Chemoenzymatic asymmetric synthesis of serotonin receptor agonist (R)-frovatriptan

Article abstract of DOI:10.1002/ejoc.201300114

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. Copyright