H, J =
Pd(OAc)
2
–aminoalcohol complexes PdCl
2
or Pd(OAc)
2
1
3
1
1
1.7 Hz, CH2b–OH). C{ H} NMR (63 MHz, CDCl
(CH ), 30.1 (CH–CH ), 62.2 (CH –OH, CH–NH ). FT-IR KBr
(cm ): 3256, 3231, 3149, 2961, 2933, 2874, 1738, 1578, 1465, 1175,
1067. Anal. Calc. for C10 Pd: C 31.31; H 6.83; N 7.30.
3
): d 19.5
◦
(
2
1 eq.) was treated with aminoalcohol (2 eq.) in CH
2
Cl
4 h under argon. The resultant mixture was evaporated to dryness,
and filtered through cotton.
The filtrate was evaporated to dryness to give the corresponding
PdCl (aminoalcohol) or Pd(OAc) (aminoalcohol) complex.
2
at 20 C for
3
3
2
2
-
1
dissolved in a minimum of CHCl
3
H
26Cl
2
N
2
O
2
+
Found: C 31.52; H 7.24; N 7.40. MS (m/z) [M+H - HCl] : Calc.
347.1. Found 347.0.
2
2
2
2
(
SP-4-1)-Bis[(1R,2S)-2-amino-1-phenyl-1-propanol-jN]-dichloro-
(SP-4-1)-Bis[(S)-2-amino-3-methyl-1-butanol-jN]-diacetato-
palladium(II) 3
palladium(II) 6
General procedure with respectively the (-)-norephedrine (85 mg,
General procedure with respectively the L-valinol (100 mg,
0
.56 mmol), PdCl
2
(50 mg, 0.28 mmol) in CH
2
Cl
2
(3 mL). Yellow
0.97 mmol), Pd(OAc)
Yellow powder. Yield: 91% (190 mg), 3 conformers (10/7/7 :
2
(109 mg, 0.48 mmol) in CH
2
Cl (5 mL).
2
◦
20
powder. Yield: 97% (131 mg). mp: dec. >159 C. [a] = -40.1 (1.13
CHCl
CH
D
1
3
◦
20
D
1
3
). H NMR (250 MHz, CDCl
3
): d 1.03 (d, 6H, J = 6.5 Hz,
X/Y/Z). mp: dec. >124 C. [a] = - 40.3 (0.87 CHCl
3
). H NMR
, 50 g L , 20 C): d 0.8–1.0 (CH ), 1.6–2.1
, OAc), 2.32 (ws, CH–NH –X), 2.44 (ws, CH–NH
Y), 2.70 (ws, CH–NH –Z), 3.1–3.5 (CH2a–OH–Z, NH2b–X), 3.68
3
-1
◦
3
), 3.01 (m, 2H, NH2a), 3.09 (d, 2H, J = 4.3 Hz, OH), 3.28
(500 MHz, CDCl
3
3
2
3
(
5
dd, 2H, J = 12.1 Hz, J = 6.0 Hz, NH2b), 3.43 (m, 2H, CH–NH
2
),
.78 (ws, 2H, CH–OH), 7.25–7.45 (10H, Ph-H). C{ H} NMR
): d 15.4 (CH ), 56.0 (CH–NH ), 74.7 (CH–OH),
28.6 (Ph–C), 127.9 (Ph–C), 128.6 (Ph–C), 140.1 (Ph–C ). FT-IR
(CH–CH
3
2
2
–
1
3
1
2
(63 MHz, CDCl
3
3
2
(ws, NH2b–Y, NH2b–Z), 3.79 (m, CH2b–OH), 4.17 (ws, CH2a–OH–
Y), 4.37 (ws, NH2a–X), 4.48 (d, J = 11.2 Hz, CH2a–OH–X),
3
1
q
-
1
13
1
KBr (cm ): 3406, 3279, 3264, 3228, 3194, 3122, 2967, 1561, 1450,
059, 991, 746, 695. Anal. Calc. for C18 Pd: C 45.06;
H 5.46; N 5.84. Found: C 44.77; H 5.42; N 6.03. HRMS m/z
4.63 (ws, NH2a–Z), 5.36 (ws, NH2a–Y), 6.81 (ws, OH). C{ H}
NMR (125 MHz, CDCl , 50 g L , 20 C): d 19.3 (CH –X, CH
Y), 20.2 (CH –Z), 21.9 (OAc–Z), 23.4 (OAc–X, OAc–Y), 29.8
(CH–CH –Z), 30.3 (CH–CH –X, CH–CH –Y), 61.6 (CH–NH
X), 62.1 (CH–NH –Y), 63.0 (CH –OH–X), 63.5 (CH –OH–Y),
67.2 (CH–NH –Z), 71.5 (CH –OH–Z). FT-IR KBr (cm ): 3320,
3235, 2933, 2871, 1600, 1567, 1390, 1372, 1332, 1069, 1051. Anal.
Calc. for C14 Pd: C 39.03; H 7.49; N 6.50. Found: C 38.63;
H 7.32; N 6.65. MS (m/z) [M+H - 2AcOH] : Calc. 311.1. Found
11.1.
-
1
◦
1
H
26Cl
2
N
2
O
2
3
3
3
–
3
+
[M+Na] calc. 501.0304. Found 501.0313.
3
3
3
2
–
2
2
2
-
1
(
SP-4-1)-Bis[(1R,2S)-2-amino-1-phenyl-1-propanol-jN]-
2
2
diacetato-palladium(II) 4
H
32
N
2
O
6
General procedure with respectively the (-)-norephedrine (337 mg,
2
Yellow powder. Yield: quantitative (587 mg), 3 conformers
+
.22 mmol), Pd(OAc)
2
(250 mg, 1.11 mmol) in CH
2
Cl
2
(10 mL).
3
◦
20
D
1
(
10/1/1 : X/Y/Z). mp: 64 C. [a] = -52.2 (1.04 CHCl
3
). H NMR
, 100 g L , 20 C): d 0.95 (d, J = 6.3 Hz, CH
–Y, CH –Z), 1.98 (s, OAc), 2.93 (m, CH–NH –X),
.14 (ws, CH–NH –Y, CH–NH –Z), 3.58 (t, J = 9.4 Hz, NH2a–X),
.92 (m, NH2b–X), 4.3–4.8 (OH–Y, OH–Z, NH –Y, NH –Z), 5.12
(
SP-4-1)-Bis[(2S)-2-amino-3-methyl-1-pentanol-jN]-dichloro-
-
1
◦
3
(500 MHz, CDCl
3
3
–
palladium(II) 7
X), 1.11 (m, CH
3
3
3
3
2
2
2
2
General procedure with respectively the L-isoleucinol (100 mg,
2
2
0.85 mmol), PdCl
2
(76 mg, 0.43 mmol) in CH
2
Cl
2
(3 mL). Yellow
This journal is © The Royal Society of Chemistry 2010
Dalton Trans., 2010, 39, 8982–8993 | 8989

View Article Online
◦
20
D
1
-1
◦
powder. Yield: 82% (144 mg). mp: dec. >176 C. [a] = -20.4 (0.80
(1.05 CHCl
d 1.4–1.8 (H3, H4), 1.81 (s, OAc), 1.87 (s, OAc), 2.60 (m, H5b–Y),
2.7–2.8 (H –X, H5b–X, H5b–Z), 2.9–3.0 (H5a–Y, H5a–Z), 3.06 (m,
5a–X), 3.15 (m, H –Y, H6b–Z), 3.21 (m, H –Z), 3.32 (m, H6a–Z),
3.52 (m, H6b–Y), 3.56 (dd, J = 12.4 Hz, J = 4.1 Hz, H6a–X), 4.07
3
). H NMR (500 MHz, CDCl
3
, 100 g L , 20 C):
1
3
CHCl
3
). H NMR (250 MHz, CDCl
3
): d 0.92 (t, 6H, J = 7.4 Hz,
3
CH
2
–CH
3
), 0.96 (d, 6H, J = 6.7 Hz, CH–CH
3
), 1.26 (m, 2H,
), 1.83 (m, 2H, CH–CH ),
), 3.00 (m, 6H, NH , OH), 3.82 (d, 2H,
2
CH2a–CH
3
), 1.50 (m, 2H, CH2b–CH
3
3
H
2
2
3
3
2
.81 (m, 2H, CH–NH
2
2
2
2
3
3
J = 12.0 Hz, CH2a–OH), 4.51 (d, 2H, J = 12.0 Hz, CH2b–OH).
(m, H6a–Y), 4.42 (dd, J = 12.4 Hz, J = 2.8 Hz, H6b–X), 4.60 (m,
NH), 5.46 (ws, OH–Y or OH–Z), 5.57 (ws, OH–Y or OH–Z),
1
3
1
C{ H} NMR (63 MHz, CDCl
3
): d 10.6 (CH
2
–CH
3
), 15.5 (CH–
1
3
1
-1
CH
(
3
), 25.8 (CH
2
–CH
3
), 36.3 (CH–CH
3
), 60.2 (CH–NH
–OH). FT-IR KBr (cm ): 3256, 3227, 3151, 2960, 2931, 2876,
2
), 62.1
6.19 (ws, OH–X). C{ H} NMR (125 MHz, CDCl
3
, 100 g L ,
-
1
◦
CH
2
20 C): d 21.8 (OAc–Y ou OAc–Z), 23.2 (OAc–Y ou OAc–Z), 23.7
1
585, 1461, 1166, 1071, 1050. Anal. Calc. for C12 Pd:
H
30Cl
2
N
2
O
2
(OAc–X), 23.8 (C
–Z, C –Y, C –Z), 49.1 (C
–X), 62.5 (C –Y), 63.1 (C
–Z), 176.0 (OAc–Z), 179.2 (OAc–Y), 180.5 (OAc–X). FT-IR
3
–X), 25.0 (C
–Z), 49.3 (C
–X), 64.1 (C
4
–X), 24.0, 24.5, 25.4, 25.9 (C
–X), 49.5 (C –Y), 61.0
–Y), 65.8 (C –Z), 71.3
3
–Y,
C 35.01; H 7.34; N 6.80. Found: C 34.96; H 7.36; N 6.91. HRMS
m/z [M+H] calc. 411.0797. Found 411.0799.
C
(C
3
4
4
5
5
5
+
6
6
2
2
2
(
C
6
-
1
(
SP-4-1)-Bis[(2S)-2-amino-3-methyl-1-pentan-1-ol-jN]-diacetato-
KBr (cm ): 3420, 1643, 1556, 1415, 1049, 426. Anal. Calc. for
Pd, 0.7 H O: C 34.59; H 5.67; N 5.49. Found: C 34.44;
H 5.73; N 6.01. MS (m/z) [M+H - 2AcOH] : Calc. 307.1. Found
07.1.
palladium(II) 8
C
14
H
28
N
2
O
6
2
+
General procedure with respectively the L-isoleucinol (100 mg,
0
3
.85 mmol), Pd(OAc)
2
(96 mg, 0.43 mmol) in CH
2
2
Cl (3 mL).
Yellow powder. Yield: 98% (384 mg), 3 conformers (10/8/7 :
◦
20
1
General procedure for the preparation of the
bis-aminoalcoholato-Pd complexes
X/Y/Z). mp: dec. >98 C. [a]D = - 36.5 (1.03 CHCl
3
).
, 50 g L , 20 C): d 0.88 (m, CH
), 1.48 (ws, CH2b–CH ), 1.7–2.0 (CH–CH
OAc), 2.45 (ws, CH–NH –X), 2.57 (ws, CH–NH –Y), 2.82 (ws,
CH–NH –Z), 3.21 (ws, CH2a–OH–Z), 3.33 (ws, CH2b–OH–Z),
.46 (m, NH2a–X), 3.6–3.9 (CH2a–OH–X, CH2a–OH–Y, NH2a
H
-
1
◦
NMR (500 MHz, CDCl
3
3
),
1
.16 (m, CH2a–CH
3
3
3
,
PdCl (1 eq) was treated with aminoalcohol (2 eq.) in THF for 24 h
2
2
2
at r.t.. Then, caesium carbonate (2 eq.) was added and the resulting
mixture was stirred for 24 h at r.t.. The resulting mixture was
2
3
–
evaporated to dryness, dissolved in CHCl
the excess of Cs CO . The filtrate was evaporated to dryness to
give the corresponding Pd(alcoholate)
3
and filtered to remove
2
Y), 4.13 (d, J = 9.5 Hz, CH2b–OH–Y), 4.20 (ws, NH2b-X), 4.41 (d,
2
3
2
J = 11.5 Hz, CH2b–OH–X), 4.70 (ws, NH2b–Y), 5.02 (ws, NH2a
–
2
complex.
1
3
1
Z), 5.34 (ws, NH2b–Z), 6.72 (ws, OH). C{ H} NMR (125 MHz,
CDCl , 50 g L , 20 C): d 11.0 (CH –CH –X and Y or Z), 11.3
CH –CH –Y or Z), 15.1 (CH–CH –X and Y or Z), 16.1 (CH–
CH –Y or Z), 22.3 (OAc–Y or Z), 23.4 (OAc–X and Y or Z), 25.9
–CH –X and Y or Z), 26.2 (CH –CH –Y or Z), 36.7 (CH–
–Y or Z), 37.0 (CH–CH –X and Y or Z), 59.6 (CH–NH –X),
–Y), 62.5 (CH –OH–X), 63.2 (CH –OH–Y), 65.5
–Z), 71.4 (CH –OH–Z). FT-IR KBr (cm ): 3373, 3319,
287, 3232, 2961, 2931, 2877, 1600, 1564, 1461, 1438, 1386, 1373,
333, 1070, 1051, 701. Anal. Calc. for C16 Pd: C 41.88; H
-
1
◦
3
2
3
2
(
SP-4-1)-Bis[(S)-2-amino-3-methylbutanolato-j N,O]-
(
2
3
3
palladium(II) 9
3
(
CH
2
3
2
3
General procedure with respectively the L-valinol (100 mg,
.96 mmol), PdCl (86 mg, 0.48 mmol) in THF (5 mL) and Cs CO
316 mg, 0.96 mmol). Bright yellow powder. Yield: 90% (136 mg).
CH
6
(
3
1
7
2
3
3
2
0
(
2
2
3
0.0 (CH–NH
CH–NH
2
2
2
-
1
2
2
◦
20
D
1
mp: dec. >115 C. [a] = - 41.4 (0.32 CHCl
CDCl
4
1
CDCl
NH
2
3
). H NMR (250 MHz,
), 1.50 (m, 2H, CH–CH ), 2.75 (ws,
), 3.30 (ws, 2H, CH2b–O), 3.44 (t, 2H, J =
3
): d 0.88 (m, 12H, CH
H, CH2a–O, CH–NH
0.2 Hz, NH2a), 6.77 (ws, 2H, NH2b). C{ H} NMR (63 MHz,
): d 19.5 (CH ), 21.8 (CH ), 30.3 (CH–CH ), 69.4 (CH–
), 72.8 (CH –O). FT-IR KBr (cm ): 3481, 3256, 3214, 3118,
960, 2927, 2875, 1564, 1465, 1384, 1259, 1137, 1067, 1045. Anal.
Calc. for C10 Pd, 0.8 H O: C 36.94; H 7.94; N 8.62. Found:
3
3
H
36
N
2
O
6
2
2
.91; N 6.10. Found: C 41.50; H 7.85; N 6.08. MS (m/z) [M+H -
13
1
+
AcOH] : Calc. 339.1. Found 339.2.
3
3
3
3
-
1
2
2
(
SP-4-1)-Bis(L-prolinol-jN)-dichloro-palladium(II) 11
H
24
N
2
O
2
2
General procedure with respectively the L-prolinol (570 mg,
+
C 37.21; H 8.31; N 8.41. HRMS (m/z) [M+H] : Calc. 311.0951
5
.64 mmol), PdCl (500 mg, 2.82 mmol) in CH Cl (10 mL).
2
2
2
◦
20
Found 311.0954.
Orange powder. Yield: 99% (1.059 g). mp: dec. >140 C. [a]
=
D
1
-
38.4 (1.02 CH
, H ), 2.76 (ws, 2H, OH), 3.0–3.5 (8H, H
J = 11.8 Hz, H6a), 4.61 (d, 2H, J = 11.8 Hz, H6b). C{ H} NMR
63 MHz, CDCl ): d 24.2 (C or C ), 25,2 (C or C ), 50.9 (C ), 60.7
), 64.4 (C ). FT-IR KBr (cm ): 3354, 3197, 2961, 2873, 1457,
261, 1115, 1056, 988, 953, 804. Anal. Calc. for C10 Pd:
C 31.64; H 5.84; N 7.38. Found: C 31.65; H 5.85; N 7.57. HRMS
2
Cl
2
). H NMR (250 MHz, CDCl
3
): d 1.5–1.9 (8H,
2
H
3
4
5
, H , NH), 3.73 (d, 2H,
2
(SP-4-1)-Bis[(S)-2-amino-3-methylpentanolato-j N,O]-
2
2
13
1
palladium(II) 10
(
(
3
3
4
3
4
5
-
1
General procedure with respectively the L-isoleucinol (111 mg,
(84 mg, 0.47 mmol) in THF (5 mL) and Cs
364 mg, 0.94 mmol). Yellow powder. Yield: 78% (124 mg). mp:
C
6
2
0
(
.94 mmol), PdCl
2
2
CO
3
1
H
22Cl
2
N
2
O
2
◦
20
1
+
72 C. [a]D = - 93.8 (0.84 CHCl
d 0.6–0.9 (12H, CH ), 1.03 (m, 2H, CH–CH
), 1.48 (m, 2H, CH2b–CH
3
). H NMR (250 MHz, CDCl
3
):
(
m/z) [M+Na] : Calc. 400.9991. Found 400.9997.
3
3
), 1.25 (m, 2H,
CH2a–CH
NH
3
3
), 2.82 (m, 4H, CH2a–O, CH–
(
SP-4-1)-Bis(L-prolinol-jN)-diacetato-palladium(II) 12
2
2
), 3.25 (ws, 2H, CH2b–O), 3.43 (t, 2H, J = 10.2 Hz, NH2a),
1
3
1
General procedure with respectively the L-prolinol (200 mg,
,98 mmol), Pd(OAc) (222 mg, 0,99 mmol) in CH Cl (5 mL).
Dark yellow oil unstable at r.t. (Pd-black). Yield: quantitative
6.59 (ws, 2H, NH2b). C{ H} NMR (63 MHz, CDCl
(CH –CH ), 17.3 (CH–CH ), 25.1 (CH –CH ), 36.4 (CH–CH
67.3 (CH–NH ), 72.7 (CH –O). FT-IR KBr (cm ): 3211, 2962,
3
): d 10.8
1
2
2
2
2
3
3
2
3
3
),
-
1
2
2
2
0
(
422 mg), 3 conformers (10/2/2 : X/Y/Z). [a]D = + 9.4
2928, 2875, 1612, 1462, 1382, 1069, 534, 513, 490. Anal. Calc. for
8
990 | Dalton Trans., 2010, 39, 8982–8993
This journal is © The Royal Society of Chemistry 2010

View Article Online
C
12
H
28
N
2
O
2
Pd: C 42.54; H 8.33; N 8.27. Found: C 42.58; H 8.35;
CCDC 767180 (3, PdCl
Pd(OAc) (valinol) ), 745867 (11, PdCl
Pd(prolinato) ) contain the supplementary crystallographic data
2
(norephedrine)
2
), 745869 (6,
+
N 7.97. HRMS (m/z) [M+H] : Calc. 339.1264 Found 339.1261.
2
2
2
(prolinol)
2
), 745868 (13,
2
2
for this paper.†
(
SP-4-1)-Bis(L-prolinolato-j N,O)-palladium(II) 13
Method A (from L-prolinol): General procedure with respectively
the L-prolinol (250 mg, 2.47 mmol), PdCl (219 mg, 1.24 mmol) in
(805 mg, 2.47 mmol). Yellow powder.
Biological evaluation
2
THF (10 mL) and Cs
Yield: 95% (359 mg).
2
CO
3
HT29 colorectal adenocarcinoma cells (ATCC HTB 38) were
cultivated in Dulbecco’s MEM supplemented with 10% FCS. Cells
from log-phase culture were seeded in 24-microwell plates (1 ml -
Method B (from 11): Complex 11 (119 mg, 0.31 mmol) was
dissolved in THF (4 mL). Caesium carbonate (205 mg, 0.63 mmol,
-
4
5 ¥ 10 cells/well) and incubated for two days. Tested compounds,
in dimethyl sulfoxide solution, were added under the minimum
volume (5 ml) in increasing concentration. Control cells received
5 ml of dimethyl sulfoxide alone. Plates were incubated 24 h, then
medium was removed and cells washed twice with phosphate
buffered saline before addition of fresh medium free of drug.
Plates were reincubated for three days before evaluation of the
cell survival using the MTT assay using 30 min incubation with
100 mg/well of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetra-
2
eq.) was added and the resulting mixture was stirred for 24 h
at room temperature. The resulting mixture was evaporated to
dryness, dissolved in CHCl and filtered to remove the excess of
Cs CO . The filtrate was evaporated to dryness to give a yellow
powder. Yield: 86% (83 mg).
3
2
3
◦
20
1
mp: dec. >145 C. [a]D = + 44.3 (1.15 CHCl
250 MHz, CDCl ): d 1.7–2.0 (4H, H3a, H4a), 2.4–2.7 (6H, H3b
4b, H5a), 2.8–3.0 (4H, H
3
). H NMR
(
H
3
,
2
2
3
, H5b), 3.02 (d, 2H, J = 10.8 Hz, H6a),
2
46
4
.01 (dd, 2H, J = 10.8, J = 3.4 Hz, H6b), 7.86 (ws, 2H, NH).
zolium bromide (MTT, Sigma). After removal of the medium,
1
3
1
C{ H} NMR (63 MHz, CDCl
3
): d 25.4 (C
6
3
or C
4
), 25.9 (C
). FT-IR KBr (cm ): 3413,
3
formazan crystals were taken up with 100 ml of dimethyl sulfoxide
and absorbance at 540 nm was measured with a microplate reader
(Model 450 Bio-Rad), survival was expressed as % of dimethyl
-
1
or C
4
), 50.0 (C
5
), 68.3 (C
2
), 70.0 (C
3009, 2968, 2845, 2828, 2680, 1086, 1038, 513. Anal. Calc. for
C
10
H
20
N
2
O
2
Pd: C 39.16; H 6.57; N 9.13. Found: C 38.85; H 6.43;
sulfoxide treated controls. All incubations were carried out at
+
◦
N 9.29. HRMS (m/z) [M+H] : Calc. 307.0638 Found 307.0641.
37 C in a water-jacketed CO
humidity).
2
incubator (5% CO , 100% relative
2
X-Ray analysis
Acknowledgements
The X-ray intensity data were collected at 100 K for 3 with a
KAPPA X8 APPEX II Bruker diffractometer with a graphite
monochromated Mo-Ka (l = 0.71073 A) radiation. The crystal
was chosen, mounted in a cryo-protectant and transferred quickly
to the cold gas stream for flash cooling.
We are grateful to the Public Authorities of Champagne-
Ardenne (Conseil R e´ gional) for material funds and fellowship
to F. A., and to C. Hammaecher for preliminary studies.
Authors thank J. Wouters and B. Norberg FUNDP Namur
˚
The X-ray intensity data were at 120 K for compounds 6 and
(FNRS grant 2.4517.07) for the X-ray data collection of 13,
˚
1
3 with a MAR345 image plate using Mo-Ka (l = 0.71069 A)
R. Guillot and F. Lachaud, ICMMO, Orsay for the X-ray data
collection of 3. The C.R.I.H.A.N computing center and the
computational center of the University of Reims Champagne
Ardenne (http://www.romeo2.fr) are acknowledged for the CPU
time donated.
radiation. The crystal was chosen, mounted in inert oil and
transferred quickly to the cold gas stream for flash cooling. For 11,
the data were collected at room temperature with a Xcalibur CCD
˚
diffractometer (Gemini ultra Mo) using Mo-Ka (l = 0.71073 A)
radiation. The unit cell parameters were refined using all the
collected spots after the integration process. Except for 11 and 3,
the data were not corrected for absorption, but the data collection
mode partially takes the absorption phenomena into account.
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