Ligand‐Enabled Pd‐Catalyzed sp3 C−H Macrocyclization: Synthesis and Evaluation of Macrocyclic Sulfonamide for the Treatment of Parkinson's Disease

The development of simplified synthetic strategy to create structurally and functionally diverse pseudo‐natural macrocyclic molecules is highly appealing but poses a marked challenge. Inspired by natural scaffolds, herein, we describe a practical and concise ligand‐enabled Pd(II)‐catalyzed sp3 C−H alkylation, olefination and arylation macrocyclization, which could offer a novel set of pseudo‐natural macrocyclic sulfonamides. Interestingly, the potential of ligand acceleration in C−H activation is also demonstrated by an unprecedented enantioselective sp3 C−H alkylation macrocyclization. Moreover, a combination of in silico screening and biological evaluation led to the identification of a novel spiro‐grafted macrocyclic sulfonamide 2 a, which showed a promising efficacy for the treatment of Parkinson's disease (PD) in a mouse model through the activation of silent information regulator sirtuin 3 (SIRT3). A practical and concise ligand‐enabled Pd(II)‐catalysed sp3 C−H alkylation, olefination, and arylation macrocyclization is reported, which provided a novel set of pseudo‐natural macrocyclic sulfonamides. A combination of in silico screening and biological evaluation led to the identification of a novel spiro‐grafted macrocyclic sulfonamide, which demonstrated a potential efficacy for the treatment of Parkinson's disease (PD) in a mouse model through the activation of SIRT3.