Estudo de reações entre piridoxaldeído e L-aminoácidos na ausência e na presença de zinco(II): o papel do metal no impedimento da ciclização Pictet-Spengler por meio de reações one-pot

Abstract

Schiff base and their metal complexes are known to have antimicrobial, antitumor, antioxidant, and anti-inflammatory activities, among others. Amino acids and their derivatives are excellent building blocks to form ligands due to their coordination properties and biological importance. Therefore, obtaining Schiff bases derivatives from amino acids and their metal complexes can be an interesting strategy for the synthesis of compounds with potential pharmacological applications. In the present work, reactions between pyridoxaldehyde (Pdx) and L-histidine (L-His) or L-tryptophan (L-Trp) were studied in the absence and presence of zinc(II). It has been observed that Schiff bases derived from pyridoxal hydrochloride and L-His or L-Trp are not formed in the absence of zinc(II). Cyclization of compounds occurs through the Pictet-Spengler reaction with formation of 4-[3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl]-4,5,6,7-tetrahydropyride[3,4-c]imidazole-6-carboxylate of potassium (1) and 1-[2-methyl-3-hydroxy-5-(hydroxymethyl)pyridin-4-yl]-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (2). It was also observed that these reactions are highly diastereoselective, producing mostly one diastereoisomer, which was identified by two-dimensional Nuclear Magnetic Resonance (NMR) techniques (NOESY and ROESY). Computational calculations using the Density Functional Theory (DFT) with the hybrid exchange-correlation functional (B3LYP) and 6-311++G** basis set were used to determine the Gibbs free energy (ΔGº) of these cyclization reactions taking into account the solvents used in each case. The species (Schiff bases and cyclic compounds) present in pH 6 (pH of reactions) were determined using the chemicalize software. A value of ΔGºcic<0 for the cyclization step of the L-His Schiff base derivative of L-His [Pdx-L-His], with the formation of the cis isomer (isomer found experimentally) and a value of ΔGºcic>0 for the cyclization step with the formation of the trans isomer, suggesting that the formation of the trans compound is not thermodynamically favorable. Values of ΔGºcic<0 were found for the cyclization of L-Trp Schiff base derivative [Pdx-L-Trp] with formation of both cis and trans isomers, suggesting that both are thermodynamically favorable. The one-pot reaction of Pdx with L-His in the presence of zinc acetate dihydrate gave rise to the complex [Zn(Pdx-L-His)].3H2O (C1). The same reaction with zinc(II) chloride gave rise to the complex [Zn(Pdx-L-His)(H2O)].1.5H2O (C2). The complex [Zn(Pdx-L-Trp)(H2O)].1.5H2O (C3) was obtained by the reaction between pyridoxal hydrochloride, L-Trp and zinc acetate dihydrate and the reaction with zinc(II) chloride gave rise to the complex [Zn(Pdx-L-Trp)(H2O)].H2O (C4). From the synthesis reaction of compound (C1) crystals were obtained crystals whose structure was determined by X-ray diffraction as being the binuclear compound [Zn2(Pdx-L-His)2Cl(H2O)].6.33H2O (C1A). The results suggest that the Schiff bases [Pdx-L-His] and [Pdx-L-Trp] can only be obtained in the form of their zinc(II) complexes and that the metal would have the role of preventing the cyclization of the compounds by the formation of their coordination compounds.