Study On The Asymmetric Synthesis And Antibacterial Activity Of Chiral 2-methoxycarbonyl-4-fluorophenyl-1,5-benzothiazepines

1,5-benzothiazepine is one of the most important active molecule. The design, synthesis and activity of its various derivatives have been concerned extensively over the years. Our group has found the racemic 2-methoxycarbonyl-4-fluorophenyl-1,5-benzothiazepines have strong antibacterial and bactericidal effects to cryptococcus neoformans. In order to reveal the relationship between antibacterial activity and its optic isomer, the paper has synthesized optically active 2-methoxycarbonyl-4-fluorophenyl-1,5-benzothiazepines via chiral auxiliaries and discussed the antibacterial activity. Works are as follows:1. The asymmetric synthesis of 2-methoxycarbonyl-4-fluorophenyl-1,5-benzothiazepine.(1) By the study on introduction and removal methods of Evans chiral auxiliary, asymmetric, synthesis method was confirmed. Evans chiral auxiliariy was introduced via the reaction between mixed anhydride of saturated acid and lithium salt of chiral oxazolidinone. The chalcone including chiral auxiliary, synthesized by followed bromination and elimination reactions, was then treated with 2-amino thiophenol and the 1,5-benzothiazepine including chiral auxiliary was obtained by asymmetric Micheal addition and dehydration condensation reactions. The destination compounds were obtained via the catalysis of ytterbium(III) triflate.(2) By the screening of Evans chiral auxiliaries, reaction solvents and temperatures, the ideal e.e. value was obtained under the condition of 4-benzyl-2-oxazolidinone, methanol solvent and room temperature.2. Asymmetric synthesis and characterization of destination compounds.According to the study on asymmetric synthesis, the compounds 9a-9i/ 14a-14 i were obtained and the structures have been characterized by 1HNMR?13CNMR?IR and HRMS. The relative configuration of compound 9h was confirmed by X-ray. And the e.e. values were satisfactory.3. The study on antibacterial activity.(1) The study on antibacterial activity of optically active 2-methoxycarbonyl-4-fluorophenyl-1,5-benzothiazepines to cryptococcus neoformans were researched by zone of inhibition. The results showed that compounds 14a-14 i, synthesized by chiral induction of S-4-benzyl-2-oxazolidinone, had better antibacterial effects than the racemic compounds and the compounds 9a-9i wich synthesized by R-4-benzyl-2-oxazolidinone.(2) According to zone of inhibition results, the compounds 14a-14 f with higher antibacterial activity were chosen to test MIC and MFC. The results revealed that the MIC and MFC values for the above compounds were much lower than those of fluconazole.