A novel method for the synthesis of γ-L-glutamyl dipeptides based on a complexing co-protection strategy

A novel method for the synthesis of γ-L-glutamyl dipeptides via a Ni(II) complex of glutamic acid Schiff base, which has been employed as co-protection of the α-amino and a-carboxyl groups of L-glutamic acid, was described. Firstly, a Ni(II) complex 2 of glutamic acid Schiff base was formed in a yield of 98.2% from chiral auxiliary 2-[N-(N-benzyl-prolyl)amino] benzopheone (1) with nickel(II) chloride hexahydrate and L-glutamic acid. Then, 2 was reacted separately with L-amino acids 3a-3h to give Ni(II) complexes 4a-4h of γ-L-glutamyl dipeptide Schiff base in yields of 93.1%-99.0% using a DIC/HOBt coupling method. Finally, after decomposition of the complexes 4a-4h with aqueous HCl, γ-L-glutamyl dipeptides 5a-5h were obtained in yields of 73.0%-86.4% and the chiral auxiliary 1 was recovered in high yields of 92.2%-97.4%, respectively. The structures of intermediates and final products were characterized by optical rotation, ¹H NMR, ¹³C NMR and HRMS techniques.