Peptide and Enzyme Catalysts Work in Concert in Stereoselective Cascade Reactions-Oxidation followed by Conjugate Addition.

Enzymes and peptide catalysts consist of the same building blocks but require vastly different environments to operate best. Herein, we show that an enzyme and a peptide catalyst can work together in a single reaction vessel to catalyze a two-step cascade reaction with high chemo- and stereoselectivity. Abundant linear alcohols, nitroolefins, an alcohol oxidase, and a tripeptide catalyst provided chiral γ-nitroaldehydes in aqueous buffer. High yields (up to 92 %) and stereoselectivities (up to 98 % ee) were achieved for the cascade through the rational design of the peptide catalyst and the identification of common reaction conditions.

Overcoming Deactivation of Amine-Based Catalysts: Access to Fluoroalkylated γ-Nitroaldehydes.

Organocatalytic conjugate addition reactions of aldehydes to fluoroalkylated nitroolefins with chiral amine catalysts offer a straightforward stereoselective path to fluoroalkylated γ-nitroaldehydes and downstream derivatives. However, amine-based catalysts suffer from deactivation by reaction with electron-poor fluoroalkylated nitroolefin. Here, we show that catalyst deactivation can be overcome by catalysts that bear an intramolecular acid for protonation and release of the alkylated catalyst through ß-elimination of the nitroolefin. NMR spectroscopic, kinetic, and molecular modeling studies provided detailed structural and mechanistic insights into the factors that control reversible catalyst alkylation and facilitate efficient catalysis.

Photo- and Metal-Mediated Deconstructive Approaches to Cyclic Aliphatic Amine Diversification.

Described herein are studies toward the core modification of cyclic aliphatic amines using either a riboflavin/photo-irradiation approach or Cu(I) and Ag(I) to mediate the process. Structural remodeling of cyclic amines is explored through oxidative C-N and C-C bond cleavage using peroxydisulfate (persulfate) as an oxidant. Ring-opening reactions to access linear aldehydes or carboxylic acids with flavin-derived photocatalysis or Cu salts, respectively, are demonstrated. A complementary ring-opening process mediated by Ag(I) facilitates decarboxylative Csp3-Csp2 coupling in Minisci-type reactions through a key alkyl radical intermediate. Heterocycle interconversion is demonstrated through the transformation of N-acyl cyclic amines to oxazines using Cu(II) oxidation of the alkyl radical. These transformations are investigated by computation to inform the proposed mechanistic pathways. Computational studies indicate that persulfate mediates oxidation of cyclic amines with concomitant reduction of riboflavin. Persulfate is subsequently reduced by formal hydride transfer from the reduced riboflavin catalyst. Oxidation of the cyclic aliphatic amines with a Cu(I) salt is proposed to be initiated by homolysis of the peroxy bond of persulfate followed by α-HAT from the cyclic amine and radical recombination to form an α-sulfate adduct, which is hydrolyzed to the hemiaminal. Investigation of the pathway to form oxazines indicates a kinetic preference for cyclization over more typical elimination pathways to form olefins through Cu(II) oxidation of alkyl radicals.

Stereoselective peptide catalysis in complex environments - from river water to cell lysates.

Many stereoselective peptide catalysts have been established. They consist, like nature's catalysts, of amino acids but have significantly lower molecular weights than enzymes. Whereas enzymes operate with exquisite chemoselectivity in complex biological environments, peptide catalysts are used in pure organic solvents and at higher concentrations. Can a peptide catalyst exhibit chemoselectivity reminiscent of enzymes? Here, we investigated the properties of tripeptide catalysts in complex mixtures in hydrophobic and aqueous solvents. We challenged the catalysts with biomolecules bearing functional groups that could interfere by coordination or reaction with the peptide, the substrates, or intermediates. H-dPro-αMePro-Glu-NHC12H15 emerged through tailoring of the trans/cis ratio of the tertiary amide as a conformationally well-defined tripeptide that catalyzes C-C bond formations with high reactivity and stereoselectivity - regardless of the solvent and compound composition. The chemoselectivity of the tripeptide is so high that it even catalyzes reactions in cell lysates. The findings provoke the question of the potential role of peptide catalysis in nature and during the evolution of enzymes.