Diastereoselective arylation of bis-lactim ethers catalyzed by N-coordinating ylide-functionalized phosphine (NYPhos)

The palladium-catalyzed diastereoselective arylation of Schöllkopf bis-lactim ethers has recently emerged as a convenient entry to enantioenriched arylglycine derivatives. Key limitations of the prototypical protocol have now been overcome by the use of the customized, diadamantyl-substituted N-coordinating ylide-functionalized phosphine ligand ^PipadYPhos. Catalyst generated from 1-methylnaphthyl palladium bromide dimer and ^PipadYPhos effectively promote the coupling of aryl chlorides with a commercially available, valine-based Schöllkopf-reagent in 97% yield and a diastereoselectivity of 98 : 2. The arylglycines are accessible in high yields and enantiomeric excess by hydrolysis of the products. The correlation between diastereoselectivity and ligand properties identified the nature of the secondary metal-ligand interaction as a key factor in determining the selectivity of the arylation of bis-lactim ethers. Computational studies in combination with a quantitative structure-activity relationship analysis revealed that the rate-limiting step varies depending on the phosphine ligands used and that the secondary metal-ligand interaction determines diastereoselectivity.