Organocatalytic Asymmetric Decarboxylative Mannich Reaction for the Synthesis of Non-Natural α-Amino Acids Bearing Alkynyl Groups

Asymmetric decarboxylative Mannich addition of beta-keto acids or malonic acid half-esters to beta,gamma-alkynyl-alpha-ketimino esters catalyzed by cinchona alkaloid-derived squaramide has been developed. The reaction proceeded by forming a nucleophilic enolate after decarboxylation, followed by its addition to beta,gamma-alkynyl-alpha-ketimino esters facilitated by the bifunctional catalyst. A broad range of substrates with various substituents are tolerated in this reaction, yielding a series of alpha,alpha-disubstituted amino acid derivatives bearing alkynyl functional groups in high yields with good to excellent enantioselectivities. The practicality of this method was demonstrated by a gram-scale reaction and subsequent elaboration of the Mannich adducts.