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<p>Optically pure non-natural <i>β</i>-amino acids are noteworthy molecular motifs of numerous pharmaceutically important molecules. Skeletal editing of abundant <i>α</i>-amino acid scaffolds via tandem radical 1,2-N-shift/cross-coupling represents a powerful tool to straightforward assemble new <i>β</i>-amino acid molecules; however, this strategy presents substantial challenges owing to difficulties in reactivity and regio-/enantiocontrol. Herein, we report a cross-electrophile C(sp<sup>2</sup>)-C(sp<sup>3</sup>) coupling of <i>β</i>-bromo <i>α</i>-amino acid esters with aryl bromides via a <i>π</i>-system-independent 1,2-N-shift, which allows access to <i>α</i>-arylated <i>β</i>-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(sp<sup>3</sup>)–C(sp<sup>2</sup>) 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(sp<sup>2</sup>)–C(sp<sup>3</sup>) cross-electrophile coupling via <i>π</i>-system-independent radical 1,2-amino migration.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月5日

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  • Zicheng Liao,
  • Zijun Li,
  • Meiqiu Xiao,
  • Youlin Deng,
  • Zehan Ma,
  • Lijuan Zhou,
  • Gangliang Dai,
  • Xinyu Li,
  • Shuowen Wang,
  • Shilu Chen,
  • Jinheng Li,
  • Shi Tang

摘要

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.