Catalyst Controlled Macrocyclization Reactions Chirality Adapted | PNAS

Abstract

Macrocycles, formally defined as compounds containing a ring of 12 atoms or more, continue to generate great interest due to their important applications in the physical, pharmacological and environmental sciences. In the syntheses of macrocyclic compounds, the promotion of intramolecular reactions over intermolecular reactions in the ring closing stage is often a major challenge. In addition, syntheses of macrocycles with stereogenic elements present an additional challenge, while access to such macrocycles is of great interest. Here we report the remarkable effect that peptide-based catalysts can have in promoting efficient macrocyclization reactions. We show that catalyst chirality is essential to promote favorable and paired transition state relationships that promote macrocyclization of substrates with pre-existing stereogenic elements; oddly enough, the chirality of the catalyst is essential for successful reactions, even if no new static (ie, non-“dynamic”) stereogenic elements are created. Control experiments involving achiral variants of the catalyst or the enantiomeric form of the catalyst fail to provide macrocycles in significant amounts in direct comparisons. The generality of the phenomenon, demonstrated here with a number of substrates, stimulates analogies with enzyme catalysts that produce natural macrocycles, presumably through related peripheral interactions defined by the catalyst with their acyclic substrates.