Síntese de compostos funcionalizados e estudos mecanísticos teórico-experimentais envolvendo reações de amidação, rearranjo de steglich e reação de Passerini

Abstract

The synthesis of biologically active amino acid derivatives appears as a promising field of Organic Chemistry. The first part of this thesis describes the development of an epimerization-free methodology for the preparation of dual-protected amino acid derivatives in yields ranging from 52 to 86%. Mechanistic studies through high-resolution mass spectrometry revealed the absence of an azalactone intermediate, and allowed the elucidation of the organocatalytic mechanism involved in this transformation. A theoretical study was also carried out in order to comprehend the azalactone ring formation and revealed that the substituent in the N-substituted amino acid substrate directly affects the intramolecular cyclization step due to dispersion interactions with some of the intermediates and transition states. The azalactone racemization process was also investigated through theoretical calculations, which indicated the probable existence of a base-mediated reaction pathway, with protonation/reprotonation steps and the formation of azalactone enolate. The synthesized compounds were also evaluated towards their antimicrobial activity against Mycobacterium tuberculosis (with three derivatives presenting a 90% inhibition of bacterial cells at concentrations below 20 μM and selectivity indexes up to 3.5), and cytotoxic in a series of normal and tumor cells strains (with the most active derivative being able to inhibit all evaluated tumor lines at concentrations near 2.0 μM and presenting a selectivity index of 3.4). The second part of this thesis describes an example of how Theoretical Chemistry can be employed to predict and drive experimental studies. The energy profile of the Steglich rearrangement of azalactones was investigated and allowed a better comprehension of the reaction regioselectivity, with the [1,3]-sigmatropic rearrangement product being kinetic and thermodynamically favorable in comparison to the [1,4]-rearrangement product. In addition, the use of a 4-substituted heterocycle bearing a sterically bulky group was able to reverse the reaction regioselectivity, preferentially favoring the formation of 2- substituted derivatives. Next, the Steglich rearrangement in isoxazolones was also evaluated. The formation of the N-substituted product was kinetically favorable when compared to the C-substituted product. Based on these data, a proposal considering both the reaction kinetics and the N-substituted product reversibility as key findings allowed the regioselective experimental preparation of the two types of products. Finally, the third chapter describes the first report of an asymmetric multicomponent Passerini reaction using asymmetric counter-anion directed catalysis. After reaction optimization, the desired derivative was isolated in 75% yield and 87% e.e. The developed methodology allowed the use of reagents in near stoichiometric concentrations and of shorter reaction times. The reaction mechanism was investigated by theoretical calculations and involves a nitrile and an imidate intermediate, as well as a Mumm rearrangement. The catalytic formation of the R stereoisomer of the product was considerably more favorable. However, the competition between reactions in the presence and absence of the catalyst difficult the control of the reaction stereoselectivity.