Synergistic Peptide and Gold Catalysis: Enantioselective Addition of Branched Aldehydes to Allenamides

The combination of a peptide catalyst and a gold catalyst is presented for enantioselective addition reactions between branched aldehydes and allenamides. The two catalysts act in concert to provide γ,δ‐enamide aldehydes bearing a fully substituted, benzylic stereogenic center – a structural motif common in many natural products and therapeutically active compounds – with good yields and enantioselectivities. The reaction tolerates a variety of alkyl and alkoxy substituted aldehydes and the products can be elaborated into several chiral building blocks bearing either 1,4‐ or 1,5‐ functional group relationships. Mechanistic studies showed that the conformational features of the peptide are important for both the catalytic efficiency and stereochemistry, while a balance of acid/base additives is key for ensuring formation of the desired product over undesired side reactions. A synergistic combination of a tripeptide and a gold complex catalyzes the enantioselective addition between branched aldehydes and allenamides to furnish synthetically versatile γ,δ‐enamide aldehydes with a fully substituted stereogenic center. Mechanistic studies offered key insights into the role of the peptide and acid/base additives.