New insights on the active species and mechanism of cytotoxicity of salan-Ti(IV) complexes: A stereochemical study

Article abstract of DOI:10.1021/ic201340m

Following the discovery of cisplatin, much effort has been devoted to the exploration of transition metal complexes as cytotoxic agents. We have recently introduced the highly efficient C₂-symmetrical salan-Ti(IV) family of complexes, demonstra

Full text of DOI:10.1021/ic201340m

ARTICLE
pubs.acs.org/IC
New Insights on the Active Species and Mechanism of Cytotoxicity of
Salan-Ti(IV) Complexes: A Stereochemical Study
Cesar M. Manna, Gad Armony, and Edit Y. Tshuva*
Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
S Supporting Information
b
ABSTRACT:
Following the discovery of cisplatin, much effort has been devoted to the exploration of transition metal complexes as cytotoxic
agents. We have recently introduced the highly efficient C2-symmetrical salan-Ti(IV) family of complexes, demonstrating high
cytotoxicity toward colon and ovarian cells and enhanced hydrolytic stability in mixed organic/water solutions. The effect of
stereochemistry is hereby reported, by comparing the cytotoxic activity and hydrolysis of pure enantiomers and their racemic
mixture for four complexes of this family with different aromatic substitutions: para-Me, para-Cl, ortho-Cl, and ortho-OMe. These
complexes include the trans-diaminocyclohexyl bridge, which enables ligand-to-metal chiral induction to give solely the Δ isomer
when starting from the R,R ligand and vice versa. Different activity is obtained for the different stereochemical forms (Δ, Λ, and rac)
in two of the four complexes, where for the other two either all forms are inactive or all are highly active. Additionally, where not all
are of similar activity, the racemic mixture is the least active of the three. We therefore conclude that the salan ligand is essential for
the fruitful biological interaction, which probably involves a chiral cellular target. The activity of the racemate differing from that
expected from a simple mixture of enantiomers operating separately may be explained by the involvement of a polynuclear active
species, where different metal centers might be of different configurations. This is particularly supported by the different polynuclear
products of hydrolysis obtained from an optically pure complex and from the racemic one, as analyzed crystallographically. The
former is an all-R,R chiral C1-symmetrical homodimer, while the latter is an achiral R,R-S,S Ci-symmetrical heterodimer obtained
through chiral recognition.
’ INTRODUCTION
Upon slow hydrolysis of the labile isopropoxo groups (within
up to weeks in 10% D2O solutions), salan-bound polynuclear
complexes are formed, which are stable for days but lack any
cytotoxicity. It was also observed that complexes of large steric
bulk that precludes formation of the cluster do not exhibit cyto-
toxicity as well, which led us to propose that the cluster formation
in the cell plays a meaningful role in activity.
The salan complexes possess a C2-symmetry, rendering chir-
ality (Figure 1). The effect of stereochemistry on biological
activity is of great importance especially for medicinal applica-
tions, as many of the biological targets in the cells are chiral. And
yet, all chiral cytotoxic Ti(IV) complexes reported prior to our
Cisplatin marked a new era in the field of chemotherapy.1
Nevertheless, its disadvantages of high toxicity and limited
activity range led to wide research of other compounds, including
transition metal complexes that are based on different metal
centers.2 The Ti(IV) complexes titanocene dichloride (Cp2TiCl2,
Scheme 1a) and budotitane ((bzac)2Ti(OEt)2, Scheme 1b), and
their derivatives based on Cp or diketonato type ligands, demo-
nstrated promising activity with lower toxicity compared to
cisplatin.3 However, rapid hydrolysis in biologically relevant solu-
tions is the main drawback of the titanium complexes which impedes
their utility.3d,f,4 We recently introduced a new family of Ti(IV)
complexes based on salan ligands (Scheme 1c), which exhibits
enhanced hydrolytic stability and cytotoxicity toward colon and
ovarian cells compared to Cp2TiCl2 and (bzac)2Ti(OiPr)2.5
Received: June 22, 2011
Published: September 16, 2011
r
2011 American Chemical Society
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Scheme 1
which are known to enable chiral induction on the metal center
and provide optically pure Ti(IV) complexes.8 Thus, when
applying the racemic diamine, a single pair of enantiomers,
namely R,R,Δ and S,S,Λ is obtained, while starting from the
optically pure diamine yields a single diastereomer.8
The synthesis of the ligands is based on a two-step procedure
involving condensation of salicylaldehyde derivatives with trans-
1,2-diaminocyclohexane followed by reduction with NaBH4.7,9
1H NMR confirmed that the desired ligand was obtained with
two doublets of an AB system representing the methylene bridge.
Rac-L1À4H2 were obtained from rac-1,2-diaminocyclohexane,
while S,S-L1À4H2 and R,R-L1À4H2 were prepared similarly,
starting from the corresponding commercially available optically
pure diamine.
The Ti(IV) complexes were obtained as previously descri-
bed,5a,b by dissolving the ligands in THF followed by addition of
titanium tetra(isopropoxide) and stirring the solution for 2 h.
The complexes rac-, Δ,R,R-, and Λ,S,S-L1À4Ti(OiPr)2 were ob-
tained in a quantitative yield (Scheme 2). The ligands L1À4H2
gave complete induction; namely, by starting the complexation
with an optically pure ligand, only a single diastereomer of the
complex was identified by 1H NMR. The complexes feature a C2-
1
symmetry as evident by H NMR, with a single type of an
aromatic ring and two doublets of the methylene protons, and as
also presented in the ORTEP diagram of one of the molecules
found in the asymmetric unit of rac-L1Ti(OiPr)2 and of Λ,S,S-
L1Ti(OiPr)2 (Figure 1).7
Cytotoxicity. The cytotoxicity of complexes rac-, Δ,R,R-, and
Λ,S,S-L1À4Ti(OiPr)2 was measured toward two representative
cell lines, HT-29 colon and OVCAR-1 ovarian cells based on the
methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay as
previously described.5a In general, similar results were obtained
for both cell types. The results for colon cells are presented in
Figure 2, and those for ovarian cells are given in Figures S1ÀS4.
The relative IC50 and maximal cell growth inhibition values are
summarized in Table 1.
Figure 1. ORTEP drawings of one molecule of Δ,R,R-L1Ti(OiPr)2
found in the asymmetric unit of rac-L1Ti(OiPr)2 (left) and Λ,S,S-
L1Ti(OiPr)2 (right).7
Scheme 2. Preparation of Complexes of Chiral Salan Ligands
The complexes exhibit variable cytotoxic activities with rela-
tive IC50 values ranging from 2 to 44 μM, depending on the
substituent on the aromatic ring and the stereochemical
configuration. Even more pronounced is the effect of these
parameters on the maximal cell growth inhibition, which
changes quite significantly for different compounds and differ-
ent configurations, varying between 55% and 100%. For two
complexes of the series, L2,4Ti(OiPr)2, the activity for all
three stereochemical configurations, namely, rac, Δ, and Λ,
is similar; either no activity (L2Ti(OiPr)2) or similarly high
activity (L4Ti(OiPr)2) is obtained for all. However, whereas
for L3Ti(OiPr)2 the two pure enantiomers are of a similar
activity that is noticeably higher than that of the racemate,
for L1Ti(OiPr)2 the activity of the two pure enantiomers is
also different. We may thus generalize and say that if not
all stereochemical combinations are of similar activity, at
least one of the pure enantiomers is the most active. These
observations suggest that the biological target is chiral, and
that the salan ligand is meaningful and is involved in the
interaction with this target, rather than the active species being
a “stripped” aquated or protein-bound ion following early
dissociation of all ligands.10 The lower activity of the racemic
mixtures than that expected of a mixture of enantiomers
operating in an unrelated fashion may suggest the involvement
of a polynuclear active species, where several metal centers may
be of different stereochemical configurations. Thus, different
studies, including budotitane and ansa-metallocenes,6 were mea-
sured as racemic only. Thus, in our recent communication we
reported our preliminary studies on the effect of stereochemistry
on cytotoxicity, with the aim of not only identifying the most
active isomer for future medicinal utility, but in particular for
elucidating mechanistic aspects relating to the importance of the
ligand and the nature of the cellular target.7 We synthesized pure
enantiomers by chiral induction from an optically pure chiral
ligand and found that for L1Ti(OiPr)2, (Scheme 2, Figure 1) the
Λ isomer is markedly more active than the Δ. Herein, we
elaborate on these investigations to include a series of four
complexes, each prepared as rac, Δ, and Λ, and evaluate the
effect of stereochemistry on cytotoxicity and hydrolysis while
analyzing mechanistic implications.
’ RESULTS AND DISCUSSION
Synthesis and Characterization. The salan ligands employed
are based on the chiral trans-1,2-diaminocyclohexyl moiety,
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Table 1. Relative IC50 and Maximal Inhibition Values for the
Complexes rac-, Λ-, and Δ-L1-4Ti(OiPr)2, and Known Com-
pounds towards HT-29 and OVCAR-1 Cell Lines Based on
3 Â 4 Independent Repetitions
HT-29
OVCAR-1
IC50
maximal
IC50
maximal
compd
[μM]
inhibition (%)
[μM]
inhibition (%)
rac-L1Ti(OiPr)2
15 ( 2
58
92
84
0
20 ( 2
55
89
74
0
Λ,S,S-L1Ti(OiPr)2 13 ( 1
13 ( 1
Δ,R,R-L1Ti(OiPr)2 26 ( 2
26 ( 2
rac-L2Ti(OiPr)2
inactive
inactive
Λ,S,S-L2Ti(OiPr)2 inactive
Δ,R,R-L2Ti(OiPr)2 inactive
0
inactive
0
0
inactive
0
rac-L3Ti(OiPr)2
17.5 ( 0.9
62
74
82
91
100
100
90
90
88
21.3 ( 0.5
5.2 ( 0.4
3.4 ( 0.2
20.2 ( 0.4
17.7 ( 0.6
23.7 ( 0.7
701 ( 4
14.9 ( 0.4
8.6 ( 0.2
62
70
75
92
100
100
90
90
90
Λ,S,S-L3Ti(OiPr)2 4.8 ( 2.2
Δ,R,R-L3Ti(OiPr)2 2.1 ( 1.0
rac-L4Ti(OiPr)2
Λ,S,S-L4Ti(OiPr)2 16.6 ( 0.6
Δ,R,R-L4Ti(OiPr)2 20.8 ( 0.6
21.7 ( 0.5
Cp2TiCl2
(bzac)2Ti(OiPr)2 15.2 ( 0.3
cisplatin 11.1 ( 0.4
609 ( 4
Figure 2. Dependence of HT-29 cell viability after 3 days incubation
period on administered concentration of rac-, Δ,R,R-, and Λ,S,S-
L1À4Ti(OiPr)2 based on 3 Â 4 independent repetitions: (a) L1Ti-
(OiPr)2, (b) L2Ti(OiPr)2, (c) L3Ti(OiPr)2, (d) L4Ti(OiPr)2.
Figure 3. ORTEP presentation of Ti2(μ-O)2(R,R-L1)(S,S-L1), product
of hydrolysis of rac-L1Ti(OiPr)2, at 50% probability ellipsoids; H atoms
and solvent were omitted for clarity.
enantiomers or diastereomers of the active species should
certainly demonstrate different activity toward a chiral target.
Hydrolysis. The hydrolytic stability of the four racemic
In order to shed light on the structure of the hydrolysis
product of this series of complexes, L1Ti(OiPr)2 was reacted
with 1000 water equivalents in THF for three days, and the
product was allowed to crystallize from methylene chloride and
hexane. The ORTEP drawings of the products of rac-L1Ti-
(OiPr)2 and Δ,R,R-L1Ti(OiPr)2 are given in Figures 3 and 4,
respectively, with a list of bond lengths and angles summarized in
Tables 2 and 3, respectively. The aromatic region of the 1H NMR
of these crystals is provided in Figure S5, featuring twice as many
signals for the product of the optically pure compound.
1
complexes at 5 mM concentration was measured by H NMR
at RT in 10% D2O (>1000 D2O equivalents relative to Ti)
solutions as previously described.5a,b The t1/2 of hydrolysis of the
labile isopropoxo groups for complexes rac-L1À4Ti(OiPr)2 is
similar, between 1 (for rac-L1,2Ti(OiPr)2) and 4 (for rac-L3,4Ti-
(OiPr)2) hours. The somewhat enhanced stability of the latter
may relate to their ortho-steric bulk, which may inhibit cluster for-
mation as observed in our previous studies.5a,b Additional measure-
ments conducted with enantiomerically pure complexes revealed
similar hydrolysis rates to those of their racemic mixtures.
The X-ray structures of both hydrolysis products feature
dinuclear species8b which are generally similar, with similar bond
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Table 3. Selected Bond Lengths (Å) and Angles (deg) for
Complex Ti2(μ-O)2(R,R-L1)2
atoms
value
atoms
value
Lengths
N(1)ÀTi(2)
N(2)ÀTi(2)
N(3)ÀTi(1)
2.2883(16)
2.2281(16)
2.2780(15)
N(4)ÀTi(1)
O(1)ÀTi(1)
O(1)ÀTi(2)
2.2021(15)
1.7827(12)
1.9579(13)
2.805
Ti(1) Ti(2)
3 3 3
Angles
Ti(1)ÀO(1)ÀTi(2)
O(1)ÀTi(1)ÀO(2)
O(1)ÀTi(1)ÀN(4)
102.06(6)
82.69(5)
95.41(6)
O(5)ÀTi(1)ÀN(4)
N(4)ÀTi(1)ÀN(3)
O(4)ÀTi(2)ÀO(1)
162.13(5)
76.88(5)
164.11(6)
Figure 4. ORTEP presentation of Ti2(μ-O)2(R,R-L1)2, product of
hydrolysis of Δ,R,R-L1Ti(OiPr)2, at 50% probability ellipsoids; H atoms
and solvent were omitted for clarity.
Figure 5. Superposition of X-ray structures of Ti2(μ-O)2(R,R-L1)(S,S-L1)
(light blue) and Ti2(μ-O)2(R,R-L1)2 (gray), presenting only the dimetal
core and the diaminocyclohexane moiety; one cyclohexyl ring is of an
identical configuration in both structures (left) while the other is in an
opposite one (right).
Table 2. Selected Bond Lengths (Å) and Angles (deg) for
Complex Ti2(μ-O)2(R,R-L1)(S,S-L1)
atoms
value
atoms
value
Lengths
N(1)ÀTi(1)
O(1)ÀTi(1)
O(2)ÀTi(1)
2.283(3)
1.784(2)
1.879(2)
N(2)ÀTi(1)
O(1)ÀTi(1)#1
O(4)ÀTi(1)
2.219(3)
1.951(2)
1.918(2)
2.793
Ti Ti
3 3 3
Angles
Ti(1)ÀO(1)ÀTi(1)#1
O(1)ÀTi(1)ÀO(1)#1
O(1)ÀTi(1)ÀO(4)
O(2)ÀTi(1)ÀO(4)
96.7(1)
83.3(1)
102.0(1)
97.2(1)
O(1)ÀTi(1)ÀN(2)
O(4)ÀTi(1)ÀN(2)
N(2)ÀTi(1)ÀN(1)
97.3(1)
81.5(1)
76.3(1)
lengths and angles around the metal center, which are also similar
to those of the mononuclear precursors.7 The two Ti(IV) centers
with a distance of 2.8 Å are bridged by two oxo atoms coming
from the water molecules replacing the labile isopropoxo ligands,
and each Ti(IV) center is bound to the salan ligand. The
configuration of the phenolato groups changes from trans in
the staring isopropoxo complex to cis in the dimer,8b,11 as
occurred for two out of the three metal centers of the trinuclear
products obtained previously for other complexes of this family.5a,b
A close look at both structures, however, reveals that the sym-
metry of the two clusters is different, due to different configura-
tions. Whereas the optically pure compound formed the chiral
C1-symmetrical homodimer Ti2(μ-O)2(R,R-L1)2, the racemic
complex formed the achiral Ci symmetrical heterodimer Ti2(μ-O)2-
(R,R-L1)(S,S-L1) with the crystallographic inversion center as
the main product,8b as also corroborated by superposition of its
1H NMR (Figure S5) with that of the crude hydrolysis
products. This indicates that a chiral recognition occurred in
the dimer formation when starting from the racemic precursor.
Figure 6. ORTEP presentation of Ti4(μ-O)4(R,R-L1)4 at 50% prob-
ability ellipsoids; H atoms and solvent were omitted for clarity.
A superposition of the metal cores of the two structures is
depicted in Figure 5, where the opposite configuration of one
diaminocyclohexyl ring may be observed.
These results make the dinuclear hydrolysis products good
candidates for the cellular active species in the cytotoxicity
mechanism, where indeed we would expect different activity
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Table 4. Selected Bond Lengths (Å) and Angles (deg) for
recognition occurs and mainly an achiral heterodinuclear com-
plex formed from a racemic precursor, which is a diastereomer of
the product obtained from the optically pure precursor. The
inactivity of the two dimers raises the possibility that the dimers
may lack cell penetration ability, but if formed inside the cells,
might manifest their activity. This emphasizes the advantage of
our precursor bis(isopropoxo) complexes in being of relatively
high hydrolytic stability, which also means that their cell pene-
tration should occur relatively rapidly. Nevertheless, the involve-
ment of other active intermediate polynuclear species formed
prior to the particular clusters characterized herein, that may
form in the outer-cellular environment and are able to penetrate
the cell membrane, cannot be ruled out.
In the edges of activity, the ortho-methoxylated complex
showed the highest activity when considering not only the
relative IC50 values, but the maximal inhibition as well, for all
stereochemical combinations, namely for the two enantiomers Δ
and Λ and for the racemate. In contrast, the para-chlorinated
complex demonstrated negligible activity in all stereochemical
forms. The different activity of differently substituted complexes
is surely a result of different features of the ligand, which may
relate either to steric and/or electronic influences, or to indirect
effects such as solubility.5a,b Nevertheless, different chiral recog-
nition in the cluster formation upon hydrolysis should also be
considered, as it is certainly possible that, for differently sub-
stituted complexes, hydrolysis of the racemic complexes may
yield the homodimeric chiral structures as the main products,
thus leading to similar activity for all stereochemical combina-
tions of the precursor bis(isopropoxo) complexes.
Complex Ti4(μ-O)4(R,R-L1)4
atoms
value
atoms
value
Lengths
N(1)ÀTi(1)
N(2)ÀTi(1)
2.274(5)
2.189(5)
O(1)ÀTi(1)
O(3)ÀTi(1)
1.755(4)
1.895(5)
3.546
Ti(1) Ti(2)
3 3 3
Angles
Ti(1)ÀO(1)ÀTi(2)
O(1)ÀTi(1)ÀO(2)
O(2)ÀTi(1)ÀO(4)
152.9(3)
O(3)ÀTi(1)ÀO(4)
O(3)ÀTi(1)ÀN(1)
O(3)ÀTi(2)ÀN(2)
96.5(2)
102.56(18)
157.22(18)
85.03(19)
163.0(2)
with a chiral target. Thus, the cytotoxicity of both dimeric
hydrolysis products Ti2(μ-O)2(R,R-L1)2 and Ti2(μ-O)2(R,R-L1)-
(S,S-L1) was tested on HT-29 colon and OVCAR-1 ovarian cells,
and no activity was detected, similarly to the observation with
trinuclear products of hydrolysis obtained for other salan com-
plexes as analyzed previously.5b This does not rule out the
possible participation of these dimers as the active species inside
the cell, as their lack of cytotoxicity may relate to their inability to
penetrate the cell membrane due to increased size, while where
formed inside the cell following penetration of a relatively stable
bis(isopropoxo) precursor, might be of fruitful biological inter-
actions.
Interestingly, additional crystals of a different hydrolysis pro-
duct of Δ,R,R-L1Ti(OiPr)2 were obtained in trace amount (<5%)
from methylene chloride (Figure 6, Table 4). A tetrameric C2-
symmetrical (Ti4(μ-O)4(R,R-L1)4 complex with a crystallographic
inversion center was obtained, with four Ti(IV) centers bridged
by four oxo atoms, and each metal atom is bound to the salan
ligand with cis orientation of the phenolato oxygen atoms as in the
dimers.12 Bondlengths and angles around the metal center are also
similar to those obtained for the dimeric structures. This indicates
that other clusters with different nuclearities are possible, although
in this case they were obtained in small amounts only.
In summary, it is clear that stereochemistry plays a major role
in determining cytotoxicity and should be considered in the
future design of active complexes. Additional studies in this
respect are underway.
’ EXPERIMENTAL SECTION
L1H2 and rac-, Δ,R,R-, and Λ,S,S-L1Ti(OiPr)2 were prepared as
previously described.7,9 All other ligands and Ti(IV) complexes were
prepared similarly. The configuration assignment of complexes was
made under the assumption that all R,R ligands of this class give Δ at
metal and vice versa, based on the observations of representative com-
plexes by us and others.8 All bis(isopropoxo) complexes were obtained
in a quantitative yield and may be further washed with diethyl ether.
NaBH4 (97%), 1,2-trans-cyclohexanediamine (99%), and all substituted
salicylaldehyde compounds (>96%) were purchased from Aldrich
Chemical Co. Inc. or Fluka Riedel-deHa€en. Titanium tetra(isoprop-
oxide) (97%) was purchased from Aldrich Chemical Co., Inc. Cp2TiCl2
(98%) for reference measurements was purchased from Arapahoe
Chemicals Inc. (bzac)2Ti(OiPr)2 for reference measurements was
synthesized based on a published procedure.3f All solvents were distilled
from K or K/benzophenone under nitrogen or dried over aluminum
column on an MBrawn drying system SPS-800. All experiments requir-
ing dry atmosphere were performed in an M. Braun drybox or under
nitrogen atmosphere using Schlenck line techniques. NMR data were
recorded using AMX-400 MHz or AMX-500 MHz Bruker spectrometer.
X-ray diffraction data were obtained with a Bruker SMART APEX CCD
diffractometer, running the SMART software package. After collection,
the raw data frames were integrated by the SAINT software package.
The structures were solved and refined using the SHELXTL software
package. Elemental analysis was conducted in the microanalytical
laboratory of our institute. Specific optical rotation measurements were
performed by Autopol I automatic polarimeter from Rudolph Research
Analytical and were calculated as the average of five measurements.
’ CONCLUSIONS
Herein we report the first analysis of the effect of stereochem-
istry on cytotoxicity and hydrolysis of chiral salan Ti(IV) com-
plexes, while pointing to the possible relationship between these
parameters. Four salan Ti(IV) complexes of different aromatic
substitutions were analyzed as enantiomerically pure and as
racemic. It appears that, on the line of activity, the effect of
stereochemistry is mostly pronounced in the intermediate cases.
The complexes of mediocre activity clearly show that the racemic
mixture is less active than at least one of the pure enantiomers
that may be of either similar or different activity. Assuming a
generally similar mechanism of all complexes of this family, this
corroborates the participation of the ligand in fruitful interaction
with the presumably chiral target, although inactivation of a
particular enantiomer by a different chiral competitor cannot be
ruled out. This also implies that the active species in the cell is
polynuclear, and that, for this series of complexes, homochiral
polynuclear complexes are more active than mixed-configured
ones that should form with preference. This was corroborated by
the crystal structures of the dimeric products of hydrolysis of
racemic and an enantiomerically pure complex, which revealed
that, despite the similar rates of cluster formation, indeed chiral
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Cytotoxicity was measured on HT-29 colon and OVCAR-1 ovarian cells
obtained from ATCC Inc. using the methylthiazolyldiphenyl-tetrazo-
lium bromide (MTT) assay as previously described.5a Cells (1.0 Â 106)
in medium (containing 1% penicillin/streptomycin antibiotics, 1%
L-glutamine, 10% fetal bovine serum (FBS), all purchased from Biolo-
gical Industries Inc.; and 88% medium RPMI-1640, purchased from
Sigma Inc.) were seeded into a 96-well plate and allowed to attach for
24 h. The cells were consequently treated with the reagent tested at
10 different concentrations. Solution of reagent was prepared by
dissolving 4 mg of the reagent in 200 μL of THF and diluting 10 μL
of this solution with 90 μL of medium. From the resulting solution, 10 μL
was added to each well already containing 200 μL of the above solution
of cells in the medium to give final concentration of up to 100 mg/L.
After a standard of 3 days incubation at 37 °C in 5% CO2 atmosphere,
MTT (0.1 mg in 20 μL) was added and the cells were incubated for
additional 3À4 h. The MTT solution was then removed, and the cells
were dissolved in 200 μL of isopropanol. The absorbance at 550 nm was
measured by a Bio-Tek EL-800 microplate reader spectrophotometer.
Each measurement was repeated at least 3 Â 4 times, namely, three
repeats per plate, all repeated four times on different days (12 repeats
altogether). Relative IC50 values with standard error of means were
determined by a nonlinear regression of a variable slope (four para-
meters) model by Graph Pad Prism 5.0 program. Kinetic hydrolysis
studies by NMR were performed at RT as previously described,5a,b using
5 mM of the complex solution in THF-d8 and adding >1000 equiv of
D2O to give a final solution of 1:9 D2O/THF-d8. The t1/2 value is based
on a pseudo-first-order fit for each compound. The results were verified
by including p-dinitrobenzene as an internal standard.
Hz, CH2), 3.82 (2 H, d, J 14.6 Hz, CH2), 2.36 (2 H, m, cy), 2.05 (2 H, s,
cy), 1.66 (2 H, m, cy), 1.16 (4 H, m, cy); δC(125 MHz; CDCl3) 153.4,
129.1, 126.7, 124.4, 121.1, 119.4, 59.9, 49.5, 30.3, 24.0. For S,S-L3H2 (1.3
g, 87%): [α]D26= 128 ( 1° (c 0.36% in CHCl3). (Found: C, 60.93; H,
6.12, N, 7.01%. Calcd for C20H24Cl2N2O2: C, 60.76; H, 6.12; N, 7.09%.)
δH(500 MHz; CDCl3) 7.18 (2 H, d, J 2.0, 5.4 Hz, Ar), 6.83 (2 H, d, J 8.0
Hz, Ar), 6.65 (2 H, m, Ar), 3.94 (2 H, d, J 14.2 Hz, CH2), 3.82 (2 H, d,
J 14.6 Hz, CH2), 2.36 (2 H, m, cy), 2.05 (2 H, s, cy), 1.66 (2 H, m, cy),
1.16 (4 H, m, cy); δC(125 MHz; CDCl3) 153.4, 129.1, 126.7, 124.4,
121.1, 119.4, 59.9, 49.5, 30.3, 24.0. These compounds were synthesized
in analogy to rac-L3H2 from R,R-1,2-diaminocyclohexane and S,S-1,2-
diaminocyclohexane, respectively.
rac-L4H2 was synthesized in analogy to rac-L1H27 from rac-1,2-diamino-
cyclohexane and 2-hydroxy-3-methoxybenzaldehyde (1.0 g, 68% yield).
(Found: C, 68.15; H, 7.69, N, 7.17%. Calcd for C22H30N2O4: C, 68.37;
H, 7.82; N, 7.25%.) δH(500 MHz; CDCl3) 6.71 (2 H, dd, J 8.3, 2.2 Hz,
Ar), 6.65 (2 H, t, J 8.0 Hz, Ar), 6.65 (2 H, d, J 7.4 Hz, Ar), 3.94 (2 H, d,
J 13.7 Hz, CH2), 3.82 (2 H, d, J 13.7 Hz, CH2), 3.79 (6 H, s, CH3) 2.36
(2 H, m, cy), 2.05 (2 H, s, cy), 1.66 (2 H, m, cy), 1.14 (4 H, m, cy);
δC(125 MHz; CDCl3) 147.8, 146.7, 124.1, 120.6, 118.8, 110.7, 60.5,
59.9, 49.1, 30.3, 24.0.
For R,R-L4H2 (1.1 g, 75%): [α]D27 = À100 ( 2° (c 0.35% in CHCl3).
(Found: C, 68.34; H, 7.75, N, 7.20%. Calcd for C22H30N2O4: C, 68.37;
H, 7.82; N, 7.25%.) δH(500 MHz; CDCl3) 6.71 (2 H, dd, J 8.0, 2.0 Hz,
Ar), 6.65 (2 H, t, J 8.0 Hz, Ar), 6.65 (2 H, d, J 7.3 Hz, Hz, Ar), 3.94 (2 H,
d, J 13.7 Hz, CH2), 3.82 (2 H, d, J 13.6 Hz, CH2), 3.79 (6 H, s, CH3)
2.36 (2 H, m, cy), 2.05 (2 H, s, cy), 1.66 (2 H, m, cy), 1.14 (4 H, m, cy);
δC(125 MHz; CDCl3) 147.8, 146.7, 124.1, 120.6, 118.8, 110.7, 60.5,
59.9, 49.1, 30.3, 24.0. For S,S-L4H213 (1.3 g, 82%): [α]D26 = 98.3 ( 0.3°,
(c 0.35 in CHCl3). (Found: C, 68.24; H, 7.91, N, 7.14%. Calcd for
C22H30N2O4: C, 68.37; H, 7.82; N, 7.25%). δH(500 MHz; CDCl3) 6.71
(2 H, dd, J 8.1, 2.0 Hz, Ar), 6.65 (2 H, t, J 8.0 Hz, Ar), 6.65 (2 H, d, J 7.2
Hz, Ar), 3.94 (2 H, d, J 13.8 Hz, CH2), 3.82 (2 H, d, J 13.6 Hz, CH2),
3.79 (6 H, s, CH3), 2.36 (2 H, m, cy), 2.05 (2 H, s, cy), 1.66 (2 H, m, cy),
1.14 (4 H, m, cy); δC(125 MHz; CDCl3) 147.8, 146.7, 124.1, 120.6,
118.8, 110.7, 60.5, 59.9, 49.1, 30.3, 24.0. These compounds were synthe-
sized in analogy to rac-L4H2 from R,R-1,2-diaminocyclohexane and S,S-
1,2-diaminocyclohexane, respectively.
7
rac-L2H2 was synthesized in analogy to rac-L1H2 from rac-1,2-
diaminocyclohexane and 5-chlorosalicylaldehyde (1.0 g, 67% yield).
(Found: C, 60.75; H, 6.07, N, 6.94%. Calcd for C20H24Cl2N2O2: C,
60.76; H, 6.12; N, 7.09%.) δH(500 MHz; CDCl3) 7.00 (2 H, dd, J 8.6,
2.3 Hz, Ar), 6.88 (2 H, s, Ar), 6.97 (2 H, d, J 8.6 Hz, Ar) 3.94 (2 H, d,
J 14.2 Hz, CH2), 3.81 (2 H, d, J 14.6 Hz, CH2), 2.34 (2 H, m, cy), 2.08
(2 H, m, cy), 1.66 (2 H, m, cy), 1.16 (4 H, m, cy); δC(125 MHz; CDCl3)
156.6, 128.6, 128.0, 124.1, 123.7, 117.7, 59.7, 49.2, 30.5, 24.0.
For R,R-L2H2 (1.1 g, 73%): [α]D25 = 4.5 ( 0.3° (c 0.13% in CHCl3).
(Found: C, 60.89; H, 5.84, N, 6.98%. Calcd for C20H24Cl2N2O2: C,
60.76; H, 6.12; N, 7.09%.) δH(500 MHz; CDCl3) 7.01 (2 H, dd, J 8.6,
2.3 Hz, Ar), 6.88 (2 H, s, Ar), 6.97 (2 H, d, J 8.6 Hz, Ar), 3.94 (2 H, d,
J 14.2 Hz, CH2), 3.81 (2 H, d, J 14.6 Hz, CH2), 2.34 (2 H, m, cy), 2.08
(2 H, m, cy), 1.66 (2 H, m, cy), 1.16 (4 H, m, cy); δC(125 MHz; CDCl3)
156.6, 128.6, 128.0, 124.1, 123.7, 117.7, 59.7, 49.2, 30.5, 24.0. For S,S-
rac-L2Ti(OiPr)2 was synthesized similarly to rac-L1Ti(OiPr)27 (0.02
g, >95%, >95% induction). (Found: C, 55.77; H, 6.27, N, 4.73%. Calcd
for C26H36Cl2N2O4Ti: C, 55.83; H, 6.49; N, 5.01%.) δH(500 MHz;
CDCl3) 6.98 (2 H, d, J 7.2 Hz, Ar), 6.83 (2 H, s, Ar), 6.52 (2 H, d, J 8.7
Hz, Ar), 4.71 (2 H, sept, J 6.0 Hz, CH), 4.65 (2 H, d, J 14.3 Hz, CH2),
3.72 (2 H, d, 14.3 Hz, CH2), 2.25 (2 H, m, cy), 2.16 (2 H, m, cy), 1.62
(2 H, m, cy), 1.20 (6 H, d, J 6.2 Hz, CH3), 1.0 (6 H, d, J 6.1 Hz, CH3),
0.97(2 H, m, cy), 0.76 (2 H, m, cy); δC (125 MHz; CDCl3) 161.0, 129.6,
25
L2H2 (1.4 g, 85%): [α]D = À4.7 ( 0.5°, (c = 0.25% in CHCl3).
(Found: C, 60.79; H, 5.78, N, 6.58%. Calcd for C20H24Cl2N2O2: C,
60.76; H, 6.12; N, 7.09%.) δH(500 MHz; CDCl3) 7.01 (2 H, dd, J 8.6,
2.3 Hz, Ar), 6.88 (2 H, s, Ar), 6.97 (2 H, d, J 8.6 Hz, Ar) 3.94 (2 H, d,
J 14.2 Hz, CH2), 3.81 (2 H, d, J 14.6 Hz, CH2), 2.34 (2 H, m, cy), 2.08
(2 H, m, cy), 1.66 (2 H, m, cy), 1.16 (4 H, m, cy); δC(125 MHz; CDCl3)
156.6, 128.6, 128.0, 124.1, 123.7, 117.7, 59.7, 49.2, 30.5, 24.0. These
compounds were synthesized in analogy to rac-L2H2 from R,R-1,2-
diaminocyclohexane and S,S-1,2-diaminocyclohexane, respectively.
128.5, 123.2, 121.5, 119.2, 77.8, 64.4, 58.0, 48.8, 29.8, 25.7, 24.4.
For Δ,R,R-L2Ti(OiPr)2 (0.02 g, >95%, >95% induction): [α]D
=
27
À110 ( 5° (c 0.14% in CHCl3). (Found: C, 55.72; H, 6.22, N, 4.69%.
Calcd for C26H36Cl2N2O4Ti: C, 55.83; H, 6.49; N, 5.01%.) δH(500
MHz; CDCl3) 6.98 (2 H, d, J 7.2 Hz, Ar), 6.83 (2 H, s, Ar), 6.52 (2 H, d,
J 8.7 Hz, Ar), 4.71 (2 H, sept, J 6.2 Hz, CH), 4.65 (2 H, d, J 14.3 Hz,
CH2), 3.72 (2 H, d, 14.3 Hz, CH2), 2.25 (2 H, m, cy), 2.16 (2 H, m, cy),
1.62 (2 H, m, cy), 1.20 (6 H, d, J 6.1 Hz, CH3), 1.0 (6 H, d, J 6.1 Hz,
CH3), 0.97(2 H, m, cy), 0.76 (2 H, m, cy); δC (125 MHz; CDCl3)
7
rac-L3H2 was synthesized in analogy to rac-L1H2 from rac-1,2-
diaminocyclohexane and 3-chlorosalicylaldehyde (1.0 g, 67% yield).
(Found: C, 60.70; H, 6.04, N, 6.98%. Calcd for C20H24Cl2N2O2: C,
60.76; H, 6.12; N, 7.09%.) δH(500 MHz; CDCl3) 7.18 (2 H, dd, J 5.2,
2.1 Hz, Ar), 6.83 (2 H, d, J 8.0 Hz, Ar), 6.65 (2 H, m, Ar), 3.94 (2 H, d,
J 14.2 Hz, CH2), 3.82 (2 H, d, J 14.6 Hz, CH2), 2.36 (2 H, m, cy), 2.05
(2 H, s, cy), 1.66 (2 H, m, cy), 1.16 (4 H, m, cy); δC(125 MHz; CDCl3)
153.4, 129.1, 126.7, 124.4, 121.1, 119.4, 59.9, 49.5, 30.3, 24.0.
161.0, 129.6, 128.5, 123.2, 121.5, 119.2, 77.8, 64.4, 58.0, 48.8, 29.8, 25.7,
27
24.4. For Λ,S,S-L2Ti(OiPr)2 (0.03 g, >95%, >95% induction): [α]D
=
111 ( 3°, (c 0.15% in CHCl3). (Found: C, 55.61; H, 6.20, N, 4.64%.
Calcd for C26H36Cl2N2O4Ti: C, 55.83; H, 6.49; N, 5.01%.) δH(500
MHz; CDCl3) 6.98 (2 H, d, J 7.2 Hz, Ar), 6.83 (2 H, s, Ar), 6.52 (2 H, d,
J 8.7 Hz, Ar), 4.71 (2 H, sept, J 6.0 Hz, CH), 4.65 (2 H, d, J 14.3 Hz,
CH2), 3.72 (2 H, d, 14.3 Hz, CH2), 2.25 (2 H, m, cy), 2.16 (2 H, m, cy),
1.62 (2 H, m, cy), 1.20 (6 H, d, J 6.0 Hz, CH3), 1.0 (6 H, d, J 6.0 Hz,
CH3), 0.97(2 H, m, cy), 0.76 (2 H, m, cy); δC (125 MHz; CDCl3)
For R,R-L3H2 (1.1 g, 73%): [α]D24 = À130 ( 8° (c 0.33% in CHCl3).
(Found: C, 61.03; H, 6.12, N, 7.11%. Calcd for C20H24Cl2N2O2: C,
60.76; H, 6.12; N, 7.09%.) δH(500 MHz; CDCl3) 7.18 (2 H, d, J 2.0, 5.0
Hz, Ar), 6.83 (2 H, d, J 8.0 Hz, Ar), 6.65 (2 H, m, Ar), 3.94 (2 H, d, J 14.2
10289
dx.doi.org/10.1021/ic201340m |Inorg. Chem. 2011, 50, 10284–10291

Inorganic Chemistry
ARTICLE
161.0, 129.6, 128.5, 123.2, 121.5, 119.2, 77.8, 64.4, 58.0, 48.8, 29.8, 25.7,
24.4 These compounds were synthesized in analogy to rac-L2Ti(OiPr)2
from R,R-L2H2 and S,S-L2H2, respectively.
chloride and hexane (0.01 g, 30%). (Found: C, 63.47; H, 6.57, N, 6.93%.
Calcd for C44H56N4O4Ti2: C, 63.47; H, 6.78; N, 6.73%.) δH(400 MHz;
CDCl3) 6.95 (2 H, dd, J 10.1, 2.2 Hz), 6.79 (2 H, dd, J 10.4, 2.7 Hz), 6.71
(2 H, s), 6.70 (2 H, d, J 10.2), 6.60 (2 H, d, J 2.2), 6.46 (2 H, d, J 10.2),
4.42 (4 H, m), 3.78 (2 H, t, J 1.2), 3.64 (2 H, dd, J 14.3, 0.8 Hz), 3.39
(2 H, d, J 10.7), 2.80 (2 H, dq, J 14.4, 4.6 Hz), 2.24 (4 H, m), 2.17 (6 H,
s), 2.10 (6 H, s), 2.24 (2 H, dq, J 14.0, 4.8 Hz), 1.68 (4 H, t, J 14.8 Hz),
1.34 (2 H, t, J 14.3 Hz), 1.13 (4 H, m), 1.00 (2 H, m), 0.68 (2 H, dq,
J 15.4, 4.1 Hz); δC (100 MHz; CDCl3) 160.8, 159.2, 129.9, 129.8, 129.8,
129.4, 127.3, 126.6, 124.9, 122.9, 117.5, 116.7, 59.9, 58.5, 49.2, 48.1, 30.3,
29.9, 24.5, 24.5, 20.5, 20.4.
rac-L3Ti(OiPr)2 was synthesized similarly to rac-L1Ti(OiPr)27 (0.02 g,
>95%, >95% induction). (Found: C, 55.45; H, 6.13, N, 5.02%. Calcd for
C26H36Cl2N2O4Ti: C, 55.83; H, 6.49; N, 5.01%.) δH(500 MHz;
CDCl3) 7.19 (2 H, d, J 7.0 Hz, Ar), 6.78 (2 H, d, J 7.6 Hz Ar), 6.52
(2 H, t, J 7.6 Hz, Ar), 4.97 (2 H, sept, J 6.2 Hz, CH), 4.78 (2 H, d, J 14.0
Hz, CH2), 3.84 (2 H, d, 14.0 Hz, CH2), 2.21 (2 H, m, cy), 2.13 (2 H, m,
cy), 1.59 (2 H, m, cy), 1.20 (6 H, d, J 6.0 Hz, CH3), 1.0 (6 H, d, J 6.0 Hz,
CH3), 0.92 (2 H, m, cy), 0.76 (2 H, m, cy); δC (125 MHz; CDCl3)
159.9, 129.0, 127.4, 123.4, 122.3, 117.0, 79.4, 67.8, 57.8, 49.3, 29.8,
Crystal data for Ti2(μ-O)2(R,R-L1)(S,S-L1) follow: C44H56N4O6Ti2
3
CH2Cl2, M = 917.65, triclinic, a = 10.531(1) Å, b = 12.598(2) Å, c =
12.731(2) Å, α = 115.766(2)°, β = 100.287(2)°, γ = 106.986(2)°, V =
1360.0(3) Å3, T = 173(1) K, space group P1, Z = 1, μ(Mo Kα) = 0.736
mmÀ1, 14 907 reflections measured, 5841 unique (Rint = 0.0302), R(Fo2)
for [I > 2σ(I)] = 0.0728, wR for [I > 2σ(I)] = 0.1842.
25.7, 24.4.
24
For Δ,R,R-L3Ti(OiPr)2 (0.02 g, >95%, >95% induction): [α]D
=
À188 ( 2° (c 0.15% in CHCl3). (Found: C, 56.03; H, 6.23, N, 5.13%.
Calcd for C26H34Cl2N2O4Ti: C, 55.83; H, 6.49; N, 5.01%). δH(500
MHz; CDCl3) 7.19 (2 H, d, J 7.0 Hz, Ar), 6.78 (2 H, d, J 7.6 Hz Ar), 6.52
(2 H, t, J 7.6 Hz, Ar), 4.97 (2 H, sept, J 6.2 Hz, CH), 4.78 (2 H, d, J 14.0
Hz, CH2), 3.84 (2 H, d, 14.0 Hz, CH2), 2.21 (2 H, m, cy), 2.13 (2 H, m,
cy), 1.59 (2 H, m, cy), 1.20 (6 H, d, J 6.0 Hz, CH3), 1.0 (6 H, d, J 6.0 Hz,
CH3), 0.92 (2 H, m, cy), 0.76 (2 H, m, cy); δC (125 MHz; CDCl3)
Ti2(μ-O)2(R,R-L1)2 was obtained from mixing Δ,R,R-L1Ti(OiPr)2
with 1000 equiv of water and further crystallized from methylene chloride
and hexane (0.01 g, 30%). (Found: C, 63.55; H, 6.67, N, 6.82%. Calcd
for C44H56N4O4Ti2: C, 63.47; H, 6.78; N, 6.73%.) δH(400 MHz;
CDCl3) 7.13 (1 H, d, J 5.5 Hz), 6.85 (1 H, d, J 8.2 Hz), 6.78 (1 H, d,
J 8.6 Hz), 6.71 (1 H, s), 6.64 (1 H, d, J 10.1 Hz), 6.55 (2 H, m), 6.42 (1 H,
s), 6.35 (1 H, d, J 8.1 Hz), 6.19 (1 H, d, J 7.9 Hz), 6.09 (1 H, d, J 7.8 Hz),
6.04 (1 H, s), 4.31 (2 H, m), 3.88 (2 H, m), 3.60 (4 H, m), 3.07 (1 H, d,
J 11.4 Hz), 2.87 (1 H, d, J 11.0 Hz), 2.20 (3 H, s), 2.16 (3 H, s), 2.13 (3 H,
s), 2.11 (3 H, s), 2.25À0.38 (22 H); δC (100 MHz; CDCl3) 161.6,
160.7, 160.2, 159.6, 130.9, 130.2, 130.2, 129.8, 129.4, 129.1, 128.9, 127.9,
126.9, 126.7, 126.6, 126.3, 124.7, 124.5, 124.2, 122.0, 117.6, 116.6, 116.4,
115.7, 60.7, 60.1, 60.1, 59.8, 49.8, 48.7, 47.8, 47.4, 30.7, 30.5, 29.4, 28.4,
25.4, 24.7, 24.6, 21.2, 20.7, 20.6, 20.5, 20.4.
159.9, 129.0, 127.4, 123.4, 122.3, 117.0, 79.4, 67.8, 57.8, 49.3, 29.8, 25.7,
24.4. For Λ,S,S-L3Ti(OiPr)2 (0.02 g, >95%, >95% induction): [α]D
=
26
195 ( 3° (c 0.13% in CHCl3). (Found: C, 56.05; H, 6.35, N, 5.14%.
Calcd for C26H34Cl2N2O4Ti: C, 55.83; H, 6.49; N, 5.01%.) δH(500
MHz; CDCl3) 7.19 (2 H, d, J 7.0 Hz, Ar), 6.78 (2 H, d, J 7.6 Hz Ar), 6.52
(2 H, t, J 7.6 Hz, Ar), 4.97 (2 H, sept, J 6.2 Hz, CH), 4.78 (2 H, d, J 14.0
Hz, CH2), 3.84 (2 H, d, J 14.0 Hz, CH2), 2.21 (2 H, m, cy), 2.13 (2 H, m,
cy), 1.59 (2 H, m, cy), 1.20 (6 H, d, J 6.2 Hz, CH3), 1.0 (6 H, d, J 6.0 Hz,
CH3), 0.92 (2 H, m, cy), 0.76 (2 H, m, cy); δC (125 MHz; CDCl3)
159.9, 129.0, 127.4, 123.4, 122.3, 117.0, 79.4, 67.8, 57.8, 49.3, 29.8, 25.7,
24.4. These compounds were synthesized in analogy to rac-L4aTi-
(OiPr)2 from R,R-L3H2 and S,S-L3H2, respectively.
Crystal data for Ti2(μ-O)2(R,R-L1)2 follow: C44H56N4O6Ti2
2
3
CH2Cl2, M = 917.65, monoclinic, a = 8.4605(7) Å, b = 14.937(1) Å,
c = 17.662(2) Å, β = 96.117(1)°, V = 2219.2(3) Å3, T = 173(1) K, space
group P21, Z = 2, μ(Mo Kα) = 0.532 mmÀ1, 25 290 reflections
measured, 10 287 unique (Rint = 0.0188), R(Fo2) for [I > 2σ(I)] =
0.0320, wR for [I > 2σ(I)] = 0.0856.
rac-L4Ti(OiPr)2 was synthesized similarly to rac-L1Ti(OiPr)27 (0.02 g,
>95%, >95% induction). (Found: C, 60.87; H, 7.70, N, 4.80%. Calcd for
C28H42N2O6Ti: C, 61.09; H, 7.69; N, 5.09%.) δH(500 MHz; CDCl3) 6.73
(2 H, t, J 5.0 Hz, Ar), 6.52 (4 H, d, J 4.0 Hz Ar), 4.78 (2 H, sept, J 6.1 Hz,
CH), 4.71 (2 H, d, J14.0Hz, CH2), 3.82(2H, d, 14.1Hz, CH2), 3.80(6H,
s, CH3), 2.35 (2 H, m, cy), 2.16 (2 H, m, cy), 1.59 (2 H, m, cy), 1.20 (6 H, d,
J 6.3 Hz, CH3), 1.0 (6 H, d, J 6.5 Hz, CH3), 0.92 (2 H, m, cy), 0.76 (2 H, m,
cy); δC (125 MHz; CDCl3) 153.5, 148.6, 122.6, 121.8, 116.2, 113.1, 77.5,
Crystal data for Ti4(μ-O)4(R,R-L1)4 follow: C88H112N8O12Ti4
3
CH2Cl2, M = 1750.38, monoclinic, a = 22.568(3) Å, b = 13.3559(15) Å,
c = 31.153(4) Å, β = 100.928(2)°, V = 9219.4(18) Å3, T = 173(1) K,
space group C2, Z = 4, μ(Mo Kα) = 0.453 mmÀ1, 50 725 reflections
measured, 19 798 unique (Rint = 0.0623), R(Fo2) for [I > 2σ(I)] =
0.0896, wR for [I > 2σ(I)] = 0.2196.
57.9, 57.0, 49.0, 29.8, 25.8, 25.7, 24.4.
27
For Δ,R,R-L4Ti(OiPr)2 (0.02 g, >95%, >95% induction): [α]D
=
À235 ( 8° (c 0.15% in CHCl3). (Found: C, 60.83; H, 7.65, N, 5.16%.
Calcd for C28H42N2O6Ti: C, 61.09; H, 7.69; N, 5.09%.) δH(500 MHz;
CDCl3) 6.73 (2 H, t, J 5.1 Hz, Ar), 6.52 (4 H, d, J 4.2 Hz Ar), 4.78 (2 H,
sept, J 6.1 Hz, CH), 4.71 (2 H, d, J 14.0 Hz, CH2), 3.82 (2 H, d, 14.2 Hz,
CH2), 3.80 (6.0 H, s, CH3), 2.35 (2 H, m, cy), 2.16 (2 H, m, cy), 1.59
(2 H, m, cy), 1.20 (6 H, d, J 6 Hz, CH3), 1.0 (6 H, d, J 6.4 Hz, CH3), 0.92
(2 H, m, cy), 0.76 (2 H, m, cy); δC (125 MHz; CDCl3) 153.5, 148.6,
122.6, 121.8, 116.2, 113.1, 77.5, 57.9, 57.0, 49.0, 29.8, 25.8, 25.7, 24.4.
For Λ,S,S-L4Ti(OiPr)2 (0.02 g, >95%, >95% induction): [α]D27= 248 (
10° (c 0.16% in CHCl3). (Found: C, 60.67; H, 7.48, N, 5.11%. Calcd for
C28H42N2O6Ti: C, 61.09; H, 7.69; N, 5.09%.) δH(500 MHz; CDCl3)
6.73 (2 H, t, J 5.0 Hz, Ar), 6.52 (4 H, d, J 4.3 Hz Ar), 4.78 (2 H, sept, J 6.1
Hz, CH), 4.71 (2 H, d, J 14.5 Hz, CH2), 3.82 (2 H, d, 14.5 Hz, CH2),
3.80 (6 H, s, CH3), 2.35 (2 H, m, cy), 2.16 (2 H, m, cy), 1.59 (2 H, m, cy),
1.20 (6 H, d, J 6.0 Hz, CH3), 1.0 (6 H, d, J 6.3 Hz, CH3), 0.92 (2 H, m,
cy), 0.76 (2 H, m, cy); δC (125 MHz; CDCl3) 153.5, 148.6, 122.6, 121.8,
116.2, 113.1, 77.5, 57.9, 57.0, 49.0, 29.8, 25.8, 25.7, 24.4. These
compounds were synthesized in analogy to rac-L5aTi(OiPr)2 from R,
R-L4H2 and S,S-L4H2, respectively.
’ ASSOCIATED CONTENT
S
Supporting Information. Cytotoxic activity for complexes
b
rac-, Δ,R,R-, and Λ,S,S-L1À4Ti(OiPr)2 toward OVCAR-1 cancer
cell lines (Figures S1ÀS4), 1H NMR (aromatic region) of Ti2-
(μ-O)2(R,R-L1)(S,S-L1) and Ti2(μ-O)2(R,R-L1)2 (Figure S5),
and CD spectra of Δ,R,R- and Λ,S,S-L1À4Ti(OiPr)2 (Figure S6).
Crystal data in CIF format. This material is available free of
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: tshuva@chem.ch.huji.ac.il.
’ ACKNOWLEDGMENT
We thank Dr. Shmuel Cohen for crystallography. We also
thank Professor David Avnir and Shahar Sukenik for assistance
with CD measurements. This research received funding from the
Ti2(μ-O)2(R,R-L1)(S,S-L1) was obtained from mixing rac-L1Ti-
(OiPr)2 with 1000 equiv of water and crystallized from methylene
10290
dx.doi.org/10.1021/ic201340m |Inorg. Chem. 2011, 50, 10284–10291

Inorganic Chemistry
ARTICLE
European Research Council under the European Community’s
Seventh Framework Programme (FP7/2007-2013)/ERC Grant
Agreement [239603], and from the Israel Science Foundation
(Grant124/09) and Israel Cancer Research Fund (ICRF).
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