Rhodium-Catalyzed Asymmetric Reductive Hydroformylation of α-Substituted Enamides

Abstract

Chiral γ-amino alcohols are prevalent structural motifs in natural products and bioactive compounds. Nevertheless, efficient and atom-economical synthetic methods toward enantiomerically enriched γ-amino alcohols are still lacking. In this study, a highly enantioselective rhodium-catalyzed reductive hydroformylation of readily available α-substituted enamides is developed, providing a series of pharmaceutically valuable chiral 1,3-amino alcohols in good yields and excellent enantioselectivities in a single step. The development of the 4,4′-bisarylamino-substituted BIBOP ligand is crucial for the success of this transformation. DFT calculations and experimental data have revealed the importance of hydrogen bonding between the N–H group in the structure of TFPNH-BIBOP and the enamide carbonyl group in promoting both high enantioselectivity and reactivity. This method has enabled the concise synthesis of several chiral pharmaceutical intermediates including a single-step synthesis of the key chiral intermediate of maraviroc.