Iron-Catalyzed Asymmetric Csp3–H/Csp3–H Coupling：Improve the Chirality Induction by Mechanochemical Liquid-Assisted Grinding

The iron-catalyzed asymmetric oxidative coupling is a challenging transformation that is typically restricted to naphthol substrates (Csp2–H) with carefully designed chiral ligands. Herein, we established a mechanochemical protocol for iron-catalyzed asymmetric Csp3–H/ Csp3–H coupling between glycines and β-ketoesters. By using size-tunable liquid additives via non-covalent bond interaction with simply designed chiral salen ligands and substrates under mechanochemical treatment, it is possible to improve the asymmetric induction and offer a variety of structurally diverse α-amino acid derivatives in high enantiopurity. Mechanistic study revealed that the iminium ion derived from acid assisted aerobic oxidation of glycine ester was the key intermediate of the reaction, and the liquid additive t-BuOH act both as a stabilizer for the iminium ion via N–H···O interaction and as an assistant for enantio-control. Moreover, a safer, cleaner, and more energy-conservation route via mechanochemical accelerated aging was first disclosed for this asymmetric Csp3–H/ Csp3–H coupling reaction.