Chemoenzymatic Asymmetric Synthesis of Serotonin Receptor Agonist (R)-Frovatriptan

A simple chemoenzymatic asymmetric route has been developed for the production of antimigraine agent (R)‐Frovatriptan. Lipases and oxidoreductases have been identified as ideal biocatalysts for the production of enantiopure adequate synthetic intermediates under safe and environmentally friendly conditions. (S)‐3‐Hydroxy‐2,3,4,9‐tetrahydro‐1H‐carbazole‐6‐carbonitrile, an optimal building block for the synthesis of the drug, has been efficiently prepared through Candida antarctica lipase type B catalyzed acylation of its corresponding racemic mixture or alcohol dehydrogenase A mediated bioreduction of the corresponding ketone. The inversion of the chiral center has been identified as a key step, optimizing the process to avoid partial racemization. Finally, amine functionalization and nitrile hydrolysis have allowed the production of (R)‐Frovatriptan in enantiomerically pure form. A simple chemoenzymatic preparation has been developed for the production of serotonin receptor agonist (R)‐Frovatriptan starting from inexpensive starting materials. The enzymatic action towards ketone or alcohol intermediates is the key step for the asymmetric total synthesis of this drug.