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

Abstract

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.