Asymmetric Synthesis of Cα‐Substituted Prolines through Curtin–Hammett‐Controlled Diastereoselective N‐Alkylation

Abstract

Asymmetric synthesis of α-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 α-carbon through a stereoselective [2,3]-Stevens rearrangement (N→C chirality transfer) to give α-substituted proline ester.