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

A new route to the isoindolinone core of dual phosphoinositide
3-kinases-γδ 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 tBuOK-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·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.