On June 10th, 2022, Prof. Yao Hequan and Prof. Lin Aijun’s team from the School of Pharmacy, CPU published their latest research in the top international journal, the American Chemical Society (JACS, impact factor 16.383), entitled “Palladium-Catalyzed Asymmetric Sequential Hydroamination of 1,3-Enynes: Enantioselective Syntheses of Chiral Imidazolidinones”. Prof. Yao Hequan and Prof. Lin Aijun are co-corresponding authors, PhD student Li Qiuyu and PhD student Fang Xinxin are the co-first authors and China Pharmaceutical University is the sole corresponding institution.
Imidazolidinones and their analogues are prevalent scaffolds encountered in numerous biologically active molecules and important pharmaceuticals, including biotin, imidapril and agelastatin. In the past two decades, several transition-metal-catalyzed strategies to synthesize enantioenriched imidazolidinones have been reported, including asymmetric diamination of alkenes and dienes, alkene carboamination, and isocyanates vinylaziridine cycloaddition. However, these methods have a few drawbacks, such as a multistep synthesis of the substrates, the requirement of oxidants that are not practical for large-scale applications. Thus, the development of novel catalytic enantioselective methods to assemble these frameworks is valuable.
Sequential hydroamination could provide a valuable approach to access structurally diverse nitrogen-containing heterocycles through consecutive C-N bond formation. However, compared to the current advances in single hydroamination reactions, the sequential hydroamination variants via transition metal catalysis remain underdeveloped (Figure 1, a and b). The key challenge is the need to identify a catalytic system that can fulfill two consecutive, but different hydroamination reactions in a one-pot procedure. Moreover, to obtain the desired sequential hydroamination product, the catalyst needs to exhibit a high level of regio-, chemo- and stereoselectivity in each step. Yao and Lin’s team developed a Pd-catalyzed sequential hydroamination of 1,3-enynes with various amine sources (Figure 1c). This redox-neutral protocol provided an efficient route to synthesize imidazolidinones, thiadiazolidines and imidazolidines bearing a tertiary or tetra-substituted stereocenter. This reaction proceeded in a high atom- and step economy manner with good functional group tolerance. Moreover, the asymmetric version was also successfully achieved, providing a series of synthetically valuable enantioenriched imidazolidinones. Mechanistic studies revealed that this transformation occurred through an intermolecular enyne hydroamination pathway to give an allene intermediate. Subsequent intramolecular hydroamination of the allene intermediate operated in the dynamic kinetic resolution manifold, and proceeds under the Curtin-Hammett principle to provide enantioenriched imidazolidinone products.
Figure 1. Palladium-Catalyzed Sequential Hydroamination of Unsaturated Hydrocarbons
This research was supported by the National Natural Science Foundation of China (NSFC22071267) and the Project Program of State Key Laboratory of Natural Medicines (SKLNMZZ202023).
Paper Link：https://pubs.acs.org/doi/10.1021/jacs.2c03620
