Copper(I)-Catalyzed\nEnantioselective α‑Alkylation\nof 2‑Acylimidazoles

Catalytic\nasymmetric α-alkylation of simple carboxylic acid\nderivatives is a challenging issue due to the difficulties in achieving\nhigh catalytic efficiency and controlling the enantioselectivity.\nHerein, by using a copper(I)-(<i>R</i>)-DTBM-SEGPHOS complex\nas a catalyst and 2-acylimidazoles as pronucleophiles, a general method\nfor the catalytic asymmetric α-alkylation of simple carboxylic\nacid derivatives is accomplished. Various alkyl electrophiles, including\nallyl bromides, benzyl bromides, propargyl bromide, and unactivated\nalkyl sulfonates, serve as efficient alkylation reagents. The reaction\nenjoys the advantages of an easy reaction protocol, good functional\ngroup tolerance, and high enantioselectivity. 2,4,6-Trimethylphenol\nis found as an effective additive to increase yields. Preliminary <sup>1</sup>H NMR experiments indicate the precoordination of 2-acylimidazoles\nto a copper(I) catalyst, which might acidify the α-hydrogens\nof 2-acylimidazoles and allow facile generation of stabilized copper(I)\nenolates. Finally, the synthetic utility of the present method is\ndemonstrated by the asymmetric formal synthesis of AZD2716, a potent\nsecreted phospholipase A<sub>2</sub> inhibitor.