Reversal of enantioselectivity in a Cu-catalyzed asymmetric conjugate addition reaction of dialkylzinc to cyclic enone with use of the same chiral ligand was successfully achieved. The reaction of 2-cyclohexen-1-one (30) with Et(2)Zn catalyzed by Cu(OTf)(2) in the presence of an azolium salt derived from a chiral beta-amino alcohol gave (S)-3-ethylcyclohexanone (31) in good enantioselectivity. Among a series of chiral azolium compounds examined, the benzimidazolium salt (10) having both a tert-butyl group at the stereogenic center and a benzyl substituent at the azolium ring was found to be the best choice of ligand in the Cu(OTf)(2)-catalyzed reaction. Good enantioselectivity was observed when the reaction was conducted by employing a benzimidazolium derivative rather than an imidazolium derivative. The influence of the substituent at the azolium ring on the stereoselectivity of the reaction was also examined. In addition, from the results of the reaction catalyzed by Cu(OTf)(2) combined with an azolium compound derived from (S)-leucine methyl ester, it was found that the hydroxy side chain in the chiral ligand is probably crucial for the enantiocontrol of the conjugate addition reaction. On the other hand, it was discovered from a screening test of copper species that the reversal of enantioselectivity was realized by allowing 30 to react with Et(2)Zn in the presence of Cu(acac)(2) combined with the same ligand precursor to afford (R)-31 as a major product. The influence of the stereodirecting group at the chiral ligand on the stereoselectivity in the Cu(acac)(2)-catalyzed reaction differed completely from that observed in the Cu(OTf)(2)-catalyzed reaction. Reaction with a cyclic enone consisting of a seven-membered ring such as 2-cyclohepten-1-one (40) resulted in increasing the enantioselectivity of the reaction. Thus, treatment of 40 with Et(2)Zn catalyzed by Cu(OTf)(2) combined with a benzimidazolium salt produced the corresponding (S)-conjugate adduct in a 92:8 enantiomer ratio (er), while the Cu(acac)(2)-catalyzed reaction with the same ligand afforded (R)-product in a 9:91 er.

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A series of hydroxy-amide functionalized azolium salts have been designed and synthesized for Cu-catalyzed asymmetric conjugate addition reaction. The (CH(2))(2)-bridged hydroxy-amide functionalized azolium ligand precursors 2, in addition to the previously reported CH(2)-bridged azolium salts 1, have been prepared from readily available enantiopure β-amino alcohols. The combination of a Cu species with 1 or 2 efficiently promoted the 1,4-addition reaction of cyclic enones with dialkylzincs. For example, the reaction of 2-cyclohepten-1-one (17) with Bu(2)Zn in the presence of catalytic amounts of Cu(OTf)(2) and 1 gave (S)-3-butylcycloheptanone (20) in 99% yield and 96% ee. On the other hand, when the reaction was carried out under the influence of Cu(OTf)(2) combined with 2, (R)-20 in preference to (S)-20 was obtained in 98% yield and 80% ee. In this manner, the enantioselecvity was switched by controlling the structure of chiral ligand. Additionally, the reversal of enantioselectivity was also achieved by changing the Cu precatalyst from Cu(OTf)(2) to Cu(acac)(2) with the same ligand. The combination of Cu(acac)(2) with CH(2)-bridged azolium salt 1 in the reaction of 17 with Bu(2)Zn led to formation of (R)-20 as a major product in 55% yield and 80% ee. This result was in contrast to the Cu(OTf)(2)/1 catalytic system, where the 1,4-adduct with opposite configuration was obtained. Moreover, use of the Cu(acac)(2)/2 catalytic system produced (S)-20, while (R)-20 was formed by the Cu(OTf)(2)/2 catalytic system. Thus, it was found that either varying the linker of the chiral ligands or changing the counterion of Cu species between a OTf and acac ligand initially on the metal led to dual enantioselective control in the 1,4-addition reaction.

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The reversal of enantioselectivity using the same catalytic system was achieved simply by changing the order of the addition of substrates.