Asymmetric synthesis of β-amino acid derivatives by stereocontrolled C(sp3)-C(sp2) cross-electrophile coupling via radical 1,2-nitrogen migration

Optically pure non-natural β -amino acids are noteworthy molecular motifs of numerous pharmaceutically important molecules. Skeletal editing of abundant α-amino acid scaffolds via tandem radical 1,2-N-shift/cross-coupling represents an attractive and powerful tool to straightforward assemble new β -amino acid molecules; however, this strategy presents substantial challenges owing to difficulties in reactivity and regio-/enantiocontrol. Herein, we report an unprecedented remote cross-electrophile C(sp ² )-C(sp ³ ) coupling of β-bromo α-amino acid esters with aryl bromides via a π -system-independent 1,2-N-shift, which allows access to α-arylated β-amino acid motifs with high efficiency and regioselectivity. Furthermore, upon the novel cooperative catalysis of the Ni(II)/new-style Box complex and chiral phosphoric acid (CPA), this migratory coupling further achieves high enantioselectivity control in C(sp ³ )–C(sp ² ) bond construction. In addition, detailed experimental studies and DFT calculations were conducted to gain insight into the mechanism and origin of the enantioselectivity, which was further evidenced by the two-step synthesis of a pan -Akt inhibitor molecule. Overall, this novel synergistic strategy expands these methods to the challenging enantioselective remote C(sp ² )–C(sp ³ ) cross-electrophile coupling via π -system-independent radical 1,2-amino migration.