Low molecular weight synthetic peptides have been demonstrated to be effective catalysts for an increasingly wide array of asymmetric transformations. In many cases, these peptide-based catalysts have enabled novel multifunctional substrate activation modes and unprecedented selectivity manifolds. These features, along with their ease of preparation, modular and tunable structures, and often biomimetic attributes make peptides well-suited as chiral catalysts, and of broad interest. Many examples of peptide-catalyzed asymmetric reactions have appeared in the literature since the last survey of this broad field in Chemical Reviews (Chem. Rev. 2007, 107, 5759-5812). The overarching goal of this new review is to provide a comprehensive account of the numerous advances in the field. As a corollary to this goal, we survey the many different types of catalytic reactions, ranging from acylation to C-C bond formation, in which peptides been successfully employed. In so doing, we devote significant discussion to the structural and mechanistic aspects of these reactions that are perhaps specific to peptide-based catalysts and their interactions with substrates and/or reagents.

Catalyst control over reactions that produce multiple stereoisomers is a challenge in synthesis. Control over reactions that involve stereogenic elements remote from one another is particularly uncommon. Additionally, catalytic reactions that address both stereogenic carbon centers and an element of axial chirality are also rare. Reported herein is a catalytic approach to each stereoisomer of a scaffold containing a stereogenic center remote from an axis of chirality. Newly developed peptidyl copper complexes catalyze an unprecedented remote desymmetrization involving enantioselective C-N bond-forming cross-coupling. Then, chiral phosphoric acid catalysts set an axis of chirality through an unprecedented atroposelective cyclodehydration to form a heterocycle with high diastereoselectivity. The application of chiral copper complexes and phosphoric acids provides access to each stereoisomer of a framework with two different elements of stereogenicity.

We report the development of a new class of guanidine-containing peptides as multifunctional ligands for transition-metal catalysis and its application in the remote desymmetrization of diarylmethanes via copper-catalyzed Ullman cross-coupling. Through design of these peptides, high levels of enantioinduction and good isolated yields were achieved in the long-range asymmetric cross-coupling (up to 93:7 er and 76% yield) between aryl bromides and malonates. Our mechanistic studies suggest that distal stereocontrol is achieved through a Cs-bridged interaction between the Lewis-basic C-terminal carboxylate of the peptides with the distal arene of the substrate.

New strategies to access radicals from common feedstock chemicals hold the potential to broadly impact synthetic chemistry. We report a dual phosphine and photoredox catalytic system that enables direct formation of sulfonamidyl radicals from primary sulfonamides. Mechanistic investigations support that the N-centered radical is generated via α-scission of the P–N bond of a phosphoranyl radical intermediate, formed by sulfonamide nucleophilic addition to a phosphine radical cation. As compared to the recently well-explored β-scission chemistry of phosphoranyl radicals, this strategy is applicable to activation of N-based nucleophiles and is catalytic in phosphine. We highlight application of this activation strategy to an intermolecular anti-Markovnikov hydroamination of unactivated olefins with primary sulfonamides. A range of structurally diverse secondary sulfonamides can be prepared in good to excellent yields under mild conditions.

A domino reaction sequence involving aldol condensation, alkene isomerization, and intramolecular hetero-Diels-Alder cycloaddition for the synthesis of [2.2.2]-diazabicyclic structures is reported. Excellent diastereofacial control during the cycloaddition is enforced with a removable chiral phenyl aminal diketopiperazine substituent. The reaction sequence rapidly generates molecular complexity and is competent with both enolizable and nonenolizable aldehyde substrates (nine examples total). Progress toward the synthesis of malbrancheamide B, a protypical member of the [2.2.2]-diazabicyclic natural product family, is also disclosed.