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

Abstract

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 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.

Recent Developments and Synthetic Applications of Nucleophilic Zirconocene Complexes from Schwartz's Reagent

“…A very interesting study concerning ACA reaction, associating both theoretical and experimental investigations, was recently reported by Maksymowicz and co‐workers . The results suggested that the phosphoramitide ligand, usually employed in ACA transformations, has a key role in the stereochemical outcome of the products.…”

Copper-catalysed alkylation of heterocyclic acceptors with organometallic reagents

“…Organozirconium compounds are another class of organometallic reagents that have been used widely in the synthesis of complex molecules. Recently, Fletcher and co-workers demonstrated the applicability of a hydrozirconation in the ACA reaction to non-heterocyclic conjugated substrates [22][23][24][25][26], while the Šebesta group was the first to report the copper-catalysed addition of organozirconium reagents to N-substituted 2,3dehydro-4-piperidones (Scheme 4A) [27]. In the latter work, the organozirconium reagents were generated first in situ by the hydrozirconation of alkenes.…”

Copper‐Catalyzed Asymmetric Arylation of N‐Heteroaryl Aldimines: Elementary Step of a 1,4‐Insertion

“…The DFT‐optimized transition states indicated that the copper catalyst ligated with a single bulky ligand L was sufficient for excellent enantiofacial induction during arylation. L adopted a specific baseball‐glove‐like conformation, by minimizing steric interaction between its two large 1‐phenylethyl groups (Figure ).…”