Modular Synthesis of Polar Spirocyclic Scaffolds Enabled by Radical Chemistry

Abstract

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.

Photoredox-Enabled Deconstructive [5 + 1] Annulation Approach to Isoquinolones from Indanones in Water

“…Subsequently, radical substitution on ArSSAr with the acyl radical II provides thioester 3, which is further converted to amide V with benzylamine in the presence of KOH. The anionic intermediate VI formed by deprotonation 16 of V initiates an intramolecular cyclization to generate 54, which reacts with ArSSAr to provide the final product 5. Lastly, selected isoquinolones were tested against three plant pathogenic fungi in vitro, including Botrytis cinerea, Colletotrichum gloeosporioides, and Phytophthora infestans (Table S1).…”

Modular Synthesis of Polar Spirocyclic Scaffolds Enabled by Radical Chemistry

“…Finally, in silico studies were carried out to support the proposed reaction pathway for the base-mediated cyclization step. 23…”

“…Furthermore, the versatility of the accessed scaffolds was highlighted by a series of derivatizations to access diverse spirocyclic cores. Finally, in silico studies were carried out to support the proposed reaction pathway for the base-mediated cyclization step …”