基于配合共保护策略合成γ-L-谷氨酰二肽的新方法

提出了一种采用谷氨酸席夫碱Ni(II)配合物共保护L-谷氨酸的α-氨基和α-羧基合成γ-L-谷氨酰二肽的新方法. 首先由手性助剂——2-N-(N-苄基-脯氨酰)氨基]二苯甲酮(1)、六水合氯化镍和L-谷氨酸反应, 得到谷氨酸席夫碱Ni(II)配合物2, 产率为98.2%; 进而采用二异丙基碳二亚胺(DIC)/1-羟基-苯并三唑(HOBt)复合缩合剂法分别与L-氨基酸3a～3h反应, 得到相应的γ-L-谷氨酰二肽席夫碱Ni(II)配合物4a～4h, 产率为93.1%～99.0%; 最后稀酸水解配合物, 得到γ-L-谷氨酰二肽5a～5h, 产率为73.0%～86.4%, 高收率(92.2%～97.4%)回收手性助剂. 中间产物和终产物的结构经由旋光, 1H NMR, 13C NMR和HRMS表征.

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-Z-glutamyl dipeptides via a Ni(Ⅱ) complex of glutamic acid Schiff base, which has been employed as co-protection of the a-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 HC1, 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, ~(13)C NMR and HRMS techniques.