Year: 2024
Type: article
Abstract: Palladium/norbornene (Pd/NBE) cooperative catalysis has emerged as a highly efficient strategy for synthesizing polysubstituted arenes. By combining different electrophiles and nucleophiles, this approach facilitates sequential bifunctional functionalization of aryl halides at the ortho and ipso positions, enabling the construction of complex polysubstituted arenes that are otherwise challenging to access. Recently, palladium/chiral norbornene (Pd/NBE*) cooperative catalysis has demonstrated notable advancements in the synthesis of chiral polysubstituted arenes, which has been successfully applied to the construction of diverse chiral elements, including central, axial, and planar chirality. In this process, the chiral norbornene derivative is very crucial, acting both as a co-catalyst and the chiral source. Particularly, the C2-substituted chiral norbornene derivatives have been widely employed in Pd/NBE* cooperative catalysis. However, current methods for synthesizing C2-substituted chiral norbornenes often require harsh conditions and the use of highly toxic, high-energy reagents. Therefore, there is an urgent need to develop a more general and efficient method for the efficient synthesis of C2-substituted chiral norbornene derivatives. Due to the norbornene skeleton being a strained and rigid [2.2.1] bicyclic scaffold, which introduces significant steric hindrance at the bridgehead carbon center, substantial challenges arise in its synthesis. Additionally, most of its derivatives have small molecular weights, high volatility, and stringent synthesis requirements, making the synthesis more challenging. Currently, there are two primary methods for synthesizing C2-substituted chiral norbornenes. The first approach utilizes quinidine-induced asymmetric synthesis, while the second relies on kinetic resolution to separate enantiomers based on differences in reaction rates. However, both methods have inherent limitations. They usually require harsh reaction conditions, high-energy and toxic reagents, and often involve multistep processes, which limit their practicality for large-scale synthesis and broader application. Therefore, a more general, efficient, and scalable synthetic approach is urgently needed to expand access to C2-substituted chiral norbornene derivatives. Such a method would not only facilitate their use in Pd/NBE* cooperative catalysis but also open new avenues in stereoselective synthesis and chiral molecule development. Here, we report an efficient synthesis of C2-substituted chiral norbornene derivatives. High-purity C2-substituted chiral norbornene derivatives are synthesized through a series of reactions, including the Diels-Alder reaction, ester hydrolysis, hydrogenation, and elimination. This approach offers several advantages, such as simple synthesis steps, scalability, inexpensive and readily available starting materials, the use of non-toxic reagents, and mild conditions. The use of non-toxic reagents is another important benefit, minimizing both health and environmental risks, a key aspect of sustainable chemistry. Finally, the reaction conditions are mild, which not only promotes high yields but also obviates the need for specialized and costly laboratory equipment. The new synthesis method enables the practical preparation of these chiral compounds, which will significantly advance and broaden related research. In conclusion, this novel synthetic pathway for C2-substituted chiral norbornene derivatives not only addresses the constraints of existing methods but also introduces a more sustainable and efficient approach to synthesis. This advancement holds the potential to significantly impact the field by enabling broader applications of Pd/NBE* cooperative catalysis and advancing research in complex chiral molecules. The streamlined, practical preparation of chiral norbornene derivatives allows for the efficient production of high-purity C2-substituted compounds, greatly enhancing the scope and feasibility of Pd/NBE* catalysis in synthesizing intricate chiral arenes. Furthermore, the increased accessibility of these chiral norbornene derivatives is likely to drive new research directions in polysubstituted arene synthesis, spanning diverse applications from stereochemically-defined drug development to the creation of advanced materials with tailored functional properties. This work represents a meaningful step forward in asymmetric catalysis, providing a scalable, environmentally friendly method that promises to elevate research capabilities and expand the practical utility of Pd/NBE* cooperative catalysis in complex molecule construction.
DOI: 10.1360/tb-2024-0973
Authors: Jinxiang Ye, Lifang Qi, Hong-Gang Cheng, Qianghui Zhou
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: bronze
OpenAlex ID: W4404426616