Abordagem organocatalítica, utilizando o (+/-)-ácido canforsulfônico, para a síntese de dipeptídeos através de azalactonas

Abstract

The synthesis of biologically functional amino acids and small peptides has been a promising area of organic chemistry. The azlactones can act as protected amino acids and are used in the synthesis of amino acid derivatives and complex heterocycles. This work describes azlactones ring opening by amino acids catalyzed by a Brønsted acid, the (+/-)-camphorsulfonic acid (CSA), resulting in the formation of dipeptides. The azlactone heterocycles were prepared in two steps: an acylation of the amino acid with benzoyl chloride under alkaline conditions leading to N-benzoyl amino acids with up to 75% yield, and an intramolecular cyclization reaction mediated by EDC, a carboxylic acid activator, affording the desired azlactones in yields ranging from 82-98%. The optimized conditions for the dipeptide formation reaction consisted of 5 mol % of camphorsulfonic acid as a catalyst, dichloromethane as solvent, stirring and at room temperature. The scope was evaluated varying the azlactones and the amino acids. Yields were satisfactory (ranging from 66 to 99%). Even the use of more sterically hindered amino acids and azlactones, such as valine and leucine derivatives, the dipeptides were obtained in good yields. The products were characterized by 1H NMR, 13C, DEPT135, IR and HRMS. The possibility of an intramolecular cyclization of the dipeptides using EDC has been demonstrated, resulting in a more complex azlactone. Finally, the substitution of the N-benzoyl group by tert-butyl carbamate allowed the synthesis of an azalactone without epimerization of the stereogenic center alpha to the carbonyl, a subsequent opening of the heterocycle by octylamine was also performed.