分子内力
化学
芯(光纤)
Diels-Alder反应
组合化学
立体化学
计算机科学
有机化学
催化作用
电信
作者
James J. Douglas,David Buttar,K. Locke,Angela Turner
标识
DOI:10.1021/acs.oprd.3c00507
摘要
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.
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