Balancing act: The correct balance of electronic factors in the naphthazarin and isocoumarin fragments facilitates the acid‐mediated spiroketalization step to afford the key densely functionalized spiroketal (see picture; EOM=ethoxymethyl) in the formal synthesis of (±)‐γ‐rubromycin. A novel regioselective allyloxylation/Claisen rearrangement of 2‐azido‐1,4‐naphthoquinone provides access to the highly oxygenated naphthazarin fragment.

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Extensive pharming: An expedient entry into the tetracycle 2, a late‐stage synthetic intermediate en route to the broad‐spectrum antibiotic (−)‐platensimycin (1) has been accomplished. The strategy involves a series of cyclizations starting from the inexpensive chiral pool starting material (R)‐(−)‐carvone.

[reaction: see text] The synthesis of the fused aromatic spiroketal core of gamma-rubromycin is described via addition of an aryl acetylide fragment to an aryl acetaldehyde fragment. In turn, the aryl acetylene precursor was readily prepared with use of a Sonogashira reaction.

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Balanceakt: Das Gleichgewicht der elektronischen Faktoren im Naphthazarin‐ und Isocumarin‐Fragment erleichtert die säurevermittelte Cyclisierung zum dicht funktionalisierten Spiroketal (siehe Bild; EOM=Ethoxymethyl) in einer formalen Synthese von (±)‐γ‐Rubromycin. Eine Sequenz aus regioselektiver Allyloxylierung und Claisen‐Umlagerung macht das hoch oxygenierte Naphthazarin‐Fragment ausgehend von 2‐Azido‐1,4‐naphthochinon zugänglich.

As part of our investigation into the pyrazolo [1,5-a]pyridines as novel PI3K inhibitors, we report a range of analogues where the central linker portion of the molecule was varied while retaining the pyrazolo [1,5-a] pyridine and arylsulfonyl or arylcarbonyl groups. Isostere generating software BROOD was used to assist with producing ideas. The isoform selectivity of the compounds varied from pan-PI3K for compound 41 to p110a-selective for compound 58 or p110d-selective for compound 57. The latter two compounds varied only in their sulphur oxidation state.