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. While hydrolases were not suitable for the resolution of these racemic cyclic nitrogenated amines, alternative chemoenzymatic strategies were designed through independent pathways leading to both amine antipodes. On one hand, the bioreduction of 1-(2-nitrophenoxy)propan-2-ones allowed the 2 recovery in high yields of the enantiopure (S)-alcohols using the alcohol dehydrogenase from Rhodococcus ruber (ADH-A), while the evo-1.1.200 ADH led to their counterpart (R)-enantiomers with also complete selectivity and quantitative conversions. 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 6 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.

Recent Advances in Lipase-Mediated Preparation of Pharmaceuticals and Their Intermediates

“…The benzoxazine moiety is part of the structures of a series of molecules with biological activities such as antibacterial, anticancer, antifungal and antimicrobial. A number of 1,4-benzoxazine derivatives (with or without substituents at the aromatic ring) were prepared by a combination of chemical steps and lipase-mediated kinetic resolution [ 70 ]. The enzymatic step was conducted with rac -1-(2-nitrophenoxy)propan-2-ols ( rac -alcohols), via acylation (route a), and with the corresponding rac -acetates, via hydrolysis (route b), as seen in Scheme 46 .…”

“…Then, the kinetic resolution of the rac -1-(2,3-difluoro-6-nitrophenoxy)propan-2-yl acetate was performed, via hydrolysis in the presence of lipase RM IM, leading to the ( R )-alcohol (>99% ee ) and the remaining ( S )-acetate (84% ee ) with c 46%. Subsequently, after several chemical steps, the ( R )-alcohol was converted into the ( S )-7,8-difluoro-3-methyl-3,4-dihydro-2 H -benzo[ b ][1,4]oxazine (36% yield, >99% ee ) Levofloxacin precursor [ 70 ].…”

“… Enzymatic kinetic resolution of racemic alcohols 1-(2-nitrophenoxy)propan-2-ols via acetylation ( a ) or via hydrolysis ( b ) of the corresponding racemic acetates. Production of ( S )-7,8-difluoro-3-methyl-3,4-dihydro-2 H -benzo[ b ][1,4]oxazine precursor of the antibacterial drug Levofloxacin ( c ) [ 70 ]. …”

Multigram‐scale HPLC enantioseparation as a rescue pathway for circumventing racemization problem during enantioselective synthesis of ethyl 3,4‐dihydro‐2H‐1,4‐benzoxazine‐2‐carboxylate

“…In 2005, an overview of different strategies to provide racemic 1,4-benzoxazine analogs has been published, 22 but only few reports brought up procedures to obtain enantiomerically pure analogs. These procedures use metal [23][24][25][26][27] or phase transfer 28 catalyzed asymmetric reactions, kinetic resolution with enzyme 29,30 or chiral resolving agents, [31][32][33] stereoselective aryl addition, 34 asymmetric baker's yeast reduction, 35 and chiral 1,2-cyclic sulfamidates nucleophilic cleavage. 36 It is interesting to note that, while our targeted scaffold 1 is a key synthon for the design of promising therapeutic drugs (Figure 1), its synthesis and characterizations (optical rotation and electronic circular dichroism [ECD]) as enantiomers were never described in the literature.…”

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“…25 For example, alcohol dehydrogenase reduction of 1-(2nitrophenoxy)propan-2-ones gave the corresponding optically active alcohols in high yields, and these were converted to the 1,4-benzoxazines in three steps using standard transformations (Scheme 2). 25 For example, alcohol dehydrogenase reduction of 1-(2nitrophenoxy)propan-2-ones gave the corresponding optically active alcohols in high yields, and these were converted to the 1,4-benzoxazines in three steps using standard transformations (Scheme 2).…”