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

Le résumé fourni par la source

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 a 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 a cross-electrophile C(sp2)-C(sp3) 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 cooperative catalysis of the Ni(II)/ cyclo-Box complex and chiral phosphoric acid, this migratory coupling further achieves high enantioselectivity control in C(sp3)–C(sp2) bond construction. In addition, detailed experimental studies and DFT calculations have been conducted to gain insight into the mechanism and origin of the enantioselectivity. Overall, this synergistic strategy expands these methods to the challenging enantioselective C(sp2)–C(sp3) cross-electrophile coupling via π-system-independent radical 1,2-amino migration. The synthesis of β-amino acid molecules via tandem radical 1,2-N-shift/cross-coupling of α-amino acid scaffolds represents an attractive and powerful tool. Herein, the authors report the cross-electrophile C(sp2)-C(sp3) 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.

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