Enantioselective Mannich-Type Reactions Using a Novel Chiral Zirconium Catalyst for the Synthesis of Optically Active β-Amino Acid Derivatives

Abstract

Catalytic enantioselective Mannich-type reactions of silyl enol ethers with aldimines have been successfully performed using a novel chiral zirconium catalyst prepared from zirconium(IV) tert-butoxide (Zr(OtBu)4), 2 equiv of (R)-6,6‘-dibromo-1,1‘-bi-2-naphthol ((R)-6,6‘-Br2BINOL), and N-methylimidazole. The use of aldimines having N-substituted hydroxyphenyl moieties is essential for obtaining high selectivities, and the N-substituted groups were converted to free amines using oxidative cleavage. Aldimines derived from aromatic aldehydes as well as heterocyclic and aliphatic aldehydes reacted with silyl enol ethers smoothly to afford the corresponding β-amino acid derivatives in high yields and high enantioselectivities. Several NMR experiments have been conducted to clarify the structure of the chiral Zr catalyst and also the catalytic cycle of this asymmetric reaction. Finally, a new BINOL derivative, (R)-6,6‘-bis(trifluoromethyl)-1,1‘-bi-2-naphthol ((R)-6,6‘-(CF3)2BINOL), has been prepared. It was shown that the turnover of the catalyst using this novel ligand was improved, and high levels of yields and selectivities were obtained in the presence of a small amount of the zirconium catalyst.