Dispersion and Steric Effects on Enantio-/Diastereoselectivities in Synergistic Dual Transition-Metal Catalysis

Comprehensive computational studies were carried out to explore the mechanisms of enantioselective Cu/Pd and stereodivergent Cu/Ir dual-catalytic syntheses of alpha,alpha-disubstituted alpha-amino acids (alpha-AAs). A chiral copper azomethine ylide undergoes facile alpha-allylation with racemic pi-allylpalladium species or stereopure pi-allyliridium complex to stereoconvergently or stereodivergently furnish single/double stereocenters, respectively. Stereoselectivity at the alpha-center is controlled by the facial selectivity of alpha-allylation with respect to the prochiral nucleophile. Despite apparently similar transition-state assemblies, computational models and distortion/interaction analyses disclose versatile modes of stereoinduction wherein the copper azomethine ylide species can face-selectively intercept metal-pi-allyl intermediates utilizing attractive dispersion interactions and/or sterically caused distortions. Generation of the beta-stereocenter in the Cu/Ir system relies on a stereospecifically generated allyliridium complex and electronically controlled branched-to-linear selectivity, while the dual Cu/Pd system yields a linear monochiral product due to steric factors and pi-pi stacking interactions. The studies demonstrate on a molecular level how ligand-encoded chiral information is transferred to the alpha-/beta-sites of the resulting alpha-AAs and how the mode of regio-/stereoselection is altered by differences in transition-metal-stabilized coupling partners. To facilitate studies of stereoselective catalysis, a suite of analytical tools to extract controlling factors for asymmetric induction is demonstrated.

Automated summary

Comprehensive computational studies were conducted to investigate the mechanisms of enantioselective Cu/Pd and stereodivergent Cu/Ir dual-catalytic syntheses of alpha,alpha-disubstituted alpha-amino acids (alpha-AAs). The results demonstrate how ligand-encoded chiral information is transferred to the alpha-/beta-sites of the resulting alpha-AAs and how the mode of regio-/stereoselection is altered by differences in transition-metal-stabilized coupling partners.