Enantioselective conjugate addition catalyzed by a copper-phosphoramidite complex: Computational and experimental exploration of asymmetric induction

Journal article

The stereochemical role of the phosphoramidite ligand in the asymmetric conjugate addition of alkylzirconium species to cyclic enones has been established for the first time through experimental and computational studies. Systematic, synthetic variation of the modular ligand established that the configuration of the binaphthol backbone is responsible for absolute stereocontrol, 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 optimisation, leading to the 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.

Authors: Ardkhean, R; Roth, P; Maksymowicz, R; Curran, A; Peng, Q

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Chemical Society
• Journal: ACS Catalysis
• Volume: 7
• Pages: 6729–6737
• Publication date: 2017-08-23
• Acceptance date: 2017-08-23
• DOI: 10.1021/acscatal.7b01453
• ISSN: 2155-5435
• Keywords: linear free energy relationship; mechanism; phosphoramidite ligand; quantum chemical calculations; copper; quantitative structure selectivity relationship; steric parameters; asymmetric catalysis