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)

Abstract

A thorough study on the amidation conditions of N-acetyl-l-phenylalanine using TBTU and various bases is reported for the synthesis of 2-(N-acetyl)-l-phenylalanylamido-2-deoxy-d-glucose (NAPA), a promising drug for the treatment of joints diseases. TBTU-mediated diastereoselective amidation reaction with 1,3,4,6-tetra-O-acetyl-β-d-glucosamine always gave racemization of N-acetyl-l-phenylalanine. The stereochemical retention under amidation conditions was studied in detail in the presence of difference bases and via other control experiments, evidencing the possibility to reduce racemization using pyridine as base.

Synthesis and Characterization of Phenylalanine Amides Active against Mycobacterium abscessus and Other Mycobacteria

“…Although phenylalanine is not known for its susceptibility to racemization, like e.g., phenylglycine containing peptides, literature shows that phenylalanine racemization can occur even in relatively mild amidation procedures. ,− To achieve mild reaction conditions, we adapted the T3P ( n -propanephosphonic acid anhydride) coupling method published by Dunetz et al The authors showed that a mixture of EtOAc and pyridine at 0 °C yielded the lowest degree of racemization. Another advantage of T3P is that the side products formed in the coupling reactions are water-soluble and hence can be readily separated by extraction during work up.…”

Epimerisation in Peptide Synthesis

“…The Nα attack from the same amino acid or peptide could lead to the epimerisation product (Figure 4). The path B mechanism was regarded as the most predominant source of amino acid racemisation during peptide synthesis [12]. [13].…”