Evolution of a Synthetic Strategy toward Highly Substituted Isoindolinone Glutarimide Fragments

Herein we report the design, development, and evolution of a first-generation synthesis of benzylamine fragment 1·HCl to a second-generation process for 2·HCl en route to highly substituted isoindolinone glutarimide degrader molecules. Salient features of the two syntheses include directed ortho-metalation of substituted benzoic acids, highly regioselective aromatic halogenations, and divergent strategies to install the key aminomethyl motif. The second-generation, stereoselective-enabling process improves on the first-generation route by transitioning from unreliable reactions to robust transformations and proceeding through isolable solid intermediates, thereby enabling improved impurity control.