title: Chemoenzymatic asymmetric synthesis of 1,4-benzoxazine derivatives: application in the synthesis of a levofloxacin precursor.
abstract: A versatile and general route has been developed for the asymmetric synthesis of a wide family of 3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazines bearing different pattern substitutions in the aromatic ring. Whereas hydrolases were not suitable for resolution of these racemic cyclic nitrogenated amines, alternative chemoenzymatic strategies were designed through independent pathways leading to both amine antipodes. On one hand, bioreduction of 1-(2-nitrophenoxy)propan-2-ones allowed the recovery of the enantiopure (S)-alcohols in high yields using the alcohol dehydrogenase from Rhodococcus ruber (ADH-A), whereas evo-1.1.200 ADH led to their counterpart (R)-enantiomers also with complete selectivity and quantitative conversion. Alternatively, lipase-catalyzed acetylation of these racemic alcohols, and the complementary hydrolysis of the acetate analogues, gave access to the corresponding optically enriched products with high stereodiscrimination. Particularly attractive was the design of a chemoenzymatic strategy in six steps for the production of (S)-(-)-7,8-difluoro-3-methyl-3,4-dihydro-2H-benzo-[b][1,4]oxazine, which is a key precursor of the antimicrobial agent Levofloxacin.
authors.affiliation: †Organic and Inorganic Chemistry Department, Biotechnology Institute of Asturias (IUBA), University of Oviedo, Avenida Julián Clavería s/n, 33006 Oviedo, Spain.
authors.forename: María
authors.initials: M
authors.lastname: López-Iglesias
authors.affiliation: ‡Department of Chemistry, Organic and Bioorganic Chemistry, University of Graz, Heinrichstrasse 28, 8010 Graz, Austria.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Busto
authors.affiliation: †Organic and Inorganic Chemistry Department, Biotechnology Institute of Asturias (IUBA), University of Oviedo, Avenida Julián Clavería s/n, 33006 Oviedo, Spain.
authors.forename: Vicente
authors.initials: V
authors.lastname: Gotor
authors.affiliation: †Organic and Inorganic Chemistry Department, Biotechnology Institute of Asturias (IUBA), University of Oviedo, Avenida Julián Clavería s/n, 33006 Oviedo, Spain.
authors.forename: Vicente
authors.initials: V
authors.lastname: Gotor-Fernández
mesh_terms: D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000737:chemistry; D048588:Benzoxazines / Q000138:chemical synthesis* / Q000737:chemistry; D002384:Catalysis; D064704:Levofloxacin / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D013237:Stereoisomerism
chemical_list: C000603529:7,8-difluoro-3-methyl-3,4-dihydro-2H-benzo-(b)(1,4)oxazine; D000890:Anti-Infective Agents; D048588:Benzoxazines; D064704:Levofloxacin