Bifunctional Cinchonine-Catalyzed Asymmetric Mannich Reaction

Significance

β-Amino acid motifs still challenge organic synthesis. The authors of this paper used a thiourea derivative of cinchonine as catalyst in an enantioselective Mannich reaction. The thiourea moiety is speculated to activate the imine via hydrogen bonding interaction, while the bridgehead nitrogen acts as a Brønsted base activating the nucleophile via deprotonation. It was found that, when employing malonate esters, increasing steric demand of the ester group dramatically reduces the enantioselectivity of the process. The aldimine may bear different aryl groups, such as phenyl, m-MeOC₆H₄, or p-ClC₆H₄, and suitable N-protecting groups are Cbz and Boc. In addition to that, the use of methylcyclopentanone-2-carboxylate is reported, which leads to the formation of two stereogenic centers in one step (70-97% yield, up to 87% ee, up to 20:1 dr), one of which is quaternary. Decarboxylation was found to proceed without racemization.