Axially chiral Ni(II) complexes of α‐amino acids: Separation of enantiomers and kinetics of racemization

Herein we present design, synthesis, chiral HPLC resolution, and kinetics of racemization of axially chiral Ni(II) complexes of glycine and di‐(benzyl)glycine Schiff bases. We found that while the ortho‐fluoro derivatives are configurationally unstable, the pure enantiomers of corresponding axially chiral ortho‐chloro‐containing complexes can be isolated by preparative HPLC and show exceptional configurational stability (t_1/2 from 4 to 216 centuries) at ambient conditions. Synthetic implications of this discovery for the development of new generation of axially chiral auxiliaries, useful for general asymmetric synthesis of α‐amino acids, are discussed.     

Synthesis and X‐ray diffraction study of a chiral bis‐phosphahelicene palladium (II) complex

As a complement to our previous studies on the development of a class of chiral phosphahelicenes, this article discloses the synthesis, spectroscopic, and structural characterizations of a new phosphahelicene transition metal complex. It demonstrates the ability of these hindered chiral ligands to coordinate Pd (II) in trans‐complexes Cl₂Pd(L*)₂. In the solid state, the complex adopts a C2‐symmetric arrangement with two ligands facing each other on the same face of the coordination plane. X‐Ray data highlight bending of the Pd (II) unit from the expected planar coordination geometry that might be due to a significant π‐π stacking effect between the central rings of two helical units.     

The epimerization of chiral half sandwich 2-phenylpyridine-based ruthenacycle

The reaction of a chiral terpenic 2-phenylpyridine with mercury (II) acetate afforded a new ortho-chloromercurated substrate, which was treated with [(η⁶-cymene)RuCl₂]₂ to afford two diastereomers of the corresponding half-sandwich cyclochlororuthenated terpenic ligand. The latter two complexes were successfully separated by conventional chromatography and their configurational stability investigated by ¹H NMR and CD spectroscopy. It was found that both isolated diastereomers displayed a fair configurational stability in CH₂Cl₂ while when dissolved in MeOH they epimerize. It was shown that the rate of epimerization is rather slow in pure MeOH, whereas in the presence of an excess of Lewis acid such as HgCl₂ it was notably accelerated suggesting that the decoordination of the chloride from the Ru(II) center is a key step in the epimerization process.     

Stereochemical Properties of Multidentate Nitrogen Donor Ligands and Their Copper Complexes by Electronic CD and DFT

UV–Vis and electronic circular dichroism (ECD) spectroscopy, complemented with Density Functional Theory (DFT) calculations, were used to elucidate the structural diversities of three multidentate nitrogen donor ligands and two associated copper complexes in solution directly. The three chiral salen ligands all consist of trans‐cyclohexane‐1,2‐diamine as a chiral scaffold and also of pyridine rings as chromophores, differing only in the linking groups between the two functional groups mentioned above. Very different ECD intensities and somewhat different ECD patterns were observed for these ligands and satisfactorily interpreted theoretically. For the geometry optimization and spectral simulation of the open‐shell metal complexes, the LANL2DZ basis set with effective core potential for the Cu and Cl atoms and pure cc‐pVTZ for the rest of the atoms was utilized. The performance of the same calculations with the polarization functions (f,g) from the cc‐pVTZ basis added to the LANL2DZ basis was compared. While the three ligands exhibit different conformational flexibility, the associated copper complexes show great rigidity imposed by the metal–ligand coordination, taking on a single structure in each case. In addition, dispersion interactions were shown to change the conformational stability ordering of the ligands noticeably and to exert considerable influence on the simulated UV–Vis and ECD spectra. Chirality 28:545–555, 2016. © 2016 Wiley Periodicals, Inc.     

Effect of substituents on the configurational stability of the stereogenic nitrogen in metal(II) complexes of α‐amino acid Schiff bases

Herein, we report a general method for quantitative measurement of the configurational stability of the stereogenic nitrogen coordinated to M (II) in the corresponding square planar complexes. This stereochemical approach is quite sensitive to steric and electronic effects of the substituents and shown to work well for Ni(II), Pd(II), and Cu(II) complexes. Structural simplicity of the compounds used, coupled with high sensitivity and reliability of experimental procedures, bodes well for application of this approach in evaluation of chemical stability and stereochemical properties of newly designed chiral ligands for general asymmetric synthesis of tailor‐made amino acids.     

Nonhanded chirality in octahedral metal complexes

Chiral molecules can either be handed (i.e., "shoes") or nonhanded ("potatoes"). The only chiral ligand partition for tetrahedral metal complexes (or for a tetrahedral carbon atom such as that found in amino acids and other chiral biological molecules) is the fully unsymmetrical degree 6 partition (1(4)), which leads to handed metal complexes of the type MABCD with a lowest-degree chirality polynomial consisting of the product of all six possible linear factors of the type (s(i)-s(j)) where 1 < or = i,j < or = 4. The lowest-degree chiral ligand partitions for octahedral metal complexes are the degree 6 partitions (31(3)) and (2(3)) leading to handed chiral metal complexes of the types fac-MA(3)BCD and cis-MA(2)B(2)C(2). The form of the lowest-degree chirality polynomial for the (31(3)) chiral ligand partition of the octahedron resembles that of the (1(4)) chiral ligand partition of the tetrahedron, likewise with four different ligands. However, the form of the lowest-degree chirality polynomial for the (2(3)) chiral ligand partition of the octahedron corresponds to the square of the chirality polynomial of the (1(3)) chiral ligand partition of the polarized triangle, which likewise has three different ligands. Ligand partitions for octahedral metal complexes such as (2(2)1(2)), (21(4)), and (1(6)), which are less symmetrical than the lowest-degree chiral ligand partitions (31(3)) and (2(3)), lead to chiral octahedral metal complexes which are nonhanded. In such complexes, pairs of enantiomers can be interconverted by simple ligand interchanges without ever going through an achiral intermediate.     

N-heterocyclic carbenes of the late transition metals: a computational and structural database study

A combined computational chemistry/crystallographic database analysis of the bonding in late transition metal N-heterocyclic carbene complexes (NHCs) is reported. The metal-carbon bond in these complexes is approximately 4% shorter than a prototypical M-C single bond, e.g., as in a metal-alkyl complex. Two hypotheses are investigated for this bond shortening - multiple-bond character in the metal-carbon linkage of the NHC complex, and a change in the hybridization of the carbenoid carbon to incorporate more p character. The results of this research support the latter hypothesis. The natural bond order analysis also suggests a substantial trans influence for NHC ligands.     

Different behavior toward racemization in basic media from chiral analogs of clofibric acid, the active metabolite of the antilipidemic drug clofibrate

Some chiral analogs of clofibric acid, the active metabolite of the antilipidemic drug clofibrate, show different configurational stability in basic conditions. Also, extensive racemization occurs when the corresponding optically active acid chlorides are treated with 3 alpha-tropanol, whereas no racemization takes place with 3 alpha-tropanol as hydrochloride salt and with 3 beta-tropanol and 1-methyl-4-hydroxy-piperidine as either the free base or hydrochloride salt. For these aminoalcohols, experimental evidence supports the hypothesis that a ketene intermediate is involved in the racemization process. Formation of intramolecular hydrogen bond is evoked to explain the different ability of aminoalcohols to induce ketene formation and consequent racemization.     

On the use of chiral compounds for probing the DNA handedness: Z to B conversion in poly(dGm5dC) upon binding of Fe(phen)3(2+) and Ru(phen)3(2+)

In order to examine whether chiral metal complexes can be used to discriminate between right- and left-handed DNA conformational states we have studied the enantioselective interactions of Fe(phen)3(2+) and Ru(phen)3(2+) (phen = 1,10-phenanthroline) with poly(dGm5dC) under B- and Z-form conditions. With the inversion-labile Fe(phen)3(2+), enantioselectivity leads to shifts in the diastereomeric binding equilibria. This effect, known as the "Pfeiffer effect" (1-4), is monitored as slowly emerging circular dichroism of the solution, corresponding to a net excess of the favoured enantiomer. With Ru(phen)3(2+), which is stable to intramolecular inversion, the difference in DNA-binding strengths of the enantiomers results in an excess of the less favoured enantiomer in the bulk solution. This excess is detected in the dialysate of the DNA/metal complex solution. With both complexes we find that the delta-enantiomer is favoured when the polynucleotide adopts the B-form, as previously shown, but also when it initially adopts the Z-form conformational state. This observation, together with evidence from UV-circular dichroism and binding data, indicates that the binding of these metal complexes induces a Z- to B-form transition in Z-form poly(dGm5dC). Consequently, neither of the studied chiral DNA-binders can easily be used to discriminate the DNA handedness.     

Synthesis of alternating metallocopolymers by chiral recognition

We report the synthesis of chiral enantiopure polytopic bridging ligands, which may lead to the formation of metallosupramolecular polymers with zinc (II) as metal linker. We show that chiral C₂‐symmetric bisoxazoline ligands are useful moieties to efficiently generate heterochiral complexes and thus polymeric entities. The corresponding metallopolymers were further characterized by powder X‐ray diffraction (PXRD) to obtain information on the level of crystallinity of our different metallopolymers.     

Enantioselective Ethylation of Various Aldehydes Catalyzed by Readily Accessible Chiral Diols

Four chiral C₂‐symmetric diols were synthesized in a straightforward three‐step reaction and demonstrated excellent enantioselectivities and good overall yields. Their catalytic activities were examined via the addition of diethylzinc to various aldehydes. The enantioselective addition of diethylzinc to 2‐methoxybenzaldehyde gave the corresponding chiral secondary alcohol with high yields (up to 95%) and moderate to good enantiomeric excess (up to 88%). All synthesized ligands were evaluated in the addition of diethylzinc to various aldehydes in the presence of an additional metal such as Ti(IV) complexes. Chirality 28:593–598, 2016. © 2016 Wiley Periodicals, Inc.     

Pyridine-2,6-bis(thiocarboxylic acid) Produced by <Emphasis Type="BoldItalic">Pseudomonas stutzeri</Emphasis> KC Reduces Chromium(VI) and Precipitates Mercury,Cadmium, Lead and Arsenic

Interactions of the Pseudomonas stutzeri KC siderophore pyridine-2,6-bis(thiocarboxylic acid) (pdtc) with chromium(VI), mercury(II), cadmium(II), lead(II), and arsenic(III) are described. Pdtc was found to reduce Cr(VI) to Cr(III) in both bacterial cultures and in abiotic reactions with chemically synthesized pdtc. Cr(III) subsequently formed complexes with pdtc and pdtc hydrolysis products, and their presence was confirmed using electrospray ionization-mass spectrometry (ESI-MS). Cr(III):pdtc complexes were found to slowly release Cr(III) as chromium sulfide and possibly Cr(III) oxides. Pdtc also formed poorly soluble complexes with Hg, Cd, Pb, and As(III). Hydrolysis of those complexes led to the formation of their respective metal sulfides as confirmed by energy dispersive X-ray spectroscopy (EDS) elemental analysis. The pdtc-producing strain P. stutzeri KC showed higher tolerance to most of these metals as compared to a pdtc-negative mutant. A novel role of pdtc is postulated as its involvement in providing an extracellular pool of thiols that are used for redox processes in detoxification of the bacterial extracellular environment. These redox processes can be mediated by transition metal:pdtc complexes.     

Influence of transition metals on halogen-bonded complexes of MCCBr∙∙∙NCH and HCCBr∙∙∙NCM' (M, M' = Cu, Ag, and Au)

We have performed quantum chemical calculations for the MCCBr???NCH and HCCBr???NCM' (M, M'?=?Cu, Ag, and Au) halogen-bonded complexes at the MP2 level. The results showed that the transition metals have different influences on the halogen bond donor and the electron donor. The transition metal atom in the former makes the halogen bond weaker, and that in the latter causes it to enhance. Molecular electrostatic potential and natural bond orbital analysis were carried out to reveal the nature of the substitution.     

In silico and in vitro studies of transition metal complexes derived from curcumin–isoniazid Schiff base

Abstract

A series of transition metal complexes have been synthesized from biologically active curcumin and isoniazid Schiff base. They are characterized by various spectral techniques like UV–Vis, Fourier transform infrared (FT-IR), nuclear magnetic resonance (NMR), electron paramagnetic resonance (EPR) and mass spectroscopies. Moreover, elemental analysis, magnetic susceptibility and molar conductivity measurements are also carried out. All these data evidence that the metal complexes acquire square planar except zinc(II) which adopts a tetrahedral geometry, and they are non-electrolytic in nature. Groove mode of binding between the calf thymus DNA (CT DNA) and metal complexes is confirmed by electronic absorption titration, viscosity and cyclic voltammetry studies. In addition to that, all the metal complexes are able to cleave pUC 19 DNA. Optimized geometry and ground-state electronic structure calculations of all the synthesized compounds are established out by density functional theory (DFT) using B3LYP method which theoretically reveals that copper(II) complex explores higher stability and higher biological accessibility. This is experimentally corroborated by antimicrobial studies. In silico Absorption, Distribution, Metabolism, Excretion (ADME) studies reveal the biological potential of all synthesized complexes, and also biological activity of the ligand is predicted by PASS online biological activity prediction software. Molecular docking studies are also carried out to confirm the groove mode of binding and receptor–complex interactions.     

On the Use of Chiral Compounds for Probing the DNA Handedness: Z to B Conversion in Poly(dGm5dC) Upon Binding of Fe(phen)3 2+ and Ru(phen)3 2+

Abstract

In order to examine whether chiral metal complexes can be used to discriminate between right- and left-handed DNA conformational states we have studied the enantioselective interactions of Fe(phen)₃ ²⁺ and Ru(phen)₃ ²⁺ (phen = 1,10-phenanthroline)with poly(dGm⁵dC) under B- and Z-form conditions. With the inversion-labile Fe(phen)₃ ²⁺, enantioselectivity leads to shifts in the diastereomeric binding equilibria. This effect, known as the “Pfeiffer effect” (1–4), is monitored as a slowly emerging circular dichroism of the solution, corresponding to a net excess of the favoured enantiomer. With Ru(phen)₃ ²⁺, which is stable to intramolecular inversion, the difference in DNA-binding strengths of the enantiomers results in an excess of the less favoured enantiomer in the bulk solution. This excess is detected in the dialysate of the DNA/metal complex solution. With both complexes we find that the Δ-enantiomer is favoured when the polynucleotide adopts the B-form, as previously shown, but also when it initially adopts the Z-form conformational state.

This observation, together with evidence from UV-circular dichroism and binding data, indicates that the binding of these metal complexes induces a Z- to B-form transition in Z- form poly(dGm⁵dC). Consequently, neither of the studied chiral DNA-binders can easily be used to discriminate the DNA handedness.     

Synthesis and Characterization of Conformationally Rigid Chiral Pyridine–N‐Heterocyclic Carbene‐Based Palladacycles with an Unexpected Pd–N Bond Cleavage

The versatility of a previously developed method for the synthesis of chiral carbene‐based palladacycles is demonstrated through the synthesis of two new chiral pyridine‐functionalized N‐heterocyclic carbene palladacycles with different wingtip groups. The efficiency in their resolution with different counter anions and different chiral amino acid salt auxiliaries has been studied. The absolute stereochemistries of all the chiral compounds were confirmed by single crystal X‐ray crystallography. An unexpected Pd–N bond cleavage that resulted in the racemization of the α‐carbon center in these complexes has also been investigated. Chirality 25:149–159, 2013. © 2013 Wiley Periodicals, Inc.     

Z-DNA is Formed by poly(dC-dG) and poly (dm5C-dG) at Micro or Nanomolar Concentrations of some Zinc(II) and Copper(II) Complexes

Abstract

We report studies on the interaction of some zinc(II) and copper(II) complexes of amines and amino acids with poly(dC-dG) and poly(dm⁵C-dG). Of the zinc complexes the species zinc-tris(2-aminoethyl) amine is found to be the most efficient for inducing Z-DNA giving a mid point at low ionic strength of 1.4μM (poly(dC-dG)) and 44μM (poly(dm⁵C-dG). While an antagonistic effect on raising the ionic strength is observed, the transition occurs at only 2μM for poly(dm⁵C-dG) at 150mM NaCl. The most efficient copper(II) complex is that of diethylene triamine, though copper(II) complexes are generally less efficient than zinc(II) complexes. We also report kinetic and thermodynamic studies upon the B-Z transition induced by these complexes. A model is proposed for the interaction of one of the zinc complexes which involves not only direct zinc-DNA binding but also the formation of hydrogen bonds between the metal bond amine groups and the residues adjacent to the coordination site.     

CD spectroscopic study on the speciation and solution structure of copper(II) complexes of some tripeptides in combination with potentiometric and spectrophotometric results.

The combination of potentiometric, spectrophotometric and CD spectroscopic studies under the same conditions is expected to yield more reliable thermodynamic and structural information for a certain system. The matrix rank analysis of both the spectrophotometric and CD spectra series gives the necessary number of species to be taken into account in the calculations. Based on such speciation diagrams the molar spectra for individual complexes in the copper(II) Gly-Gly-Ala, Gly-Ala-Gly, Ala-Gly-Gly and Ala-Ala-Ala systems were obtained. The results allowed us to assign these spectra to two types of coordination species with the compositions CuLH(-1) and [CuLH(-2)](-). The sign and the intensity of the CD spectra are well related to the chirality and distance of the chiral center(s) in the ligand from the metal ion chromophore and the stability of the metal complexes. They are further on additive within the experimental error in both cases with respect to chiral centers: the sum of the CD spectra of the Gly-Gly-Ala, Gly-Ala-Gly and Ala-Gly-Gly complexes equals those of Ala-Ala-Ala complexes. The CD spectra strongly support the coordination also of the C-terminal part of the peptide in the CuLH(-1) complex of GGA, and even the deprotonation of the Ala peptide group instead of that belonging to Gly cannot be excluded.     

Identification and characterization of intramolecular γ-halo interaction in d<Superscript>0</Superscript> complexes: a theoretical approach

A mechanistic investigation to detect intramolecular M?X–C type interactions in d⁰ neutral and cationic complexes was carried out through a benchmark study employing different density functional methods. As γ-halogen is involved in M?X–C type interactions, it is denoted as a γ-halo interaction and the respective conformers are designated as halo-conformers. By analyzing the geometrical parameters of halo-conformers, it was observed that, irrespective of the nature of the metal and the halogen, the C_γ–X bond distance increases compared to the usual C–X bond, which brings the M and X centers close enough to generate a weak interaction. Generation of the M?X–C interaction was confirmed by performing NBO, AIM and Wiberg bond index analyses, from which the persistence of γ-halo interaction was seen to be prominent. Moreover, for each neutral and cationic complex, the values of Wiberg bond order are in good agreement with the AIM results. The effect of the metal center, as well as γ-halogen substitution, on γ-halo interaction was also studied in the present work. To justify the practical subsistence of the halo-conformers, we checked the stability of the conformers with respect to their β-conformers by comparing the zero-point-corrected electronic energies. Therefore, the entire study was designed in such a way that it can provide evidence in support of intramolecular M?X–C interactions, where, instead of the C–H bond, the C_γ–X bond will interact with the central transition metal.     

Metal Ion Binding and Conformational Transitions in Concanavalin A: A Structure-Function Study

Abstract

The affinity of the lectin Concanavalin A (Con A) for saccharides, and its requirement for metal ions such as Mn²⁺ and Ca²⁺, have been known for about 50 years. However the relationship between metal ion binding and the saccharide binding activity of Con A has only recently been examined in detail. Brown et al. (Biochemistry 16, 3883 (1977)) showed that Con A exists as a mixture of two conformational states: a “locked” form and an “unlocked” form. The unlocked form of the protein weakly binds metal ions and saccharide, and is the predominate conformation of demetallized Con A (apo-Con A) at equilibrium. The locked form binds two metal ions per monomer with the resulting complex(es) possessing full saccharide binding activity. Brown and coworkers measured the kinetics of the transition of the unlocked form to the fully metallized locked conformation containing Mn²⁺and Ca²⁺. They also demonstrated that Mn²⁺ alone could form a locked ternary complex with Con A, and that rapid removal of the ions resulted in a metastable form of apo-Con A in the locked conformation which slowly (hours at 25°C) reverted back to (predominantly) the unlocked conformation. The ability to form either conformation in the absence or presence of metal ions has thus allowed us to explore the relationship between metal ion binding and conformational transitions in Con A as determinants of the saccharide binding activity of the lectin.

Based on the kinetics of the transition of unlocked apo-Con A to fully metallized locked Con A, and X-ray crystallographic data, it appears that the transition between the two conformations of Con A involves a cis-trans isomerization of an Ala-Asp peptide bond in the backbone of the protein, near one of the two metal ion binding sites. The relatively large activation energy for the transition (～ 22 kcal M^?1) results in relatively slow interconversions between the conformations (from minutes to days), whereas the equilibria with metal ions and saccharide are rapid. Thus, many metastable complexes can be formed and a variety of transition pathways between the two conformations studied.

We have identified and characterized binary, ternary, and quaternary complexes of both conformations of Con A containing Mn²⁺ and saccharide, and have determined both metalion and saccharide dissociation constants for all of them, as well as equilibrium and kinetic values for the conformational transitions between them. The main finding is that saccharide binds very weakly (K_d～2 M) to unlocked apo-Con A and very tightly to the locked ternary Mn²⁺-Con A complex (K_d～ 10^?4 M). Saccharide binding increases along the various pathways connecting these two species in a nonadditive fashion. Thus, both conformation and metal ion binding determine the saccharide affinity of each complex, although the specificity of saccharide binding of the various species is maintained throughout.