Development of Scalable Synthesis of Chiral Tetralol via Hydrogen Borrowing and Dynamic Kinetic Resolution

Herein, we describe a two-step alkylation and asymmetric transfer hydrogenation telescope process for the synthesis of an enantioenriched substituted tetralol, a key intermediate in the synthesis of active pharmaceutical ingredient udifitimod (BMS-986166). A hydrogen borrowing alkylation catalyzed by an iridium catalyst was developed to replace an asymmetric alkylation that utilized an alkyl iodide with a costly stoichiometric chiral auxiliary under cryogenic conditions. In the following step, construction of the key stereocenter on the tetralin core was enabled by dynamic kinetic resolution using Ru-catalyzed asymmetric transfer hydrogenation. Process optimization allowed for a telescoped process that delivered the chiral alcohol product with high yield, purity, and enantio- and diastereoselectivity as well as controlled levels of residual metal content acceptable for downstream processing.