An Intramolecular Diels-Alder Approach to the Isoindolinone Core of AZD8154

A new route to the isoindolinone core of dual phosphoinositide 3-kinases-gamma delta inhibitor AZD8154 was required to enable multikilogram supply during development toward first in human (FIH) trials and beyond. Aiming to avoid a problematic benzyl bromide intermediate encountered in the medicinal chemistry synthesis, we report a proof-of-concept convergent route featuring a key intramolecular Diels-Alder aromatization sequence. Critical to the success of this approach was the identification of (BuOK)-Bu-t-mediated aromatization conditions, reliant upon an electron-withdrawing sulfone moiety installed at an early stage. More conventional protic acid dehydration/aromatization conditions were unsuccessful, and using the Lewis acid BF3<middle dot>Et2O gave an unexpected sulfone rearrangement product. Overall, the new route proceeded in 38% yield (four-step longest linear sequence) in <10 total steps and was considered viable for further optimization and scale-up.