Total Synthesis via Biomimetic Late-Stage Heterocyclization: Assignment of the Relative Configuration and Biological Evaluation of the Nitraria Alkaloid (±)-Nitrabirine.

The racemic total synthesis of nitrabirine () together with its previously undescribed epimer 2- nitrabirine () is accomplished via a six-step route based on a biomimetic late-stage heterocyclization. This allowed the assignment of the relative configuration of nitrabirine by the lanthanide-induced shifts (LIS) experiment, which was later on confirmed by X-ray diffraction of obtained single crystals. Furthermore, oxidation studies demonstrated that the direct -oxidation of nitrabirine does not yield nitrabirine -oxide as reported earlier. In contrast, the reaction of hydrogen peroxide with nitrabirine () yields the salt , whereas 2- nitrabirine () surprisingly leads to a previously uncharacterized product under the same conditions. Finally, a Fischer indole reaction gave access to novel tetracyclic nitrabirine derivatives -. A comprehensive biological evaluation of nitrabirine (), 2- nitrabirine (), and all derivatives synthesized in this study revealed general biofilm dispersal effects against . Moreover, specific compounds showed moderate antibacterial activities as well as potent cytotoxic activities.