Enantioselective Conjugate Addition Catalyzed by a Copper Phosphoramidite Complex: Computational and Experimental Exploration of Asymmetric Induction

The stereochemical role of the phosphoramidite ligand in the asymmetric conjugate addition of alkylzirconium species to cyclic enones has been established through experimental and computational studies. Systematic, synthetic variation of the modular ligand established that the configuration of the binaphthol backbone is responsible for absolute stereo control, whereas modulation of the amido substituents leads to dramatic variations in the level of asymmetric induction. Chiral amido substituents are not required for enantioselectivity, leading to the discovery of a new family of easily synthesized phosphoramidites based on achiral amines that deliver equal levels of selectivity to Feringa's ligand. A linear correlation between the length of the aromatic amido groups and experimentally determined enantioselectivity was uncovered for this class of ligand, which, following an optimization, led to highly selective ligands (up to 94% ee) with naphthyl rather than phenyl groups. An electronic effect of sterically similar aromatic substituents was investigated through NMR and DFT studies, showing that electron-rich aryl groups allow better Cu coordination. An interaction between the metal center and an aromatic group is responsible for this enhanced affinity and leads to a more tightly coordinated transition structure, leading to the major enantiomer. These studies illustrate the use of parametric quantitative structure selectivity relationships to generate mechanistic models for asymmetric induction and catalyst structures that may be further probed by experiment and computation. This integrated approach leads to the rational modification of chiral ligands to achieve enhanced levels of selectivity.