Rhodium-Catalyzed Asymmetric\nReductive Hydroformylation\nof α‑Substituted Enamides

Chiral γ-amino alcohols are prevalent structural\nmotifs in\nnatural products and bioactive compounds. Nevertheless, efficient\nand atom-economical synthetic methods toward enantiomerically enriched\nγ-amino alcohols are still lacking. In this study, a highly\nenantioselective rhodium-catalyzed reductive hydroformylation of readily\navailable α-substituted enamides is developed, providing a series\nof pharmaceutically valuable chiral 1,3-amino alcohols in good yields\nand excellent enantioselectivities in a single step. The development\nof the 4,4′-bisarylamino-substituted BIBOP ligand is crucial\nfor the success of this transformation. DFT calculations and experimental\ndata have revealed the importance of hydrogen bonding between the\nN–H group in the structure of TFPNH-BIBOP and the enamide carbonyl\ngroup in promoting both high enantioselectivity and reactivity. This\nmethod has enabled the concise synthesis of several chiral pharmaceutical\nintermediates including a single-step synthesis of the key chiral\nintermediate of maraviroc.