Synthesis of α-substituted iminodiacetate ligands: α-hexadienyl derivatives for the selection of lipoxygenase mimics

Abstract

Derivatives of iminodiacetic acid (IDA) are important as ligands for metal ions, having numerous applications in separations, sensing, catalysis and medicine. This report describes the preparation of two types of IDA derivatives ( 1 , 2 ) that could be covalently attached to a polymer or protein surface via a variable length spacer chain. The parent compounds 1 (R′=H) were easily prepared via N-alkylation of dimethyl iminodiacetate with esters of 6-bromo-hexanoic acid and subsequent selective ester hydrolysis. Metal complexes of IDA derivatives having an α-dienyl side chain are required for the selection of histidine-rich proteins with potential lipoxygenase activity. The α-hexadienyl side chain of IDA derivative 2 was selectively introduced in the reaction of (2,4-hexadienyl acetate)Fe(CO) 3 with a glycine-derived TMS–enol ester. Subsequent demetallation, followed by N-carboxymethylation, N-deacylation, N-alkylation with a trichloroethyl 6-halohexanoate, and TCE–ester cleavage provided the desired α-hexadienyl IDA derivative 2 . Amide formation with IDA acid 1b demonstrates the feasibility of conjugating the IDA ligands to polymers and proteins while Ni(II)-complexation with the derived IDA triacid 1e shows the complexing ability of the tethered IDA ligand.