Direct Catalytic Asymmetric Michael Reaction of Hydroxyketones:  Asymmetric Zn Catalysis with a Et2Zn/Linked-BINOL Complex

Full details of our direct Michael addition of unmodified ketones using new asymmetric zinc catalysis are described. Et2Zn/(S,S)-linked-BINOL complexes were successfully applied to direct 1,4-addition reactions of hydroxyketones. The first generation Et2Zn/(S,S)-linked-BINOL 1 = 2/1 system was effective for 1,4-addition of 2-hydroxy-2‘-methoxyacetophenone (3). Using 1 mol % of (S,S)-linked-BINOL 1 and 2 mol % of Et2Zn, we found that a 1,4-addition reaction of β-unsubstituted enone proceeded smoothly at 4 °C to afford products in high yield (up to 90%) and enantiomeric excess (up to 95%). In the case of β-substituted enones, however, the first generation Et2Zn/(S,S)-linked-BINOL 1 = 2/1 system was not at all effective. The second generation Et2Zn/(S,S)-linked-BINOL 1 = 4/1 with MS 3A system was developed and was effective for various β-substituted enones to afford products in good dr, yield (up to 99%), and high enantiomeric excess (up to 99% ee). With the Et2Zn/1 = 4/1 systems, catalyst loading for β-unsubstituted enone was reduced to as little as 0.01 mol % (substrate/chiral ligand = 10 000). The new system was also effective for 1,4-addition reactions of 2-hydroxy-2‘-methoxypropiophenone (9) to afford chiral tert-alcohol in high enantiomeric excess (up to 96% ee). Mechanistic investigations as well as transformations of the Michael adducts into synthetically versatile intermediates are also described.