A dinuclear biomimetic Cu complex derived from l-histidine: synthesis and stereoselective oxidations

Abstract

A dinuclear copper(ii) complex derived from the chiral N ligand (2S,2'S)-N,N'-(ethane-1,2-diyl)bis(2-((1-methyl-1H-imidazol-4-ylmethyl)-amino)-3-(1-trityl-1H-imidazol-4-yl)propanamide) (EHI) was synthesized and studied as a catalyst in stereoselective oxidation reactions. The ligand contains two sets of tridentate binding units, each of them giving rise to a coordination set consisting of a pair of 5- and 6-membered chelate rings, connected by an ethanediamide linker. Stereoselectivity effects were studied in the oxidations of a series of chiral l/d biogenic catechols and the pair of l/d-tyrosine methyl esters, in this case as their phenolate salts. The oxidation of β-naphthol has also been studied as a model monooxygenase reaction. The catechol oxidation was investigated in a range of substrate concentrations at slightly acidic pH and exhibited a marked dependence on the concentration of the [CuEHI] complex. This behavior has been interpreted in terms of an equilibrium between a monomeric and a dimeric form of the catalyst. Binding studies of l- and d-tyrosine were performed as a support for the interpretation of the stereoselectivity effects observed in the reactions. In general, [CuEHI] exhibits a binding preference for the l- rather than the d-enantiomer of the substrates, but it appears that in the catecholase reaction the oxidation of the d-isomer occurs at a faster rate than for the l counterpart. The same type of enantio-discriminating behavior is observed in the oxidation of l-/d-tyrosine methyl esters. In this case the reaction produces a complex mixture of products; the main product consisting of a trimeric compound, likely formed by radical coupling reactions, has been isolated and characterized. The oxidation of β-naphthol yields an additional product of the expected quinone but labeling experiments with 18-O show no oxygen incorporation into the product, confirming that the oxidation likely proceeds through a radical mechanism.

Binding and Reactivity of Copper to R1 and R3 Fragments of tau Protein

“…Here, we see that the CD trace at pH 6.7 (green trace) has a similar trend to that of the CD spectrum of copper­(II)/R 1 at pH 7.3 (Figure ), but the sign of the curve is inverted at pH 7.8 (violet trace). We can attribute this CD change to conformational inversion of the six-membered histidine chelate ring occurring upon binding of the axial ligand in [Cu­(LH –1 )] + , as this effect has been observed systematically for a number of copper­(II) complexes with histidine-containing multidentate ligands. − The much stronger CD activity observed in the visible range at high pH for both Cu 2+ /R 1 and Cu 2+ /R 3 complexes cannot be attributed to vicinal or conformational effects and is probably due to coupling of transition moments of d–d transitions with the three strong π­(amide)–copper­(II) charge transfer bands in the near-UV. In the literature, a (3N,O) binding mode at pH 7.4 for copper­(II) with several model peptides of R 1 and R 3 was proposed .…”

A Stereoselective Tyrosinase Model Compound Derived from an m-Xylyl-l-histidine Ligand

“…Recently, we tried to simplify the ligand design focusing on the combination of two tridentate metal binding motifs constituted by amino-bis(imidazole) residues containing the chiral L-histidine group, yielding a pair of fused five-membered and six-membered chelate rings, and connected by a linker in the system labeled EHI. 25 The resulting dinuclear copper(II) complex exhibited appreciable enantio discriminating capacity in the aerobic oxidation of biogenic catechols. However, in the case of phenol oxidations, the reactions did not produce the desired monooxygenation product but oligomeric products resulting from radical coupling reactions.…”

“…However, in the case of phenol oxidations, the reactions did not produce the desired monooxygenation product but oligomeric products resulting from radical coupling reactions. 25 Fine tuning of the structural motif is thus important to direct the reactivity of the dimetal site toward the desired monooxygenase reactivity, because this requires a strong cooperation between the metal centers. For this reason, we reasoned that replacing the short and relatively rigid ethanediamide linker in EHI with the more flexible and extensively used meta-xylyl-diamine moiety could allow the two copper centers to approach and facilitate an intramolecular dioxygen binding and activation.…”

“…The synthetic route to mXHI is outlined in Scheme 1. The N τ -benzyl substitution at histidine groups of mXHI replaces the more sterically hindered trityl group used in EHI 25 or the smaller methyl group in PHI. 19,21 The histidyl-containing arms of the ligand were built in by reacting N-benzyl histidine methyl ester, intermediate 5, with isophthaldialdehyde.…”

“…This feature indicates that the histidine chelate ring bears a preference for the conformation of λ chirality, with the carboxymethyl ester side chain in pseudoequatorial disposition and the imidazole group bound in a Cu II axial position (Scheme 2). This conformational preference is the same as for Cu II −PHI complexes 19 but opposite to that of [Cu 2 (EHI)] 4+ , 25 where the side chain of the histidine chelate ring is actually constituted by the linker ethanediamide chain.…”