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

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. C→N→C chirality transfer: An efficient chirality‐transfer process was established for the asymmetric synthesis of α‐substituted proline derivatives. Using a 2,3‐disubstituted benzyl group as the N‐substituent, a high level of C→N chirality transfer was achieved, which enabled the enantioselective synthesis of the α‐substituted prolines through [2,3]‐Stevens rearrangement (N→C chirality transfer). DFT calculations suggested that this selective N‐alkylation follows Curtin–Hammett kinetics. [ABSTRACT FROM AUTHOR]