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. An enzyme and a peptide catalyze—in an aqueous buffer—a two‐step cascade reaction with high chemo‐ and stereoselectivity in one pot. The optimization of the modular peptide catalyst and the identification of common reaction conditions were key for bringing the two worlds of enzyme and peptide catalysis together.