Concise synthesis of Azilect via cobalt-catalyzed enantioselective hydrogenation in a bio-based solvent

An asymmetric synthesis of rasagiline (Azilect), an anti Parkinson's therapeutic, was developed employing an earth-abundant metal catalyst in a bio-based solvent. The asymmetric hydrogenation of the indanone-derived enamide was performed using [Co(OTf)(2)]/(S,S)-(BPE)-B-Ph as the precatalyst as the key step for enantioselection. The effect on enantio-induction in structurally different indenyl acetamides was also examined. Rasagiline was synthesized in 70% overall yield and 98% ee. Based on the experimental results, including isotope labelling and EPR studies, we propose the involvement of a redox active Co(0)/Co(II) cycle in the asymmetric hydrogenation pathway.