Effects of Solvents and Additives on the Reaction of N-Benzyloxycarbonyl-L-Aspartic Anhydride with L-Phenylalanine Methyl Ester ( Synthesis of Aspartame)

Article abstract of DOI:10.1021/jo00376a025

N-Benzyloxycarbonyl-L-aspartic anhydride (Z-L-aspartic anhydride) was reacted with L-phenylalanine methyl ester.The nature of the ring-opening reaction was effected by the organic solvent.In Me2SO, DMF, and dimethylacetamide the β-isomer of Z-L-aspartyl-L-phenylalanine methyl ester (ZAPM) was predominant while in glacial acetic acid, esters, ketones, ethers, chlorohydrocarbons, acetonitrile, toluene, etc. the α-isomer of ZAPM prevailed.Especially in glacial acetic acid, the yield of α-form ZAPM reached more than 85percent.The results of reactions in mixed solvents like acetonitrile-Me2SO and ethyl acetate-acetonitrile showed that the yield of α-ZAPM changed linearly with a change in the composition of the mixed two solvents.The reaction in acetonitrile-acetic acid and Me2SO-acetic acid showed that the addition of acetic acid not only caused a solvent effect by itself, but that the acid also affected the reaction.Therefore, the yield of α-ZAPM was increased by use of a mixed solvent containing only a small amount of glacial acetic acid.A mechanism to explain these experimental phenomena is presented.