Dual-functional directing group enables a general synthesis of tryptophan-crosslinked macrocyclic peptides
Researchers at Princeton University in the United States reported in Nature Synthesis, published online on 13 October, a general chemical route to tryptophan-crosslinked macrocyclic peptides using rhodium-catalysed intramolecular transannular macrocyclization.
Summary. Researchers at Princeton University in the United States reported in Nature Synthesis, published online on 13 October, a general chemical route to tryptophan-crosslinked macrocyclic peptides using rhodium-catalysed intramolecular transannular macrocyclization. Such natural-product-like scaffolds are structurally intricate, yet broadly useful laboratory syntheses have been scarce. Guided by mechanism and computation, the team designed a dual-function nucleophilic pyridyl directing group that supports ortho-metalation and carbon–nitrogen bond formation in complex peptide settings; the group can be installed by cross-coupling, carried through peptide coupling and removed after the macrocycle forms.
Research context (RUO). The authors demonstrate the method on several targets, including the pharmacophores of micitide 982 and the antibiotic natural product tryglysin, as examples of chemical synthesis capability. The paper is a synthetic-methods report with crystallographic and computational support; it does not present a clinical trial or any administration schedule. For laboratories that build constrained peptide macrocycles, it offers a documented rhodium-catalysed cyclization tactic rather than a therapeutic recommendation. Full scope tables, directing-group chemistry and characterisation data are in the article and supplementary files.
