A General Approach for Strained Ring Functionalization via Nucleophilic Catalysis

Nucleophilic addition to strained rings offers an efficient route to small aliphatic rings, which serve as valuable bioisosteres in drug development. However, these reactions often require external stoichiometric bases, additives, or strong nucleophiles, limiting their practicality, compatibility, and scope. Moreover, achieving diastereocontrol in these reactions remains challenging, and direct addition of sp³ C-H bonds continues to be difficult owing to their lack of electron lone pairs and weak acidity. Here, we present, for the first time, a nucleophilic catalysis strategy that addresses these challenges, enabling not only the direct and diastereoselective addition of a wide range of sp³ C-H bonds, but also diverse heteroatom-based nucleophiles, including carboxylic acids, amides, phosphine oxides, and thiols, to strained rings without the need for external bases or additives. Mechanistic studies suggest the involvement of a covalent intermediate, generated through the nucleophilic addition of the catalyst to the strained ring substrate.