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

Abstract

The combination of a peptide catalyst and a gold catalyst is presented for enantioselective addition reactions between allenamides and branched aldehydes. 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 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 fine balance of acid/base additives is key for ensuring formation of the desired product over undesired side reactions.