Improved Synthesis of MediPhos Ligands and Their Use in the Pd‐Catalyzed Enantioselective N‐Allylation of Glycine Esters

A new class of chiral C 2 ‐symmetric diphosphines (MediPhos) was recently shown to give superior results in the Pd‐catalyzed asymmetric N‐allylation of amino acid esters. We here describe a new, improved protocol for the preparation of such ligands through bidirectional S N 2‐coupling of a tartrate‐derived ditosylate with 6‐alkyl‐2‐bromophenols followed by double lithiation/phosphanylation. This method gave access to a series of nine ligands with branched alkyl substituents, which were benchmarked in the enantioselective Pd‐catalyzed N ‐allylation of tert ‐butyl glycinate with racemic ( E )‐2,8‐dimethylnona‐5‐en‐4‐yl methyl carbonate (up to 95 % ee ). In addition, the analogous transformation of tert ‐butyl glycinate with methyl ( E )‐nona‐5‐en‐4‐yl carbonate was optimized. The obtained allylic amines were then used in the stereoselective synthesis of the conformationally restricted proline‐derived dipeptide analogs ProM‐17 and ProM‐21 .