Chiral Lewis acid-bonded picolinaldehyde enables enantiodivergent carbonyl catalysis in the Mannich/condensation reaction of glycine ester

Abstract

A new strategy of asymmetric carbonyl catalysis via a chiral Lewis acid-bonded aldehyde has been developed for the direct Mannich/condensation cascade reaction of glycine ester with aromatic aldimines. The co-catalytic system of 2-picolinaldehyde and chiral Yb^III-N,N′-dioxides was identified to be efficient under mild conditions, providing a series of trisubstituted imidazolidines in moderate to good yields with high diastereo- and enantioselectivities. Enantiodivergent synthesis was achieved via changing the sub-structures of the chiral ligands. The reaction could be carried out in a three-component version involving glycine ester, aldehydes, and anilines with equally good results. Based on control experiments, the X-ray crystal structure study and theoretical calculations, a possible dual-activation mechanism and stereo-control modes were provided to elucidate carbonyl catalysis and enantiodivergence.