Titanium-Catalyzed Synthesis of Multisubstituted Glutarimides Bearing Quaternary Carbon Centers-Scope, Mechanism, and Bioactivity Studies.

Glutarimides possess prominent pharmacological activities. Nevertheless, general and facile synthetic approaches toward multisubstituted glutarimides remain scarce, particularly for analogues with α, α-disubstituted structures and substitutions at diverse sites of the imide core. In this work, we developed a radical alkylation/cyclization cascade of α-tertiary haloamides and acrylates using earth-abundant titanium as the catalyst. This transformation provides a practical route to glutarimides featuring quaternary carbon centers and multi-functionalized imide skeletons. Both N-unsubstituted glutarimides and derivatives with tunable N-substituents can be readily accessed, including analogues derived from bioactive and pharmaceutical scaffolds. Furthermore, the antiproliferative potency of these newly synthesized glutarimides was assessed using HeLa and glioblastoma U87 cell lines.