Chirality-matched catalyst-controlled macrocyclization reactions

Significance Chiral catalysts are generally used to control stereochemistry in organic reactions. Generally, they control enantioselectivity or diastereoselectivity. In recent years, applications have expanded to include control over site selectivity in reactions involving complex molecules. Even more rarely, they can control chemoselectivity along with stereochemistry. We report herein that a carefully chosen chiral catalyst can also be decisive for efficient macrocyclization reactions in cases where simple achiral catalysts or stereochemically mismatched catalysts fail. Notably, in these reactions, a chiral catalyst proves essential for control of a reaction in which no new static (i.e., not “dynamic”) stereogenic elements are introduced. While fundamentally intriguing, these observations could also influence strategies for efficient synthesis of macrocyclic compounds in a variety of settings. Macrocycles, formally defined as compounds that contain a ring with 12 or more atoms, continue to attract great interest due to their important applications in physical, pharmacological, and environmental sciences. In syntheses of macrocyclic compounds, promoting intramolecular over intermolecular reactions in the ring-closing step is often a key challenge. Furthermore, syntheses of macrocycles with stereogenic elements confer an additional challenge, while access to such macrocycles are of great interest. Herein, we report the remarkable effect peptide-based catalysts can have in promoting efficient macrocyclization reactions. We show that the chirality of the catalyst is essential for promoting favorable, matched transition-state relationships that favor macrocyclization of substrates with preexisting stereogenic elements; curiously, the chirality of the catalyst is essential for successful reactions, even though no new static (i.e., not “dynamic”) stereogenic elements are created. Control experiments involving either achiral variants of the catalyst or the enantiomeric form of the catalyst fail to deliver the macrocycles in significant quantity in head-to-head comparisons. The generality of the phenomenon, demonstrated here with a number of substrates, stimulates analogies to enzymatic catalysts that produce naturally occurring macrocycles, presumably through related, catalyst-defined peripheral interactions with their acyclic substrates.