Synthesis of Large‐ and Medium‐Sized Heterobiaryl Atropisomeric Rings and Atropopeptides by Catalytic Intramolecular S N Ar

ABSTRACT We report the first examples of catalytic, intramolecular N‐heterocycle arylation by nucleophilic aromatic substitution (S N Ar), a general method for synthesis of highly strained macrocycles and medium‐sized heterobiaryl atropisomeric rings. Key to the approach is the ability to generate a strong base catalytically, as the desired cyclizations can be problematic under non‐catalytic conditions. Substitution reactions catalyzed by Brønsted bases often suffer from poor turnover because leaving groups are poorly basic. We put forth a process in which base regeneration does not depend on p K a considerations, but on reaction of a fluoride catalyst (Lewis base) with an organosilane (base‐embedding electrophile). Our protocol is amenable to an unprecedented broad range of heterocycles and highly functionalized and sterically hindered fluoroarenes. Despite ring strain, direct formation of C─N stereogenic axis can be carried out with linear substrates unbiased for cyclization and with tryptophan‐containing peptides. We provide synthesis of drug‐like cyclic and atropisomeric molecules which are elusive in medicinal chemistry screenings, as well as a direct macrocyclization route toward stereochemically and structurally diverse atropopeptides, molecules inspired by bioactive and naturally occurring ribosomally synthesized post‐translationally modified peptides (RiPPs). This work establishes a unique disconnection toward cyclic heterobiaryl molecules and catalysis that is to unlock other transformations.