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

Abstract

The racemic total synthesis of nitrabirine (5) together with its previously undescribed epimer 2-epi nitrabirine (5′) 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 N-oxidation of nitrabirine does not yield nitrabirine N-oxide as reported earlier. In contrast, the reaction of hydrogen peroxide with nitrabirine (5) yields the salt 24′, whereas 2-epi nitrabirine (5′) surprisingly leads to a previously uncharacterized product 22 under the same conditions. Finally, a Fischer indole reaction gave access to novel tetracyclic nitrabirine derivatives 26a–d. A comprehensive biological evaluation of nitrabirine (5), 2-epi nitrabirine (5′), and all derivatives synthesized in this study revealed general biofilm dispersal effects against Candida albicans. Moreover, specific compounds showed moderate antibacterial activities as well as potent cytotoxic activities.

Seleno/Thio-functionalized ipso-Annulation of N-Propiolyl-2-arylbenzimidazole to Construct Azaspiro[5,5]undecatrienones

“…Azaspiro­[5,5]­undecane is an important structural motif that constitutes the basic skeleton of several biologically active alkaloids, such as erysotamidine (I), discorhabdin C (II), (+)-isonitramine (III), etc . In addition, the structure of (+)-nitrabirine (IV) isolated from Nitraria sibirica has also comprised a 2-azaspiro[5.5]­undecan-7-ol framework with an extra annulated imidazole ring and its derivatives showed potent antimicrobial activities . Likewise, imidazole-fused azaspiro[5.5]­undecanone acts as antagonists of TGF b -type I receptors .…”