Chemo-Enzymatic Synthesis of Enantiopure β-Blocker (S)-Metoprolol and Derivatives

Abstract ( S )-Metoprolol, ((2 S )-1-4-(2-methoxyethyl)phenoxy-3-(propan-2-ylamino)propan-2-ol has been synthesised in 99% ee with high yield by a four step chemoenzymatic protocol. Several preparations of Candida antarctica lipase B have been screened in a kinetic resolution of the secondary chlorohydrin 1-chloro-3-(4-(2-methoxyethyl)phenoxy)propan-2-ol. We here report specific rotation values of the enantiopure chlorohydrins from the enzyme catalysed kinetic resolution, in addition to a specific rotation value for ( S )-metoprolol, which determines the absolute configuration of the drug, and also the absolute configuration of the chlorohydrin enantiomers.