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

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.