Nitrobenzoxadiazole derivatives of the rat selective toxicant norbormide as fluorescent probes for live cell imaging.

Norbormide [5-(α-hydroxy-α-2-pyridylbenzyl)-7-(α-2-pyridylbenzylidene)-5-norbornene-2,3-dicarboximide] (NRB, 1), an existing but infrequently used rodenticide, is known to be uniquely toxic to rats, but relatively harmless to other rodents and mammals. As a vasoactive agent, NRB induces a species-specific vasocontractile effect that is restricted to the peripheral arteries of the rat. Despite the precise mechanisms behind this phenomenon having yet to be fully clarified, it is postulated that the molecular target of NRB could be located within the plasma membrane of rat peripheral artery myocytes (e.g. rat caudal artery myocytes). As such, the primary objective of this study was to develop a fluorescently labelled derivative of NRB to investigate its subcellular distribution/localization in both NRB-sensitive (freshly isolated rat caudal artery myocytes, FIRCAMs) and NRB-insensitive (human hepatic stellate, LX2) cells. Of the examples prepared, lead structure endo-NRB-NBD-bPA subsequently demonstrated retention of the parent toxicant's pharmacological profile (in terms of its ability to induce both a vasocontractile response in rat caudal artery rings in vitro, and a lethal end-point in rats in vivo). Endo-NRB-NBD-bPA was also shown to be significantly less permeable (an integral feature in the design of fluorescent probes targeting cell-surface receptors) to both LX2 cells and FIRCAMs. Disappointingly, no fluorescence could be observed on the plasma membrane of FIRCAMs stained with endo-NRB-NBD-bPA.

Gold catalysis: synthesis of spiro, bridged, and fused ketal natural products.

In the last decade the use of homogenous gold catalysts has rapidly grown and become a valuable tool for complex natural product synthesis. Spiroketal natural products are valuable targets for total synthesis and medicinal chemistry applications. The use of gold catalysts has emerged as a useful tool to synthesise these privileged scaffolds. This review summarises the application of gold catalysis for the syntheses of spiro, bridged and fused ketal natural products.

Total Synthesis of the Resorcyclic Acid Lactone Spiroketal Citreoviranol.

The first total synthesis of resorcyclic acid lactone spiroketal citreoviranol (1) is described. The synthesis was completed in nine steps and via Sonogashira cross-coupling, gold-catalyzed cyclization, and an unusual base-induced ketalization. The relative and absolute stereochemistry of citreoviranol was unambiguously confirmed using 2D NMR spectroscopy and X-ray crystallography.

Recent developments in transition metal-catalysed spiroketalisation.

The spiroketal motif occurs in a wide range of biologically active natural products and represents a valuable target in medicinal chemistry and total synthesis. In recent years, innovative new synthetic methods have substantially expanded the range of potential precursors, cyclisation modes and opportunities for asymmetric catalysis and tandem processes. This Perspective aims to highlight recent rapid advances in the use of transition metal catalysis for spiroketal formation, in the context of our own investigations into gold-catalysed asymmetric spiroketalisation.