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 ω‐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.