CHEMICAL SCIENCE

Copper-catalyzed stereoconvergence asymmetric Michaelis–Becker cross-coupling reaction


On February 23, 2023, Professor Liu Xinyuan’s team of Southern University of Science and Technology published a research result entitled “A general copper-catalysed enantioconvergent radical Michaelis–Becker-type C(sp3)–P cross-coupling” in the journal Nature Synthesis.

The research group successfully realized the stereopolymerization asymmetric Michaelis–Becker cross-coupling reaction between racemic alkyl halogenates and phosphite. The corresponding author of the paper is Liu Xinyuan; The co-first authors are Wang Lilei, Zhou Huan, and Cao Yuxi.

α-chiral alkylphosphine compounds are important molecular building blocks in organic synthesis and key functional units widely used in active molecules, pesticides, and materials (Figure 1a). Therefore, it is important to develop asymmetrically catalyzed methods for constructing chiral C(sp3)–P bonds. The Michaelis–Becker reaction was first discovered in the late 19th century and has been used for more than a century to this day as one of the most effective methods for rapidly constructing C(sp3)–P bonds. However, due to its stereospecific SN2 mechanism, this method has never been able to be used to construct chiral C(sp3)–P bonds (Figure 1b). In recent years, with the development of 3D transition metal catalysis, the asymmetric transformation of such reactions has ushered in an opportunity. The 3D transition metal can convert racemic alkyl halides into latent alkyl radical species by single-electron reduction, and through this reaction mechanism, stereoconvergent asymmetric Michaelis–Becker reactions can be achieved (Figure 1c). However, the realization of this reaction still faces problems such as strong background reaction, catalyst poisoning, difficulty in initiating the reaction, and side reactions with P-P coupling.

Figure 1: Background and design of the reaction

Professor Xinyuan Liu’s team has been working on the development of copper-catalyzed asymmetric radical reactions, and in their previous work, they found that chiral anionic ligands can improve the reduction of monovalent copper, so that racemic alkyl halides can be reduced to latent alkyl radicals. Under such a catalytic system, the team has realized a series of stereoconvergent radical C(sp3)–C/N cross-coupling reactions (J. Am. Chem. Soc. 2022, 144, 17319; Nat. Chem. 2019, 11, 1158; J. Am. Chem. Soc. 2021, 143, 15413; Nat. Chem. 2022, 14, 949; etc.)。

Based on the previous work, Liu Xinyuan’s team successfully overcame the above problems and developed a class of copper-catalyzed stereoconvergent asymmetric Michaelis–Becker cross-coupling reactions (Figure 1d). The authors first tested the background reaction to find a suitable solvent that could inhibit the background reaction. Then, through ligand screening, the authors found that the N, N, P ligand of the cinchona skeleton can effectively improve the yield and enantioselectivity of the reaction, and after further modification of the ligand and optimization of reaction parameters such as copper catalyst and temperature, the target product can finally be obtained with higher yield and enantioselectivity (Figure 2). The reaction is well compatible with benzyl, propargyl, and carbonyl α halogenates (Figure 3-4). The practicability of this approach is illustrated by simple conversion of products into a wide variety of chiral phosphorus-containing building blocks and lead drugs (Figure 5). The mechanism experiment can fully support the mechanism proposed by the author.

Figure 2: Effect of ligands on the reaction

Figure 3: Benzyl halogenated substrate scope of application

Figure 4: Application range of propargyl and carbonyl α substrates

Figure 5: Reaction applicability and mechanism studies

The project has been strongly funded by the National Natural Science Foundation of China, the Ministry of Science and Technology, the Department of Science and Technology of Guangdong Province, and the Shenzhen Science and Technology Innovation Commission. (Source: Science Network)

Related paper information:https://doi.org/10.1038/s44160-023-00252-3



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