Recent Advances in the Synthesis of Chiral Compounds via Palladium/Norbornene Cooperative Catalysis

Abstract

Since its discovery in 1997, the Catellani reaction, enabled by palladium/norbornene (Pd/NBE) cooperative catalysis, has matured into a powerful strategy in organic synthesis for the iterative ortho- and ipso-difunctionalization of aryl halides. This methodology is fundamentally dependent on the formation of key aryl-norbornyl-palladacycle intermediates, which facilitate the one-step assembly of multiple C–C bonds. Recently, the emergence of Pd/NBE catalysis has broadened the applicability of this platform, allowing for efficient and stereocontrolled construction of chiral compounds. In this review, we comprehensively summarize recent advances in Pd/NBE cooperative catalysis for the synthesis of diverse chiral compounds, with a focus on four dominant strategies: chiral substrate control (exploiting inherent substrate chirality), chiral ligand control (introducing chirality during the termination step), organocatalytic control (via enamine intermediates generated from chiral amines), and chiral norbornene control (wherein the norbornene conveys stereochemistry through sequential stages, including C–H activation, kinetic resolution, axial chirality induction and desymmetrization). These developments have enabled highly asymmetric transformations of aryl iodides, triflates, and boronates, granting efficient access to diverse, complex chiral compounds including C-aryl glycosides, carbon- and phosphorus-stereogenic centers, varied axial chiral motifs, planar chiral ferrocenes, and inherently chiral aromatics. Collectively, these accomplishments underscore the considerable potential of this catalytic platform for constructing core scaffolds in bioactive molecules and functional materials. Despite these advances, key challenges persist. The structural diversity of directly accessible chiral compounds remains narrow; stereocenters bearing heteroatoms (e.g., sulfur, boron, or silicon), C–B axial chirality, and planar or helical chiral macrocycles remain particularly underexplored. Furthermore, the functionalization of sterically hindered substrates, especially those governed by the “meta-constraint”, remains a significant challenge, and the scope of compatible electrophiles and terminating reagents requires significant broadening. Looking ahead, integrating this asymmetric catalytic strategy with emerging techniques such as photocatalysis and electrosynthesis offers a promising avenue to overcome current mechanistic and selectivity limitations, thereby opening new frontiers for the design of chiral compounds with novel scaffolds and unique functionalities.

Keywords

Chiral compounds / Asymmetric catalysis / C–H activation / Palladium / Norbornene / Cooperative catalysis / Catellani reaction / Organic synthesis

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