Chemoenzymatic asymmetric synthesis of 1,4-benzoxazine derivatives: application in the synthesis of a levofloxacin precursor

The Journal of Organic Chemistry
María López-IglesiasVicente Gotor-Fernández

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.

References

Jun 26, 2003·Bioorganic & Medicinal Chemistry Letters·Jeffrey L GrayBenoit Ledoussal
Jul 31, 2007·Organic Letters·John F BowerTimothy Gallagher
Oct 23, 2009·Chemical Society Reviews·Tomas Hudlicky, Josephine W Reed
Jan 12, 2012·Chemical Society Reviews·Christopher M Clouthier, Joelle N Pelletier
Apr 14, 2012·Angewandte Chemie·Dipti S KunduSiegfried Blechert
Aug 25, 2012·The Journal of Organic Chemistry·María López-IglesiasVicente Gotor-Fernández
Nov 6, 2012·European Journal of Medicinal Chemistry·Miloš IlićDanijel Kikelj
Jun 25, 2013·Organic Process Research & Development·Wolfgang KroutilElina Siirola

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Citations

Oct 31, 2015·The Journal of Organic Chemistry·Paweł BorowieckiJan Plenkiewicz
Dec 23, 2015·International Journal of Molecular Sciences·Ana Caroline Lustosa de Melo CarvalhoImmacolata Serra
Dec 19, 2018·The Journal of Organic Chemistry·Nadine ZumbrägelHarald Gröger
Apr 1, 2016·ACS Catalysis·Kostiantyn O Marichev, James M Takacs

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