Atroposelective Access to Bicyclic Peptides via an Amide Photocaging Strategy

The fungal toxin α‐amanitin is a structurally complex bicyclic octapeptide featuring a macrolactam scaffold stabilized by a tryptathionine crossbridge critical for its conformational stability. Building on the prior development of the ansamer ( P ansa /M ansa ) nomenclature for an amatoxin isomer classification, the challenge of atroposelective synthesis of both isomers, the natural P ansa and non‐natural M ansa, remained. This work introduces an innovative amide bond photocaging strategy implemented on monocyclic peptide precursors, enabling the control of conformational selectivity during bicyclization to achieve the directed formation of the P ansa or M ansa atropisomer. Density functional theory (DFT) calculations and molecular dynamics simulations provide strong theoretical support for the experimentally observed atroposelectivity in M ansa formation. The methodology described could establish a paradigm for conformational control in the synthesis of bicyclic peptides, with implications for a rational conformational design across diverse peptide architectures.