DFT investigation of Cu(i)-catalyzed addition of 1,4-pentadiene to acetophenone: mechanism and selectivity for the synthesis of a chiral tertiary alcohol with a 1,3-diene unit

Abstract

Extensive DFT calculations have been performed to obtain a better understanding of the mechanism and selectivity for the synthesis of chiral tertiary alcohols containing a terminal 1,3-diene unit by Cu(I) catalysis with a chiral phosphoric acid ligand. The reaction occurs through three fundamental steps: generation of the catalytically active species (an allyl–Cu(I) species), formation of the Cu(I)–alkoxide intermediate, and production of the chiral tertiary alcohol bearing a 1,3-diene unit with regeneration of the catalytically active species. It is established that the first step serves as the rate-determining step, the regioselectivity is governed by the second step, and the stereoselectivity (including (Z)/(E)-selectivity and enantioselectivity) is determined by the third step. The calculated results validate the experimental observation that the (R)-DTBM-SEGPHOS ligand primarily delivers the linear (Z)-(R)-product, while the (R,R)-Ph-BPE ligand results in the predominant formation of the linear (Z)-(S)-product. The formation of the branched product is found to be highly unfavorable due to the weaker nucleophilicity of the C3 atom compared to the C1 atom in the allyl–Cu(I) species. The (Z)/(E)-selectivity of the reaction is controlled by the steric effect between the 1,3-pentadiene moiety and the phosphine ligand, and the enantioselectivity is attributed to non-covalent interaction between the acetophenone and the phosphine ligand.