Copper/ruthenium relay catalysis for stereodivergent construction of 1,4-nonadjacent stereocenters: mechanistic investigation using DFT calculations†

Recent research has developed a Cu/Ru dual catalysis system for the hydroalkylation of racemic allylic alcohols and racemic ketimine esters. This method is distinguished by its ability to stereodivergently generate 1,4-nonadjacent stereocenters. This study employs density functional theory calculations to elucidate how copper and ruthenium synergistically drive this transformation and to reveal why this dual-catalyst system is more efficient than systems using either copper or ruthenium independently. The findings show how different combinations of chiral catalysts influence the formation of two stereogenic centers. We highlight the critical roles of noncovalent interactions and steric effects in determining the most energetically favorable transition states for each catalyst combination. Additionally, this study elucidates the significant role of potassium phosphate (K₃PO₄) in enhancing the reaction efficiency. Specifically, K₃PO₄ facilitates the dehydrogenation and hydrogenation processes across all three stages of the catalytic cycle. We also explore the reaction's chemoselectivity by computing the formation mechanisms of three potential by-products and analyzing the driving forces behind the generation of the desired product. These mechanistic insights can support advancements in stereodivergent synthesis using cooperative bimetallic catalysis.