Old Drawback on Azlactone Formation Revealed by a Combination of Theoretical and Experimental Studies

Abstract

New insights into the formation of azlactone heterocycles bearing different substituents are hereby presented. The sum of both kinetic and thermodynamic factors contributes for the formation of 2-alkyl or 2-aryl substituted azlactones, while the cyclization of 2-alcoxy azlactones is less favored. These results are in perfect accordance with experimental observations obtained by infrared (IR) and electrospray ionization mass spectrometry (ESI(+)-MS) of the crude reaction mixture.

N-Acetyl-l-phenylalanine Racemization during TBTU Amidation: An In-Depth Study for the Synthesis of Anti-Inflammatory 2-(N-Acetyl)-l-phenylalanylamido-2-deoxy-d-glucose (NAPA)

“…Hence, further experiments have been carried out, keeping in mind the importance of base choice in the coupling of N -Ac- l -phe. As previously mentioned, the racemization of amino acids occurs during the activation step, particularly in the cases of N -acetyl or N -benzoyl amino acids [ 28 , 29 ], and it is ascribed to the cyclization of the activated intermediate to give a heterocyclic azlactone ( L-3 in Figure 4 ). An intramolecular reaction between the oxygen at the acetyl N -protector group and the electrophilic site in C-1 promotes its formation [ 30 ].…”

Recent Advances in Azlactone Transformations

“…[22] This study showed that 2-aryl or 2-alkyl-substituted oxazolones are readily formed through the intramolecular cyclization of N-acyl amino acids, while the same process is less favored (due to a sum of both kinetic and thermodynamic factors) in carbamate protected amino acids. DFT (Density Functional Theory) calculations were performed in order to investigate the real role related to the synthesis of different 2-substituted azlactones.…”

“…Our research group recently reported a study involving the dimerization of azlactones (22) under Brønsted base catalysis. [28] Potassium or sodium trichloroacetate salts were employed as catalysts (30 mol-%) and the desired derivatives (23) were isolated in good to excellent yields (between 60 and 93 %) and with moderate to excellent diastereomeric ratio (up to > 19:1 d.r.)…”

“…Finally, a recent contribution concerning the formation of azlactones was described in 2018 by our research group. DFT (Density Functional Theory) calculations were performed in order to investigate the real role related to the synthesis of different 2‐substituted azlactones . This study showed that 2‐aryl or 2‐alkyl‐substituted oxazolones are readily formed through the intramolecular cyclization of N ‐acyl amino acids, while the same process is less favored (due to a sum of both kinetic and thermodynamic factors) in carbamate protected amino acids.…”