A Trapped Intermediate in the Copper(II)-Mediated Template Synthesis of an Amino Acid-Containing Ligand

A transition metal ion-templating reaction that has been widely exploited for the synthesis of nitrogen macrocycles, sepulchrates, and linear tetradentate ligands is the template-directed Mannich condensation of carbon acid and aldehyde equivalents with amines. In the course of investigating the copper(II) template-directed synthesis of linear tetradentate amino acid-containing ligands for the design and synthesis of double-strand DNA cleavage agents, we have trapped and characterized an intermediate in the templating reaction. Condensation of bis(phenylalaninato)copper(II) with formaldehyde and nitroethane led to a nitro-substituent-bearing precursor complex that upon reduction is crystallographically characterized as ((2S)-5-amino-2-benzyl-6-hydroxy-5-methyl-3-azahexanoate)copper(II) (space group P2(1)2(1)2(1), a = 9.0066(5) Å, b = 11.1040(6) Å, c = 16.009(2) Å, alpha = beta = gamma = 90.0 degrees, Z = 4, R(1) = 0.0265, wR(2) = 0.0612). NMR investigation of the precursor complex and the precursor and product ligands shows that the templated ligands each contain only a single phenylalanine unit, not the two phenylalanine units expected on the basis of similar synthetic procedures. The structure of the reduced product confirms this conclusion and provides structural characterization of a template intermediate trapped during ligand assembly.