Molecular Ring Remodeling through C-C Bond Cleavage.

Abstract

ConspectusStable and inert C-C bonds form the fundamental framework of organic compounds. Consequently, direct transformations involving C-C bond cleavage present an innovative approach for the rapid modification and remodeling of molecular skeletons. In recent years, the concept of molecular skeletal editing has garnered widespread attention and has been significantly developed, providing new opportunities for the late-stage modification of bioactive molecules, the high-value transformation of bulk chemicals, and a revolution in the traditional fragment coupling strategies of chemical synthesis. Notable advancements in this field have focused on C-C bond cleavage and the remodeling of cyclic molecules, including ring expansion, ring contraction, and ring-opening reactions, thereby enriching the synthetic toolbox available to chemists. However, selective C-C bond transformation remains a formidable challenge, especially in the remodeling of complex molecules, due to the high bond dissociation energy and the difficulty in achieving precise selectivity control. Over the past few years, our group has made efforts to address these challenges. We have demonstrated the potential of cyclic molecule remodeling reactions as an efficient strategy for the synthesis and modification of complex molecules.Herein, we present two major thematic advancements achieved by our group, utilizing cascade activation and entropy-driven reconstruction strategies for molecular ring remodeling via C-C bond cleavage. These strategies are characterized by mild conditions, the accessibility of catalysts and reagents, and exceptional functional group compatibility, thereby emerging as novel approaches for molecular ring remodeling through atom-incorporation reactions mainly on nitrogenation, oxygenation, and halogenation to synthesize pharmaceuticals, natural products, and material molecules. (1) Ring expansion reactions: We developed novel reactions that enable the insertion of C-, N-, and O-containing units into molecular rings. These methodologies offer practical and efficient routes for synthesizing amides, amines, lactones, and nitrogen-containing heterocycles. (2) Ring-opening reactions: C-C bond cleavage in ring-opening reactions enables the efficient construction of distally difunctionalized molecular frameworks. By utilizing a transition metal catalysis and radical-mediated process, we have successfully achieved the cleavage of both C-C single bonds and C═C double bonds within molecular rings. Furthermore, we have tackled the highly challenging arene ring-opening (ARO) reaction, enabling the construction of stereoselective conjugated systems through the unsaturation liberation of aromatic systems. Mechanistic studies and DFT calculations have provided critical insights into these processes. We have also identified key intermediates involved in C-C bond cleavage, including benzyl azide, O-acetyl hydroxylamine, β-azido peroxyl radical, copper bisnitrene, and 2-nitrene indazole. These findings have deepened our understanding of the mechanisms and the entropy-driven reconstruction strategy, which has further promoted the discovery of related C-C bond transformations of acyclic substrates.