Inversions in asymmetric conjugate addition reaction of cyclic enones catalyzed by the Cu/NHC-AgX system: Factors affecting the stereoselective formation of both enantiomers

Abstract

A switchable enantioselectivity was achieved in a Cu-catalyzed asymmetric conjugate addition (ACA) reaction. The ethylene-bridged, hydroxyamide-functionalized NHC-AgI complex, readily accessible from a chiral β-amino alcohol, was found to be a versatile chiral ligand precursor for dual enantioselective control. The stereocontrol of the catalytic ACA reaction depended on the order of addition of the substrates. To a THF solution containing CuOTf (6 mol %), NHC-AgI complex (1b, R1 = Et, R2 = Bn, 4 mol %), and 2-cyclohexen-1-one (3) was added Et2Zn to yield (R)-3-ethylcyclohexanone ((R)-4) in 74% enantioselectivity (method A). In stark contrast, when 3 was added as a last component to a mixture of CuOTf (4 mol %), 1b (10 mol %), and Et2Zn in THF (method B), the ACA reaction afforded (S)-4 with 87% ee. In order to obtain an insight into various aspects of the present ACA reaction, the chiral NHC ligand precursors, substrates, and NHC skeletons were fully evaluated. A study of the relationship between the catalyst ee (eecat) and the product ee (eepro) revealed a chiral amplification phenomenon. Moreover, it was found that the ACA reaction using method A was not affected by the halide ion on the NHC-AgX complex, whereas the halide ion on the silver complex showed a significant influence on the enantiocontrol of the ACA reaction using method B. In particular, a Cu/NHC/I catalytic ratio of 1/1/2 was needed for a successful ACA reaction using method B. According to these factors affecting the reversal of enantioselectivity in the ACA reaction, a possible reaction pathway was proposed.