Ligand design for dual enantioselective control in Cu-catalyzed asymmetric conjugate addition of R2Zn to cyclic enone

A new chiral N-heterocyclic carbene (NHC) ligand derived from a natural alpha-aminoester has been designed and synthesized. The coupling of N-methylbenzimidazole with an alpha-chloroacetamide derivative, which was prepared from chloroacetyl chloride and (S)-serine methyl ester, gave the corresponding ester/amide-functionalized azolium compound 20. The reaction of 2-cyclohexen-1-one (17) with Et2Zn in the presence of catalytic amounts of Cu(OTf)(2) and 20 produced (R)-3-ethylcyclohexanone (18) as a major product. In contrast, the enantioselective conjugate addition (ECA) reaction catalyzed by Cu(OTf)(2) under the influence of a hydroxy-amide-functionalized azolium compound 15, which was derived from (S)-tert-leucinol, produced (S)-18 in preference to (R)-18. A series of azolium salts were synthesized from (S)-serine esters, and the reaction conditions for the ECA reaction were optimized to produce (R)-18 with 69% ee. The best results were obtained in the case of the reaction of 4,4-dimethyl-2-cyclohexen-1-one (34) with Et2Zn catalyzed by Cu(OTf)(2) in combination with azolium compounds. When the reaction of 34 with Et2Zn was carried out in the presence of catalytic amounts of Cu(OTf)(2) and 20, (S)3-ethyl-4,4-dimethylcyclohexanone (35) was obtained with 97% ee, whereas the ECA reaction under the influence of hydroxy-amide-functionalized azolium 15 afforded (R)-35 with >99% ee. In this manner, the reversal of enantioselectivity was achieved by controlling the structure of chiral ligands. (C) 2011 Elsevier Ltd. All rights reserved.