From Cyclic Ketimines to α-Substituted Cyclic Amino Acids and their Derivatives: Influence of Ring Size and Substituents on Stability and Reactivity of Cyclic Aminonitriles

A general route to alpha-substituted cyclic amino acids was elaborated. The approach is based on Strecker reaction with cyclic ketimines. The influence of ring size and substituent at the alpha-position of cyclic ketimine on the hydrocyanation was studied. It was found that five-membered aminonitriles have a tendency to eliminate HCN very easily, especially in the case of aryl-substituted derivatives. A series of 5-7 membered amino nitriles with different substituents was prepared. Subsequent hydrolysis allows the preparation of alpha-substituted pipecolic acids. In the case of seven-membered derivatives, it was necessary to use a formylation-hydrolysis sequence. Synthesis of alpha-substituted prolines and their amides was elaborated starting from the corresponding five-membered ketimines through a benzylation-hydrolysis-hydrogenation sequence.