Synthetic and quantum chemical study on the regioselective addition of amines to methyl maleamate

Synthetic and theoretical studies were performed to gain insight into the regioselectivity in the mechanism of aspartyl-isoaspartyl formation, modeled by additions of ammonia and primary amines to methyl maleamate. Reactions between maleamate and aliphatic, araliphatic amines or O-methyl acetimidate lead to the formation of N-substituted isoasparaginates. The size of the amine and the activating effect of the amide and ester group on the double bond are the determining factors of the site of addition. The formation of both isomers was observed only in the case of ammonia addition. The regioselectivity was predicted on the basis of the charge distribution for low-energy methyl maleamate conformers, calculated at the B3LYP/6-311++G(2df,2pd)//B3LYP/6-31+G(d) level, both in gas phase and in methanol. The methyl isoasparaginate over methyl asparaginate product ratio was computed based on the free energy Boltzmann distribution of their conformers. The calculated 2 : 1 ratio is in agreement with the experimental regioselectivity of the addition of nitrogen nucleophiles.