Manganese(I)-Catalyzed Enantioselective Formal Anti-Markovnikov Hydroalkoxylation of Racemic Allylic Alcohols: A Borrowing Hydrogen Access

An enantioselective manganese(I)-catalyzed formal anti-Markovnikov hydroalkoxylation of racemic allylic alcohols has been developed using a chiral N6-type macrocyclic ligand, affording a wide range of chiral γ-alkoxypropyl alcohols in high isolated yields with excellent enantioselectivities. The synthetic utility of this protocol was further proven by gram-scale synthesis of chiral γ-alkoxypropanol 3n and derivatization of chiral γ-alkoxypropanol 3a to a drug molecule, (S)-dapoxetine, for the treatment of premature ejaculation and erectile dysfunction. Mechanistic studies support that the reaction proceeds via a hydrogen-borrowing cascade reaction pathway.