Peptide catalyzes macrocycle formation

Abstract

Macrocycles are difficult to synthesize because there’s an entropic penalty associated with the ring closure. Chemists have multiple approaches to overcome that penalty and make the rings, each with advantages and disadvantages. For example, ring-closing metathesis has good yields but requires metal catalysts that can be tough to remove from product mixes. Samuel H. Gellman and coworkers at the University of Wisconsin–Madison have now come up with a metal-free approach in which they use a synthetic peptide called a foldamer to catalyze macrocycle formation with yields as high as 97% (Science 2019, DOI: 10.1126/science.aax7344). Their seven-residue foldamer catalyzes macrocycle formation via an aldol condensation. Two amine groups—a cyclic secondary amine and a primary amine—form reactive intermediates with aldehydes in the substrate. The foldamer backbone acts as a scaffold that holds the two amine groups in the right orientation so that the resulting intermediates react to close the ring. The secondary