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.