An Enantioselective Synthesis of the Key Intermediate for Triazole Antifungal Agents; Application to the Catalytic Asymmetric Synthesis of Efinaconazole (Jublia)

Abstract

A new synthetic route, the shortest reported to date, to access a key intermediate for the synthesis of various triazole antifungal agents was developed. The elusive tetrasubstituted stereogenic center that is essential in advanced triazole antifungal agents was constructed via the catalytic asymmetric cyanosilylation of a ketone. The subsequent transformations were performed in two one-pot operations, enhancing the overall synthetic efficiency toward the intermediate. This streamlined synthetic approach was successfully applied to efficient enantioselective syntheses of efinaconazole (Jublia) and ravuconazole.