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Chemoenzymatic Asymmetric Synthesis of 1,4-Benzoxazine Derivatives: Application in the Synthesis of a Levofloxacin Precursor
journal contribution
posted on 2015-04-17, 00:00 authored by María López-Iglesias, Eduardo Busto, Vicente Gotor, Vicente Gotor-FernándezA 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.
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stereodiscriminationchemoenzymatic strategymethylyieldbioreductionracemic cyclic nitrogenated aminesselectivityApplicationDerivativeaccessantimicrobial agent Levofloxacinalternative chemoenzymatic strategiesRhodococcus ruberprecursorcounterpartenantiopureracemic alcoholsacetate analogueshydrolasepattern substitutionsADHacetylationhydrolysisamine antipodessynthesisChemoenzymatic Asymmetric SynthesisconversionrecoverypathwayBenzoxazinenitrophenoxyalcohol dehydrogenaseLevofloxacin PrecursorA
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