Control of the platinum(II) ligating properties of rigid 1,2-diamines: the case of trans-2,3-diaminonorbornane

Article abstract of DOI:10.1016/j.tetlet.2006.09.054

Guided by a simple predictive model, a norbornane-based trans-1,2-diamine was identified as a potential bridging ligand for di-nuclear platinum complex formation; efficient synthesis and product characterization confirmed this hypothesis.

Full text of DOI:10.1016/j.tetlet.2006.09.054

Tetrahedron Letters 47 (2006) 8091–8093
Control of the platinum(II) ligating properties of rigid
1
,2-diamines: the case of trans-2,3-diaminonorbornane
Aur e´ lie Maisonial, Mounir Traikia, Arnaud Gautier and David J. Aitken*
*
Laboratoire SEESIB, CNRS-UMR 6504, D e´ partement de Chimie, Universit e´ Blaise Pascal, Clermont-Ferrand II,
4 avenue des Landais, 63177 Aubi e` re cedex, France
2
Received 21 July 2006; revised 11 September 2006; accepted 12 September 2006
Available online 2 October 2006
Abstract—Guided by a simple predictive model, a norbornane-based trans-1,2-diamine was identified as a potential bridging ligand
for di-nuclear platinum complex formation; efficient synthesis and product characterization confirmed this hypothesis.
Ó 2006 Elsevier Ltd. All rights reserved.
H2
N
Pt
H2
N
H2N PtX3
Polyfunctional ligands serve as convenient molecular
scaffolds for the preparation of multinuclear transition
metal complexes. From Farrell’s pioneering work, inter-
est has emerged for di and trinuclear platinum(II)
complexes, featuring flexible aliphatic 1,x-diamines as
bridging ligands, that exhibit cytotoxicity and overcome
the resistance phenomena often encountered with
X
X
PtX3
PtX3
H2N PtX3
H2N PtX3
N
N
H2
2
H N PtX3
H2
85°
Bi nuclear
Intermediate
H2
N
Pt
58°
120°
X
X
50°
N
1
H2
cisplatin. Another class of di-nuclear platinum com-
pounds, based on 1,2-azole ligands have been intro-
duced recently by Komeda, Reedijk and co-workers.
Mono nuclear
2
By a fine tuning of the inter-platinum distance, ligation
occurs with a minimum kink of the DNA, rendering the
enzymatic repair processes inefficient. The distance
between the metal centres is of a paramount importance
for directing intra- or inter-strand ligation.
Scheme 1. Relationship between ligand bite angle and behaviour.
which can dispose four different vicinal diamines motifs
(
Scheme 2).
The N–C–C–N dihedral angle of a 1,2-diamine deter-
mines the formation of a mono- or a di-nuclear
complex, according to Scheme 1. Two domains are
established: at a low dihedral angle, chelation occurs
and a 1:1 ligand:metal stoichiometry is observed,
whereas at a high dihedral angle, bridging behaviour
and a 1:2 stoichiometry predominate. The transition
from mono to di-nuclear domains is located somewhere
between 60° and 80°.
Quantum screening at the HF/6-31G level (Gaussian,
gas phase) indicated that among the four structures
depicted in Scheme 2, only 1 (or its dihydrochloride salt
4a
3
1
Æ2HCl) possesses an appropriate dihedral angle for
forming a di-nuclear platinum complex. Reinvestigation
++
4
at B3LYP/6-31G
(water) level indicates the follow-
ing angles: for 1, N –C –C –N : 104° and H –C –C –
1
1
2
2
1
1
2
H : 125° for 1Æ2HCl, N –C –C –N : 112° and H –C –
2
1
1
2
2
1
1
C –H : 125°. The bite angle depends to a certain extent
2
2
on whether the nitrogen lone pairs are involved in
bonding.
To extend the suite of fixed dihedral angle ligands for
fine tuning of platinum complex formation, here we con-
sider the bicyclo[2.2.1]heptane (norbornane) skeleton,
5
After consulting the literature precedents, we devised a
more convenient synthesis of 1 (Scheme 3). Evans aziri-
6
*
Corresponding authors. Fax: +33
4
73 40 77 17; e-mail
dination of norbornene 5 afforded 6 as expected. The
addresses: Arnaud.Gautier@univ-bpclermont.fr; David.Aitken@
univ-bpclermont.fr
challenging step consisted of the aziridine ring opening
of 6 by nitrogen nucleophile attack on the endo face.
7
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.054

8092
A. Maisonial et al. / Tetrahedron Letters 47 (2006) 8091–8093
NH2
NH2
NH2
H N
2
H N
2
NH2
NH2
H N
2
1
2
3
4
Scheme 2. Different norbornane-based 1,2-diamines envisaged.
NHTos
NTos
i
ii
iii
5
6
7
N3
Cl
NHTos
NH3
X
H N
2
Pt
dmso
Cl
iv
vi
Cl
NH2
NH3
X
H N
Pt
dmso
1
·2HBr
·2HCl
2
8
v
Cl
9
1
Scheme 3. Reagents and conditions: (i) PhINTos, Cu(Acac)
2
(5 mol %), MeCN, 66%; (ii) NaN
3
, Bu
4
NBr (15 mol %), DMF, 125 °C, 21 h, 88%; (iii)
(DMSO), KOH (2.0 equiv), H O, 84%.
H
2
, Pd/C, MeOH, 95%; (iv) HBr/AcOH (32%), 100 °C, 82%; (v) Dowex marathon 11, 98%; (vi) KPtCl
3
2
To our satisfaction, sodium azide and a catalytic
Kukushkin’s salt, KPtCl (DMSO), is an ideal partner
3
amount of TBAB in hot DMF provided azide 7
smoothly. This compound was easily hydrogenated to
for the formation of
complex.
a
1:2 ligand:Pt bridging
The reaction of 1Æ2HCl with 2 equiv of this
reagent led to the formation of a pale yellow solid within
8
11,3
amine 8 in a 95% yield. Deprotection was achieved using
HBr/AcOH (82%) followed by an anion exchange to
yield dihydrochloride 1Æ2HCl. Overall, this new synthe-
sis provided a rapid and secure access to 1 in 67% from
the published aziridine 6. The H –C–C–H dihedral
1
2
a few minutes, isolated by filtration (84% yield). The
structure of the complex was confirmed as 9 from
1
95
Pt NMR (resonance at d ꢀ3115 ppm, characteristic
1
3
of an N SCl coordination set ), electrospray mass
1
2
2
angle was determined on the intermediate dihydrobro-
spectroscopy and elemental analysis.
mide 1Æ2HBr with the aid of the Diez–Altona–Donders
9
(
DAD) Karplus type equation, which is more accurate
In conclusion, we have demonstrated a new access to
diamine 1, which behaves appropriately for the prepara-
tion of single l-ligand di-nuclear platinum(II) struc-
tures. Further work is now in progress to extend this
approach to the preparation of other platinum com-
plexes for cytotoxicity evaluation.
than the classical version and takes into account the
solvent effect, the nature of the substituents and their
3
1
1
spatial relationship. The measured J ( H– H) value
was 3.80 Hz; application of the DAD equation gives a
dihedral angle of 124.7°, a value very close to our
predicted value of 125°.
Hatano and Saito reported that a single enantiomer of
Acknowledgement
2
,3-diamino[2.2.1]heptane, 1, reacted with PtCl (en) to
2
give a di-nuclear complex of formula [Pt (en) 1 ] featur-
2
2 2
We thank B. Legeret and R. Egros for technical support.
We are grateful to the Cancerop oˆ le d’Auvergne for
financial support.
ing two l-1 ligands; only limited structural support was
1
0
presented however. This preliminary observation was
encouraging but such a structure does not form the basis
for useful interactions with DNA since (a) no room is
left for the modulation of leaving groups on the Pt cen-
tres, and (b) a double-bridging structure imposes exces-
sively severe constraints on the relative dispositions of
the two square planar Pt centres. It was thus important
to demonstrate access to a di-nuclear species with a
single l-1 ligand.
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8
H: 3.24%, N: 3.53%.
6
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