A novel method for the synthesis of glutathione based on a co-protection strategy

A novel method for the synthesis of glutathione (γ-L-glutamyl-L- cysteinyl-glycine) via a Ni(II) complex of glutamic acid Schiff base, which has been employed as co-protection of the α-amino and α-carboxyl groups of L-glutamic acid, was described. Firstly, a Ni(II) complex 2 of glutamic acid Schiff base was formed in a 98% yield from chiral auxiliary 2-[N-(N′- benzyl-prolyl)amino]benzopheone (1) with nickel(II) chloride hexahydrate and L-glutamic acid. Then, 2 reacted with S-benzyl-L-cysteine to give Ni(II) complex 3 of S-benzyl-γ-L-glutamyl-L-cysteine Schiff base in a yield of 90% using a N,N′-diisopropylcarbodiimide (DIC)/l-hydroxybenzotrizole (HOBt) coupling method. Thirdly, 3 reacted with glycine to give Ni(II) complex 4 of S-benzyl-γ-L-glutamyl-L-cysteinyl-glycine Schiff base in a yield of 95% using the same DIC/HOBt coupling method. Fourthly, after decomposition of 4 with aqueous HCl, S-benzyl-γ-L-glutamyl-L-cysteinyl-glycine (5) was obtained in a 70% yield. Finally, the S-benzyl was removed by catalytic transfer hydrogenation with ammonium formate, while glutathione (6) was synthesized in an 87% yield. Structures of intermediates and final products were characterized by optical rotation, ¹H NMR, ¹³C NMR and HRMS techniques.