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<p>Largamides A–H and tiglicamides A–C comprise a rare class of marine-derived cyclic peptides characterized by protease inhibitory activity and highly intricate molecular architectures. Their pronounced biological relevance, coupled with their limited natural abundance, has rendered these compounds longstanding and compelling targets for total synthesis. In this study, we report comprehensive synthetic investigations of largamides B and H, together with the first total synthesis and biological evaluation of tiglicamide B as a novel inhibitor of nitric oxide (NO) production. Our synthetic strategy employs carefully designed protecting-group manipulations in conjunction with a convergent fragment-assembly approach, enabling the efficient construction of these densely functionalized peptide frameworks. Notable features of this work include the utilization of threonine-derived selenide precursors for the stereoselective installation of 2,3-dehydro-2-aminobutanoic acid motifs; the synthesis of the 2,5-dihydroxylated β-amino acid residue of largamide H via Brown allylation followed by Sharpless asymmetric epoxidation; and the preparation of the structurally unusual bis-protected L-Ahppa fragment through site-selective C–H bond functionalization. Collectively, these studies not only provide streamlined and robust synthetic access to members of this challenging peptide family but also establish broadly applicable methodologies for the synthesis of bioactive analogues and other structurally complex peptide architectures.</p> Graphical abstract <p></p>

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Total synthesis of marine cyclopeptide largamides B and H, and tiglicamide B

  • 期刊论文

  • 发表日期：

    2026年2月25日

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  • Youzhi Li,
  • Yuzhao Chen,
  • Shuo Liang,
  • Shiwei Qu,
  • Jia-Lei Yan,
  • Tao Ye,
  • Zhongliang Dai

摘要

Largamides A–H and tiglicamides A–C comprise a rare class of marine-derived cyclic peptides characterized by protease inhibitory activity and highly intricate molecular architectures. Their pronounced biological relevance, coupled with their limited natural abundance, has rendered these compounds longstanding and compelling targets for total synthesis. In this study, we report comprehensive synthetic investigations of largamides B and H, together with the first total synthesis and biological evaluation of tiglicamide B as a novel inhibitor of nitric oxide (NO) production. Our synthetic strategy employs carefully designed protecting-group manipulations in conjunction with a convergent fragment-assembly approach, enabling the efficient construction of these densely functionalized peptide frameworks. Notable features of this work include the utilization of threonine-derived selenide precursors for the stereoselective installation of 2,3-dehydro-2-aminobutanoic acid motifs; the synthesis of the 2,5-dihydroxylated β-amino acid residue of largamide H via Brown allylation followed by Sharpless asymmetric epoxidation; and the preparation of the structurally unusual bis-protected L-Ahppa fragment through site-selective C–H bond functionalization. Collectively, these studies not only provide streamlined and robust synthetic access to members of this challenging peptide family but also establish broadly applicable methodologies for the synthesis of bioactive analogues and other structurally complex peptide architectures.

Graphical abstract