Rh(III)-catalyzed late-stage C-H alkenylation and macrolactamization for the synthesis of cyclic peptides with unique Trp(C7)-alkene crosslinks

• Published in: Chinese chemical letters 2024-08, Vol.35 (8), p.109408, Article 109408
• Main Authors: Hu, Shulei, Zhang, Yu, Xie, Xiong, Li, Luhan, Chen, Kaixian, Liu, Hong, Wang, Jiang
• Format: Article
• Language: English
• Subjects: Alkenylation; C-H functionalization; Cyclic peptides; Macrolactamization; Rh(III)-catalyzed
• ISSN: 1001-8417; 1878-5964
• DOI: 10.1016/j.cclet.2023.109408

Heterocycle-braced cyclic peptides have demonstrated enhanced metabolic stability, increased potency and selectivity. Here, we present a rapid synthesis method for constructing Trp(C7)-alkene(E)-crosslinked cyclic peptides with potent anti-proliferative activities against cancer cells, through C-H alkenylation and macrolactamization. This report addresses critical challenges associated with the installation and removal of the directing group N-Piv, configuration selectivity of the olefin, and intramolecular cyclization. Notably, this method exhibits mild reaction conditions, traceless removal of the directing group, and high configuration selectivity. Special E-configuration Trp-alkene crosslinks can be constructed at various linear peptides utilizing air-stable Rh(III) catalyst. In addition, an efficient synthesis method for constructing Trp(C7)-alkene(E)-crosslinked cyclic peptides was developed, and this method demonstrates several advantages, including mild reaction conditions, traceless removal of the directing group, and specific configuration selectivity. [Display omitted]