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.

The extraordinary rate accelerations and control of reactivity exhibited by enzymes have long inspired efforts to develop synthetic catalysts. Foldamers, which are oligomers with a strong tendency to adopt a specific conformation, represent unique platforms for efforts to harness principles of enzyme function for catalyst design. Well-defined helical structures that have been identified in several foldamer families can serve as scaffolds for the predictable spatial arrangement of functional groups. The chirality of these helices offers a basis for asymmetric catalysis. Thus, foldamer-based approaches to catalyst development represent an attractive alternative to well-developed strategies involving small molecules or conventional peptides.

What is the best spatial arrangement of a pair of reactive groups for bifunctional catalysis of a chemical transformation? The conformational versatility of proteins allows reactive group geometry to be explored and optimized via evolutionary selection, but it has been difficult for chemists to identify synthetic scaffolds that allow broad comparative evaluation among alternative reactive group geometries. Here we show that a family of helices, adopted predictably by oligomers composed partially or exclusively of β-amino acid residues, enables us to explore a range of orientations for a pair of pyrrolidine units that must work in tandem to catalyze a crossed aldol reaction. Thus, the crossed aldol reaction serves as an assay of reactive diad efficacy. We have chosen a test reaction free of stereochemical complexity in order to streamline our study of reactivity. The best geometry enhances the initial rate of product formation by two orders of magnitude. Our findings raise the possibility that rudimentary catalysts involving an isolated secondary structure might have facilitated the development of prebiotic reaction networks.

We report a pairing of known catalysts that enables intramolecular conjugate additions of aldehyde-derived enamines to α,β-unsaturated esters. Despite extensive prior exploration of conjugate additions of aldehyde-derived enamines, catalytic conjugate additions to unactivated enoate esters are unprecedented. Achieving enantioselective and diastereoselective six-membered ring formation requires the coordinated action of a chiral pyrrolidine, for nucleophilic activation of the aldehyde via enamine formation, and a hydrogen bond donor, for electrophilic activation of the enoate ester. Proper selection of the hydrogen bond donor is essential for chemoselectivity, which requires minimizing competition from homoaldol reaction. Utility is demonstrated in a six-step synthesis of (−)-yohimbane from cycloheptene.Letter pubs.acs.org/OrgLett

Stereochemical control of photochemical reactions that occur via triplet energy transfer remains a challenge. Suppressing off-catalyst stereorandom reactivity is difficult for highly reactive open-shell intermediates. Strategies for suppressing racemate-producing, off-catalyst pathways have long focused on formation of ground state, substrate-catalyst chiral complexes that are primed for triplet energy transfer via a photocatalyst in contrast to their off-catalyst counterparts. Herein, we describe a strategy where both a chiral catalyst-associated vinylpyridine and a nonassociated, free vinylpyridine substrate can be sensitized by an Ir(III) photocatalyst, yet high levels of diastereo- and enantioselectivity in a [2 + 2] photocycloaddition are achieved through a preferred, highly organized transition state. This mechanistic paradigm is distinct from, yet complementary to current approaches for achieving high levels of stereocontrol in photochemical transformations.