Concise synthesis of Azilect via cobalt-catalyzed enantioselective hydrogenation in a bio-based solvent†
Soumyadeep
Chakrabortty, 
a
Felix J.
de Zwart,
b
Joost N. H.
Reek,
b
Bas
de Bruin
b
and
Johannes G.
de Vries
*a
a
Felix J.
de Zwart,
b
Joost N. H.
Reek,
b
Bas
de Bruin
b
and
Johannes G.
de Vries
*a
Abstract
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)-PhBPE 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.
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