Modular Synthesis of Polar Spirocyclic Scaffolds Enabled by Radical Chemistry

Exploration of three-dimensional structural space has become crucial for the development of novel bioactive molecules. In this context, polar spirocycles have emerged as key scaffolds due to their enhanced 3D character and well-defined spatial orientation. Herein, we report the development of a highly modular strategy to access beta-spirocyclic pyrrolidine derivatives from readily available starting materials, i.e., cyclic ketones and amino or oxamic acids. The sequence proceeds through a straightforward Knoevenagel condensation, followed by a domino Giese-type reaction/base-mediated cyclisation process, delivering a broad scope of polar spirocyclic scaffolds in good to excellent yields. The products can be readily diversified to access a wider range of spirocyclic cores (such as lactams or succinimides), thus increasing the versatility of our method to gain rapid access to libraries of potential drug-like molecules.