Amino acids as selective sulfonamide acylating agents

Acylation of antimalarial and bacteriostatic sulfonamides with N-protected amino acids and peptides was carried out using standard peptide coupling methods. These acylation reactions are regioselective for the N⁴ nitrogen atom of diazine-containing sulfonamides. In contrast, only N¹ coupling was found for sulfisoxazole, an isoxazole-based sulfonamide. Computational studies suggest that a combination of geometrical, thermodynamic and electronic factors are responsible for the different reactivities reported.