Synthesis and crystal structure of the bis-calcimycin anion–Ni 2+ complex

The X-ray structure of [Ni(calcimycin) 2 ] complex shows two essentially identical conformations of the two calcimycin ligands in the dimeric association, in this ionophore family. In the title complex, the nickel (II) cation has a distorted O 4 N 2 octahedral coordination environment


Introduction
2] Its non-fluorescent 4-bromo derivative was subsequently described and found suitable for the same application in the presence of fluorescent probes.Erdahl and colleagues 4a recently showed that 4-bromo derivative of compound (I) transports Zn 2+ and Mn 2+ with high selectivity over Ca 2+ in phospholipid vesicles, and they made interesting findings concerning the stochiometry of species involved in the transport.However, information on the structure of cation complexes with this natural ligand was lacking.
We recently undertook the preparation of crystalline adducts of (I) with various divalent cations suitable for X-ray analysis.Here we report the crystal structure obtained for a cation of topical biological interest, Ni 2+ , which reveals unusual features.

Synthesis of bis-calcimycin anion-Ni 2+ complex
To obtain the complex, we used a (H 2 O / CH 2 Cl 2 ) biphasic system in which the free calcimycin acid dissolved in the organic layer was stirred with an aqueous NiCl 2 solution at pH superior of 10. 1 H and 13 C NMR data 1 H and 13 C NMR data of calcimycin acid as free ligand were acquired as previously described 4b using either Bruker 300 or AX 400 spectrometers.Chemical shifts are referred to tetramethylsilane (Figures 2 and 4).
It will be difficult to elucidate the correct coordination of nickel from 1 H and 13 C NMR data of compound II.By compareason with the 1 H and 13 C NMR data of free ligand I.The hydrogen

Crystallographic structure analysis
The crystal structure determination by X-ray diffraction was consistent with the neutral dicarboxylate complex [Ni(calcimycin) 2 ] (Fig. 6).The nickel atom occupied the centre of a slightly distorted octahedron (Table 2).
The two ligands show very similar conformations, bind the nickel through the same groups and are related by pseudo-twofold symmetry.
Coordinations of Ni were provided by O2, N2, O6 of the first calcimycin ligand; L1, and correspondingly by O8, N5 and O12 of the second ligand, L2 of L2.Note that the ligands are tridentate (Figure 6).Octahedral arrangements of the same type of ligand were recently described for Zn(II) complexes containing more simple aromatic moities with nitrogen and carboxylate coordinating sites, but no such unsymmetrically bound ligand with a bidentate/ tridentate arrangement has been described. 5The specific conformation adopted by L1 and L2 did not permit the two head-to-tail intermolecular chelations observed in the well-known calcimycin dimeric complexes [6][7][8] described for Ca 2+ , Mg 2+ and Fe 2+ .Two intermolecular hydrogen chelation remained for Ni-O2…N6 of pyrrol and Ni-O8…N3 of pyrrol rings.
Also, the 3-aminomethyl substituent which was NH-chelated with the carboxylate group for Calcimycin [6][7][8] was moved out of the aromatic plane owing to the presence of the bulky carboxylate groups in the C7 of L1 or C31 position of L2, and the existing intramolecular hydrogen bonding was thus suppressed.Absorption correction:.multi-scan (SADABS) 10 Structure determination: SIR97 11 Refinement: full matrix least-squares SHELXL-97 12 CCDC 663241 contains the supplementary crystallographic data for this paper.These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.  ARKAT USA, Inc.
Interestingly, for both L1 and L2 the ketopyrrole arm adopted the preferential orientation already observed in the solid [6][7][8] and liquid state 13 for calcimycin with the characteristic antiperiplanar position of H atoms.
All these observations suggest that in the complex formation, a 2...1 (L1-Ni + ) association occurs followed by the simultaneous approach of the two ligands L1 and L2.The latter is able to displace the remaining water ligand by its ketone function to give a final 2...1 supramolecular association.This may be related to the transport experiments in vesicles. 4We could suppose that Ni 2+ is transported, in part, as a 2...1 and 1…1 complexes in a pH-dependent stoichiometry.

Conclusions
In conclusion, we describe here what is to our knowledge the first Nickel complex structure obtained with calcimycin.Furthermore, the Ni 2+ complex studied shows an unusual supramolecular scaffold compared with known calcimycin Ca 2+ , Mg 2+ and Fe 2+ dimeric arrangements and with other described carboxylate zinc complexes.As recently stated, 14 zinc homeostasis studies in higher animals and humans have proved difficult.This work may therefore help gain a better understanding of the difference in mechanism of cellular transport of zinc and nickel through biological membranes.

Experimental Section
Preparation.A solution of calcimycin free acid (2 mmol) in CH 2 Cl 2 (20 mL) was stirred with aqueous solution of NiCl 2 .6H 2 O (50 mL).The pH of (H 2 O / CH 2 Cl 2 ) solution containing organic ligand and metallic precursor was adjusted to ca. 10.5 by addition of tetrabutylammonium hydroxide.The mixture was stirred at 20°C for 4 h under atmospheric pressure in the dark.The organic layer was then dried over anhydrous Na 2 SO 4 , filtered and evaporated.The solid residue was dissolved in MeOH and the solvent was left to evaporate at 20 °C for 2 week in the dark.Pale green crystals obtained proved suitable for X-ray analysis.

Crystal structure analysis
The crystal structure of the title compound has been determined at room temperature.Data were collected using a Bruker SMART APEX-II CCD diffractometer system, using graphite-ARKAT USA, Inc. monochromated MoK α radiation.Molecules crystallize in the orthorhombic space group P 2 1 2 1 2 1 .
The crystallographic details are given in Table 1.The structure was solved by direct methods by using SIR-97 program 11 and refined by least-squares on F obs 2 in SHELXL-97 program. 12All H atoms bonded to C and N were inserted at calculated positions and refined using a riding model.The isotropic displacement parameters for H atoms were assigned U iso (H) = 1.2U eq or 1.5U eq (carrier atom).A displacement ellipsoid plot with the atomic numbering scheme of the title compound is shown in Figure 2; with selected bond angles and hydrogen-bond parameters in Tables 2 and 3.
The structure shows an approximately octahedral coordination pattern for the Ni II atom.The mean Ni-N and Ni-O distances are 2.0635 (7) and 2.0475(5) Å.These distances in agreement with values reported previously for Ni II complexes. 15The Flack parameter is 0.01 (2), thus the absolute configuration is determined reliably. 16The piperidine rings adopts a chair conformation and 3,4-dihydro-2H-pyrrole rings are planar.The molecular structure of the title compound is stabilized by intramolecular N-H O intermolecular interactions (Table 3).

Figure 6 .
Figure 6.ORTEP drawing of [Ni(calcimycin) 2 ] crystal structure showing the very similar conformations in the ligands and intramolecular N-H…O bonds.H atoms have been omitted for clarity.Displacement ellipsoids are drawn at the 10% probability level.

Figure 7 .
Figure 7.A representation of L1 and L2 ligands structure coordinated with Ni 2+ showing no specific benzoxazole rotation in L2 or L1.

Table 1 .
Crystal and experimental data