Design and Synthesis of Chiral Diene Ligands for RhI-Catalyzed Enantioselective Arylation of N-DPP-protected Aldimines: Synthesis of the Antifungal Agent Bifonazole

Herein we describe the design and synthesis of a novel family of bifunctional, chiral bicyclo[2.2.1]heptadiene ligands bearing aryl and secondary amido groups, and demonstrate their usefulness in the Rh-I-catalyzed enantioselective addition reaction of arylboronic acids to N-diphenylphosphinyl (N-DPP)-protected aldimines. Unlike the analogous Rh-I-catalysts comprising diene ligands substituted with aryl and carboxylic ester groups, or only with aryl groups, the addition reaction proceeded with high stereoselectivity. The protocol tolerated a range of N-DPP-aldimines and arylboronic acids, producing the desired optically active N-DPP protected amines with yields between 31-99% and with ee values up to 91-99%. The synthetic utility of the method was demonstrated by the conversion of N-DPP-protected amine 3 ae into the antifungal agent, bifonazole (13).