Synthesis of Large- and Medium-Sized Heterobiaryl Atropisomeric Rings and Atropopeptides by Catalytic Intramolecular SNAr.

Abstract

We report the first examples of catalytic, intramolecular N-heterocycle arylation by nucleophilic aromatic substitution (SNAr), 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 pKa 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.