American Chemical Society
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Hydroxy-amide Functionalized Azolium Salts for Cu-Catalyzed Asymmetric Conjugate Addition: Stereocontrol Based on Ligand Structure and Copper Precatalyst

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journal contribution
posted on 2012-04-20, 00:00 authored by Naoatsu Shibata, Misato Yoshimura, Haruka Yamada, Ryuichi Arakawa, Satoshi Sakaguchi
A series of hydroxy-amide functionalized azolium salts have been designed and synthesized for Cu-catalyzed asymmetric conjugate addition reaction. The (CH2)2-bridged hydroxy-amide functionalized azolium ligand precursors 2, in addition to the previously reported CH2-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 Bu2Zn 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 CH2-bridged azolium salt 1 in the reaction of 17 with Bu2Zn 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.