Obtainment of <i>Threo</i> and <i>Erythro</i> Isomers of the 6-Fluoro-3-(2,3,6,7,8,9-hexahydronaphtho[2,3-<i>b</i>][1,4]dioxin-2-yl)-2,3-dihydrobenzo[<i>b</i>][1,4]dioxine-5-carboxamide

Abstract

2,6-difluorobenzamides have been deeply investigated as antibacterial drugs in the last few decades. Several 3-substituted-2,6-difluorobenzamides have proved their ability to interfere with the bacterial cell division cycle by inhibiting the protein FtsZ, the key player of the whole process. Recently, we developed a novel family of 1,4-tetrahydronaphthodioxane benzamides, having an ethoxy linker, which reached sub-micromolar MICs towards Gram-positive Staphylococcus aureus and Bacillus subtilis. A further investigation of their mechanism of action should require the development of a fluorescent probe, and the consequent definition of a synthetic pathway for its obtainment. In the present work, we report the obtainment of an unexpected bicyclic side product, 6-fluoro-3-(2,3,6,7,8,9-hexahydronaphtho[2,3-b][1,4]dioxin-2-yl)-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamide, coming from the substitution of one aromatic fluorine by the in situ formed alkoxy group, in the final opening of an epoxide intermediate. This side product was similarly achieved, in good yields, by opening the ring of both erythro and threo epoxides, and the two compounds were fully characterized using HRMS, 1H-NMR, 13C-NMR, HPLC and DSC.

Keywords

• 2,6-difluorobenzamide
• FtsZ inhibitors
• nucleophilic aromatic substitution
• side product