The total synthesis of the potent respiratory chain inhibitor ajudazol A was accomplished by a concise strategy in 17 steps (longest linear sequence). The modular approach was based on a direct oxazole functionalization strategy involving a halogen dance reaction for selective halogenation in combination with a challenging combination of sp2–sp2 and sp2–sp3 Negishi cross coupling reactions. The applicability of this strategy for analogue synthesis was demonstrated by the synthesis of a simplified as well as stabilized ajudazol analogue.

Vacuolar-type H(+) -ATPases (V-ATPases) have gained recent attention as highly promising anticancer drug targets, and therefore detailed structural analyses and studies of inhibitor interactions are very important research objectives. Spin labeling of the V-ATPase holoenzyme from the tobacco hornworm Manduca sexta and V-ATPase in isolated yeast (Saccharomyces cerevisiae) vacuoles was accomplished by two novel methods involving the covalent binding of a (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) derivative of N,N'-dicyclohexylcarbodiimide (DCC) to the essential glutamate residue in the active site and the noncovalent interaction of a radical analogue of the highly potent inhibitor archazolid, a natural product from myxobacteria. Both complexes were evaluated in detail by electron paramagnetic resonance (EPR) spectroscopic studies and double electron-electron resonance (DEER) measurements, revealing insight into the inhibitor binding mode, dynamics, and stoichiometry as well as into the structure of the central functional subunit c of these medicinally important hetero-multimeric proton-translocating proteins. This study also demonstrates the usefulness of natural product derived spin labels as tools in medicinal chemistry.

Novel types of spin-labeled N,N'-dicyclohexylcarbodiimides (DCC) are reported that bear a 2,2,6,6-tetramethylpiperidinyloxyl (TEMPO) residue on one side and different aromatic and aliphatic cyclohexyl analogues on the other side of the diimide core. These readily available novel reagents add efficiently to aliphatic and aromatic carboxylic acids, forming two possible spin-labeled amide derivatives with different radical distances of the resulting amide. The addition of aromatic DCC analogues proceeds with excellent selectivity, giving amides where the carboxylic acid is exclusively connected to the aromatic residue, while little or no selectivity was observed for the aliphatic congeners. The usefulness of these adducts in structural studies was demonstrated by EPR (electron paramagnetic resonance) measurements of biradical adducts of biphenyl-4,4'-dicarboxylic acids. These analyses also reveal high degrees of conformational bias for aromatic DCC derivatives, which further underlines the powerfulness of these novel reagents. This observation was further corroborated by quantum chemical calculations, giving a detailed understanding of the structural dynamics, while detailed information on the solid state structure of all novel reagents was obtained by X-ray structure analyses.

A general study on selective functionalization of unsubstituted oxazole is reported. Specific halogenation at C2 and C5 was enabled by a sequential deprotonation strategy that was based on the different pKa values of these positions, while a halide at C4 may be introduced by an optimized halogen dance reaction. Efficient protocols for subsequent sp2-sp2 and sp2-sp3 cross coupling reactions of the derived oxazole halides were then established. This modular approach was applied in the total synthesis of ajudazol A and a selected analog, demonstrating the general feasibility of these conditions in a complex setting.

The back cover pictures shows the use of spin‐labeled derivatives of vacuolar‐type ATPase (V‐ATPase) inhibitors archazolid and N,N′‐dicyclohexylcarbodiimide (DCC) to gain insight into the binding dynamics and stoichiometry, as well as the structure, of the central functional subunit c of V‐ATPase by electron paramagnetic resonance (EPR) spectroscopy and double electron—electron resonance (DEER) measurements. V‐ATPases are hetero‐multimeric ion pumps present in the membranes of organelles of eukaryotic organisms. Their involvement in many human diseases, notably their role in the development, invasion, and progression of cancer cells makes their detailed structural analysis and molecular inhibitor interactions very important research objectives. More information can be found in the Full Paper by Markus Huss, Johann P. Klare, Dirk Menche et al. on page 420 in Issue 4, 2016 (DOI:10.1002/cmdc.201500500).