Asymmetric Synthesis and Antibacterial Evaluation of β-Substituted (S)-α-Alanine Analogs Containing a Piperazine...

A series of novel enantiomerically enriched α-amino acids containing piperazine fragments were synthesized via nucleophilic addition of piperazine derivatives (2a-d) to the C = C bond of a square-planar Ni (II) complex of the Schiff base derived from dehydroalanine and the chiral auxiliary (S)-BPB (1). The reactions proceeded under basic catalysis and were thermodynamically controlled, affording the major (S,S)-diastereomers with high diastereomeric excess (88%-92%). Acid hydrolysis of the diastereomeric Ni (II) complexes, followed by ion-exchange purification and crystallization, yielded the corresponding α-amino acids (4a-d) with high enantiomeric purities (ee 95%-99%). The chiral auxiliary (S)-BPB was recovered in > 96% yield without loss of enantiomeric purity, demonstrating the method's efficiency and sustainability. The antibacterial activity of the synthesized α-amino acids (4a-d) was evaluated against selected Gram-positive and Gram-negative bacterial strains, including Pseudomonas fluorescens 9150, Escherichia coli DH5α, and Staphylococcus aureus MDC 5233, using the standard microdilution method. All tested compounds exhibited moderate antibacterial activity, with MIC values of approximately 5 mM against E. coli and S. aureus. Notably, compounds 4c and 4d demonstrated significantly enhanced activity against P. fluorescens 9150, with MIC values of 0.675 mM (corresponding to ~ 0.144 and ~ 0.168 mg/mL, respectively). These results indicate that structural modification of piperazine-containing α-amino acids can significantly influence their antibacterial properties and highlight this scaffold as a promising platform for the development of new antimicrobial agents.