Glucokinase Activator: Practical Asymmetric Hydrogenation and Scalable Synthesis of an API Fragment

The enantioselective synthesis of (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl propionic acid (R)-2 is described. The key intermediate (E)-7, a trisubstituted α-aryl β-alkyl acrylic acid, was conveniently accessed as its dicyclohexylamine salt by Perkin reaction in good yield and purity. Subsequent asymmetric hydrogenation with ruthenium catalysts was achieved with complete conversion and catalyst loadings up to S/C 75000 and enantiomeric excess up to 99% after crystallization.