Chemoenzymatic Asymmetric Synthesis of 1,4-Benzoxazine Derivatives: Application in the Synthesis of a Levofloxacin Precursor

A versatile and general route has been developed for the asymmetric synthesis of a wide family of 3-methyl-3,4-dihydro-2<i>H</i>-benzo­[<i>b</i>]­[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 (<i>S</i>)-alcohols in high yields using the alcohol dehydrogenase from <i>Rhodococcus ruber</i> (ADH-A), whereas evo-1.1.200 ADH led to their counterpart (<i>R</i>)-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 (<i>S</i>)-(−)-7,8-difluoro-3-methyl-3,4-dihydro-2<i>H</i>-benzo-[<i>b</i>]­[1,4]­oxazine, which is a key precursor of the antimicrobial agent Levofloxacin.