Reactions between pyridoxal and L-amino acids in the absence and in the presence of zinc(II): The role of the metal in the prevention of Pictet-Spengler cyclization

Abstract

Attempts to obtain Schiff bases from the reactions of pyridoxal with l-histidine and l-tryptophan resulted in Pictet-Spengler cyclization, with formation of potassium 4-[3-hidroxy-5-(methylpyridin-4-yl]-4,5,6,7-tetrahydropyrido[3,4-c]imidazole-6-carboxylate (1) and 1-[2-methyl-3-hydroxy-5-(hydroxymethyl)pyridine-4-yl]-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (2). Investigations on the diastereoselectivity of the reactions by means of NOESY and ROESY bidimensional NMR spectra of 1 and 2 revealed the presence of the cis isomer in both cases. Theoretical calculations of the reactions’ free energies showed that only the formation of the cis isomer of 1 is thermodynamically favored, in accordance with the experimental results. However, the formations of both cis and trans isomers of 2 are thermodynamically favored, suggesting that other factors might have been responsible for the experimental detection of only the cis isomer. One-pot reactions of pyridoxal with l-histidine or l-tryptophan in the presence of zinc acetate or zinc chloride resulted in the formation of [Zn2(Pdx-l-His)2(H2O)2]·4H2O (C1) and [Zn(Pdx-l-Trp)(H2O)]·1.5H2O (C2) complexes in which Pdx-l-His and Pdx-l-Trp are the pyridoxal-l-histidine and pyridoxal-l-tryptophan Schiff bases, respectively, indicating that the metal prevents cyclization upon coordination of the Schiff base intermediate.