Highly efficient asymmetric conjugate hydrocyanation of aromatic enones by an anionic chiral phosphate catalyst

Chiral keto nitriles (β-cyano ketones) have been prepared by a facile and efficient asymmetric conjugate hydrocyanation of poorly active chalcone-type enones with benzophenone cyanohydrin. Using in situ generated 5-10 mol-% of sodium (S)-6,6′-di(1-adamantyl)-1,1′-binaphthyl-2,2′-diyl phosphate as catalyst and 5-10 mol-% of 2-tert-butylphenol as an additive, high yields and excellent enantioselectivities were obtained within 2 h in toluene at 80 °C. The development of catalysts, optimization of the reaction parameters, and substrate scope are reported. On the basis of the experimental results, HCN is shown to be the real cyanide source and a mechanism is proposed to explain the origin of the enantioselectivity with the chiral-anion-modified nucleophile HCN. The asymmetric conjugate hydrocyanation of poorly reactive chalcone-type enones with benzophenone cyanohydrin using an anionic chiral phosphate catalyst has been achieved in high yields (72-96 %) and excellent enantioselectivities (92-98 % ee). It is proposed that the chiral anion modifies HCN, the real nucleophile, in the transition state through hydrogen bonding.