title: Asymmetric chemoenzymatic synthesis of ramatroban using lipases and oxidoreductases.
abstract: A chemoenzymatic asymmetric route for the preparation of enantiopure (R)-ramatroban has been developed for the first time. The action of lipases and oxidoreductases has been independently studied, and both were found as excellent biocatalysts for the production of adequate chiral intermediates under very mild reaction conditions. CAL-B efficiently catalyzed the resolution of (±)-2,3,4,9-tetrahydro-1H-carbazol-3-ol that was acylated with high stereocontrol. On the other hand, ADH-A mediated bioreduction of 4,9-dihydro-1H-carbazol-3(2H)-one provided an alternative access to the same enantiopure alcohol previously obtained through lipase-catalyzed resolution, a useful synthetic building block in the synthesis of ramatroban. Inversion of the absolute configuration of (S)-2,3,4,9-tetrahydro-1H-carbazol-3-ol has been identified as a key point in the synthetic route, optimizing this process to avoid racemization of the azide intermediate, finally yielding (R)-ramatroban in enantiopure form by the formation of the corresponding amine and the convenient functionalization of both exocyclic and indole nitrogen atoms.
authors.affiliation: Departamento de Química Orgánica e Inorgánica, Instituto Universitario de Biotecnología de Asturias, Universidad de Oviedo, 33006 Oviedo, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Busto
authors.forename: Vicente
authors.initials: V
authors.lastname: Gotor-Fernández
authors.forename: Vicente
authors.initials: V
authors.lastname: Gotor
mesh_terms: D000215:Acylation; D002227:Carbazoles / Q000138:chemical synthesis* / Q000737:chemistry*; D002384:Catalysis; D008049:Lipase / Q000737:chemistry* / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009584:Nitrogen / Q000737:chemistry*; D010088:Oxidoreductases / Q000737:chemistry* / Q000378:metabolism*; D013237:Stereoisomerism; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry*
chemical_list: C574781:4,9-dihydro-1H-carbazol-3(2H)-one; D002227:Carbazoles; D013449:Sulfonamides; D010088:Oxidoreductases; D008049:Lipase; D009584:Nitrogen; C063119:ramatroban