Synthesis of a 6-Aza-Isoindolinone-Based Inhibitor of Phosphoinositide 3-Kinase γ via Ruthenium-Catalyzed 2 + 2 + 2 Cyclotrimerization

Phosphoinositide 3-kinase (PI3Kγ) is a drug target that has been implicated in the treatment of a range of diseases. We have developed a synthesis of a novel PI3Kγ inhibitor containing a 1,2-dihydro-3H-pyrrolo3,4-cpyridin-3-one scaffold. The key step in the synthesis involved a ruthenium-catalyzed 2 + 2 + 2 cyclotrimerization reaction between a diyne and an alkoxycarbonyl isocyanate, a previously unreported coupling partner in such a reaction.