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.
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.