Practical Access to Key Intermediates of Crizotinib, Lorlatinib, and Pibrentasvir Enabled by Oxa-Spirocyclic Ligands

Optically active secondary alcohols are key building blocks for a variety of chiral drugs, and transition-metal-catalyzed asymmetric hydrogenation represents one of the most efficient and direct methods for the preparation of chiral secondary alcohols. We herein report a practical and efficient asymmetric hydrogenation catalyzed by a chiral iridium complex bearing (R)-O-SpiroPAP as the ligand, producing intermediates of crizotinib, ensartinib, lorlatinib, and pibrentasvir in up to 99% yield with up to 99% ee and >20:1 dr. The synthetic potential of the current catalytic system was demonstrated by experiments on the gram and kilogram scales.