Organic Chemistry

Total Synthesis via Biomimetic Late-stage Heterocyclization, Assignment of the Relative Configuration and Biological Evalu-ation of the Nitraria Alkaloid (±)-Nitrabirine

Authors

  • Mervic Dongock Kagho Institute of Organic Chemistry, TU Braunschweig ,
  • Helen Hintersatz Organic Chemistry, Technische Universität Chemnitz ,
  • Andreas Ihle Organic Chemistry, Technische Universität Chemnitz ,
  • Haoxuan Zeng Department of Microbial Drugs, Helmholtz Centre for Infection Research and German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig ,
  • Hedda Schrey Department of Microbial Drugs, Helmholtz Centre for Infection Research and German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig ,
  • Wera Colisi Department of Microbial Drugs, Helmholtz Centre for Infection Research and German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig ,
  • Philipp Klahn Institute of Organic Chemistry, TU Braunschweig ,
  • Marc Stadler Institute of Microbiology, Technische Universität Braunschweig & Department of Microbial Drugs, Helmholtz Centre for Infection Research and German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig ,
  • Clemens Bruhns Institut für Chemie und CINSaT, Universität Kassel ,
  • Tobias Rüffer Inorganic Chemistry, Technische Universität Chemnitz ,
  • Heinrich Lang Inorganic Chemistry, Technische Universität Chemnitz ,
  • Klaus Banert Organic Chemistry, Technische Universität Chemnitz

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, later on confirmed by X-ray diffrac-tion 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, under the same conditions, 2-epi nitrabirine (5’) surprisingly leads to a beforetime uncharac-terized product 22. 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 as well as potent cytotoxic activities.

Content

Thumbnail image of Nitrabirine Manuscript JOC_09.07.2021_ChemRxiv.pdf

Supplementary material

Thumbnail image of Nitrabirine Supporting Information JOC_09.07.2021_final version.pdf
Supporting Information: Total Synthesis via Biomimetic Late-stage Heterocyclization, Assignment of the Relative Configuration and Biological Evaluation of the Nitraria Alkaloid (±)-Nitrabirine.
LIS experiment for 5 and 5’, HRMS, NMR spectra, IR spectra, anti-microbial, anti-biofilm and cytotoxicity assay (data and protocols). Description and illustration of the crystal structure of 5. CCDC 2093114 (5) contains the sup-plementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystal-lographic Data Centre.