Macrocycles, compounds containing a ring of 12 or more atoms, find use in human medicine, fragrances, and biological ion sensing. The efficient preparation of macrocycles is a fundamental challenge in synthetic organic chemistry because the high entropic cost of large-ring closure allows undesired intermolecular reactions to compete. Here, we present a bioinspired strategy for macrocycle formation through carbon–carbon bond formation. The process relies on a catalytic oligomer containing α- and β-amino acid residues to template the ring-closing process. The α/β-peptide foldamer adopts a helical conformation that displays a catalytic primary amine–secondary amine diad in a specific three-dimensional arrangement. This catalyst promotes aldol reactions that form rings containing 14 to 22 atoms. Utility is demonstrated in the synthesis of the natural product robustol.

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Use of a tunable molecular scaffold to align a reactive diad for bifunctional catalysis can reveal relationships between functional group identity and reactivity that might otherwise be impossible to identify. Here we use an α/β-peptide helix to show that an aligned pair of primary amine groups is uniquely competent to catalyze crossed aldol condensations with an aryl aldehyde as the electrophile. Geometrically similar diads in which one amine group is secondary, or both are secondary, are good catalysts for other types of aldol condensations but not those involving an aryl aldehyde. Catalytic efficacy requires β-amino acid residues that are preorganized for helix formation via cyclic constraint. Conventional peptides (exclusively α-amino acid residues) that display the primary amine diad are poor catalysts, which highlights the critical role of the foldamer scaffold.

Assemblies of racemic β‐sheet‐forming peptides have attracted attention for biomedical applications because racemic forms of peptides can self‐associate more avidly than do single enantiomers. In 1953, Pauling and Corey proposed “rippled β‐sheet” modes of H‐bond‐mediated interstrand assembly for alternating L‐ and D‐peptide strands; this structural hypothesis was complementary to their proposal of “pleated β‐sheet” assembly for L‐peptides. Although no high‐resolution structure has been reported for a rippled β‐sheet, there is strong evidence for the occurrence of rippled β‐sheets in some racemic peptide assemblies. Here we compare propensities of peptide diastereomers in aqueous solution to form a minimum increment of β‐sheet in which two antiparallel strands associate. β‐Hairpin folding is observed for homochiral peptides with aligned nonpolar side chains, but no β‐hairpin population can be detected for diastereomers in which one strand contains L residues and the other contains D residues. These observations suggest that rippled β‐sheet assemblies are stabilized by interactions between β‐sheet layers rather than interactions within these layers.

Peptide catalysts based on TrpZip scaffolds for the hydrolysis of para-nitrophenylacetate in aqueous media were found to have higher catalytic activity in sequences without β-hairpin character.