Asymmetric Synthesis of Cα-Substituted Prolines via Curtin-Hammett Controlled Diastereoselective N-Alkylation.

Asymmetric synthesis of alpha-substituted proline derivatives has been accomplished by an efficient chirality-transfer method. High diastereoselectivity of the N-alkylation of the proline ester (C -> N chirality transfer) was achieved when a 2,3-disubstituted benzyl group was used as the N-substituent. DFT calculations provided a mechanistic rationale for the high degree of stereoselectivity. The generated N-chirality of the quaternary ammonium salt was transferred back to the alpha-carbon through a stereoselective [2,3]-Stevens rearrangement (N > C chirality transfer) to give alpha-substituted proline ester.