Asymmetric Synthesis of Cα‐Substituted Prolines through Curtin–Hammett‐Controlled Diastereoselective N‐Alkylation. Issue 10 (21st January 2019) - Cho, Hyunkyung
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. Abstract : 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.