Exploiting the Biocatalytic Toolbox for the Asymmetric Synthesis of the Heart-Rate Reducing Agent Ivabradine

Several chemoenzymatic routes have been evaluated for the production of the heart-rate reducing agent ivabradine. Lipases and w-transaminases have been identified as useful biocatalysts for the preparation of key enantiopure precursors. The lipase-catalysed kinetic resolution by alkoxycarbonylation of a racemic primary amine and subsequent chemical reduction of the resulting carbamate provided an N-methylated (S)-amine, one step away from ivabradine. Alternatively, the dynamic kinetic resolution by asymmetric bioamination of an aldehyde precursor enabled, in a four-step sequence, the preparative scale synthesis of enantiopure ivabradine in 50% overall yield.